CN108997328B - Iminothiadiazine dioxide derivatives and their use - Google Patents

Abstract

The invention discloses iminothiadiazine dioxide derivatives and application thereof, and particularly relates to novel iminothiadiazine dioxide derivatives and a pharmaceutical composition containing the same, which can be used as a BACE-1 inhibitor. The invention also relates to processes for preparing such compounds and pharmaceutical compositions, and their use in the preparation of medicaments for the treatment of diseases associated with beta-amyloid (' a β '), in particular alzheimer's disease.

Description

Iminothiadiazine dioxide derivatives and their use

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to novel iminothiadiazine dioxide derivatives, a pharmaceutical composition containing the same, and a using method and application thereof. In particular, the novel iminothiadiazine dioxide derivatives of the present invention are useful as BACE-1 inhibitors for the prevention, treatment or alleviation of diseases associated with beta-amyloid ("a β"), especially alzheimer's disease.

Background

Beta-amyloid ("a β") is a major component of β -amyloid fibrils and plaques, and diseases associated with a β include, but are not limited to: dementia, senile dementia, presenile dementia, dementia associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, attention deficit symptoms associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, memory loss associated with Parkinson's disease, memory loss associated with Alzheimer's disease, stroke, neurodegeneration, amyloidosis, beta-amyloid angiopathy, cerebral amyloid angiopathy, hereditaryCerebral hemorrhage, hemodialysis complication (from beta)₂Small globulin and thus complications in hemodialysis patients), glaucoma, type II diabetes, diabetes-associated amyloidogenesis, traumatic brain injury ("TBI"), bovine spongiform encephalopathy, corticobasal degeneration, progressive supranuclear palsy, microglial hyperplasia and encephalitis, olfactory impairment associated with alzheimer's disease, parkinson's disease and/or down's syndrome, scrapie, Creutzfeld-Jakob disease, mild cognitive impairment ("MCI") or alzheimer's disease.

Alzheimer's Disease (AD) is a major type of senile dementia, a major cause of cognitive and mental decline in the elderly, and a progressive neurodegenerative disease that severely affects the quality of life of the elderly. Clinically, it is characterized by generalized dementia such as memory impairment, aphasia, disuse, agnosia, impairment of visual-spatial skills, dysfunction in executive functioning, and personality and behavioral changes. Alzheimer's disease not only deteriorates the quality of personal and social life, but also causes pain to the patient and other people around. Alzheimer's disease is the fourth leading cause of death after cancer, heart disease and cerebral hemorrhage.

It is estimated that more than 2 million people worldwide have AD, and AD is considered to be the most common cause of dementia. AD is a disease characterized by degeneration and loss of neurons, and also forms neurofibrillary tangles and senile plaques.

According to a plurality of epidemiological investigation results in China, the prevalence rate of AD in people over 65 years old is about 5%, and the prevalence rate generally increases with the increase of age. The statistics of the study in the developed world show that the proportion of patients with alzheimer's disease also increases with age. Wherein the prevalence rates in the population at 60, 70 and 80 years are 15-20%, 30-40% and 60%, respectively. It follows that AD is severe in people over 80 years of age, and one person in each pair of spouses has alzheimer's disease.

There are various causes of alzheimer's disease. First, according to the existing studies, patients with alzheimer's disease have low concentrations of acetylcholine, and when acetylcholinesterase is inhibited, the symptoms of alzheimer's disease are improved by increasing the concentration of acetylcholine; second, further exacerbation of alzheimer's disease can be prevented indirectly by the use of estrogens, antioxidants, radical scavengers, or anti-inflammatory agents; third, alzheimer's disease is treated by preventing gradual and irreversible degeneration of synapses and neurons; fourth, the progression of alzheimer's disease is delayed by studying the genetic factors of alzheimer's disease that are involved in the synthesis, progression, accumulation of neurons, and deposition of β -amyloid in the cortex. Similarly, alzheimer's disease can be treated by finding a controlling factor that reduces the extracellular concentration of beta-amyloid, and selectively removing beta-amyloid deposits in the brain.

Currently, treatment of alzheimer's disease is limited to treating its symptoms rather than its underlying cause. Agents approved for the amelioration of symptoms include, for example, N-methyl-D-aspartate receptor antagonists (e.g., memantine), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacrine). There is no clinically available drug for treating alzheimer's disease that can effectively reverse cognitive impairment. Acetylcholinesterase inhibitors (donepezil, rivastigmine, huperzine a, galantamine) have a certain therapeutic effect on light-to-moderate AD patients, but also only temporarily relieve symptoms, cannot further prevent the attenuation of nerve cells, and are accompanied by serious adverse reactions. The combined use of cerebral blood flow and cerebral metabolism improving agents such as oxiracetam (oxiracetam) has a certain effect in improving memory, but more often exists as nootropic agents. Therefore, there is an urgent need to develop new drugs capable of improving or treating alzheimer's disease. The development of drugs around the target of Abeta is always considered as a new promising approach.

The a β peptide is a short peptide produced by the proteolytic cleavage of a transmembrane protein known as amyloid precursor protein ("APP"). Cleavage of APP produces a β peptide: cleavage by β -secretase activity at a position near the N-terminus of a β and by γ -secretase activity at a position near the C-terminus of a β (APP can also be cleaved by α -secretase activity to produce a secreted, non-starch-like fragment, referred to as soluble APP α). Beta site APP cleavage Enzyme ("BACE-1") is the major aspartyl protease responsible for the production of A β by β -secretase activity. Studies have shown that the production of A.beta.can be inhibited by inhibiting BACE-1.

In AD, the a β peptide formed by β -secretase and γ -secretase activity can form a ternary structure, which aggregates to form amyloid fibrils. In addition, a β peptides can form a β oligomers (also referred to as "a β aggregates" or "Abeta oligomers"). A β oligomers are small multimeric structures consisting of 2-12 a β peptides (which differ structurally from a β fibrils). Amyloid fibrils can deposit in a dense form outside neurons in brain regions important for memory and cognitive ability, called neuritic, senile, or diffuse plaques. When injected in cell culture or in the brain of rats, a β oligomers are cytotoxins. This a β plaque formation and deposition, and/or a β oligomer formation, and the resultant neuronal death and cognitive impairment, are some of the hallmarks of AD pathophysiology. Other markers of AD pathophysiology include: intracellular neurofibrillary tangles and neuroinflammation consisting of abnormally phosphorylated tau protein.

Evidence suggests that a β, a β plaques, a β fibrils, a β aggregates and/or a β oligomers play a causative role in AD pathophysiology (Ohno, et al neurobiology of Disease,2007, No.26, 134-145). It is known that genetic mutations in APP and presenilins 1/2(PS1/2) can lead to familial AD, and the cause of familial AD is thought to be increased production of the 42-amino acid form of a β. A β has been shown to be neurotoxic in culture and in vivo. For example, when injected into the brain of an old primate, fibrillar a β causes neuronal death around the injection site. Further direct and indirect evidence of the role of a β in the etiology of AD has also been reported.

BACE-1 has become a therapeutic target for the treatment of Alzheimer's disease. For example, the mccorlogue panel has demonstrated that partial reduction of BACE-1 enzymatic activity and concomitant reduction of a β levels can significantly inhibit a β -stimulated AD-like lesions, making β -secretase a target for therapeutic intervention in AD (mccorlogue, et al.j.bio.chem., sep.2007, vol.282, No. 36). The Luo group has reported that BACE-1 deficient mice still have a normal phenotype and abrogate β -amyloid formation (Luo, et al. Nature Neuroscience, March 2001, Vol.4, No. 3). The Roberts group has determined that inhibition or loss of beta-secretase activity does not cause extreme phenotypic defects, while resulting in concomitant reductions in A β (Roberts, et al. HumanMol. genetics,2001, Vol.10, No.12, 1317-1324). The Ohno group has reported that genetic deletion of BACE-1 abrogates a β formation, hinders amyloid deposition, prevents neuronal loss found in the cerebral cortex and lower feet (brain regions that show the most severe amyloidosis in 5XFAD mice), and can rescue memory deficits in 5XFAD mice. The group also reported that A β was ultimately responsible for neuronal death in AD and concluded that BACE-1 inhibition could be an effective method for treating AD (Ohno, et al neurobiology of Disease,2007, No.26, 134-145).

Currently, the therapeutic potential to inhibit A β deposition has prompted many groups to characterize BACE-1 and identify BACE-1 inhibitors. Several studies have also been carried out on BACE-1 inhibitors:

WO 2011044181a1 discloses iminothiadiazine dioxide compounds that are BACE inhibitors (BACE-1 or BACE-2 inhibitors), compositions and their use for the prevention or treatment of various pathologies associated with β -amyloid ("a β") production, including alzheimer's disease.

WO 2016118404A1 discloses iminothiadiazine dioxide compounds substituted with an amino linking group as BACE inhibitors (BACE-1 or BACE-2 inhibitors), compositions and their use for preventing or treating Alzheimer's disease.

WO 2014093190A1 discloses iminothiadiazine dioxide compounds as BACE inhibitors (BACE-1 or BACE-2 inhibitors), compositions and their use for preventing or treating Alzheimer's disease.

WO 2016040226A1 discloses S-imino-S-oxyiminothiadiazine compounds that are BACE inhibitors (BACE-1 or BACE-2 inhibitors), compositions, and their use for preventing or treating Alzheimer' S disease.

WO 2015187437a1 discloses C2-carbocyclic iminothiazine dioxide compounds as BACE inhibitors (BACE-1 or BACE-2 inhibitors), compositions and their use for the prevention or treatment of alzheimer's disease.

Disclosure of Invention

The present invention provides a novel class of iminothiadiazine dioxide derivatives which are BACE-1 inhibitors and which inhibit the production of A.beta.by inhibiting BACE-1 and, therefore, are useful in the treatment of diseases mediated by beta-amyloid (' A.beta '), and in particular in the treatment of Alzheimer's disease. Experiments show that the iminothiadiazine dioxide derivative has stable property, good safety, good pharmacodynamics and pharmacokinetic properties, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability and the like. Therefore, the method has good clinical application prospect.

The invention also provides a method for preparing the compound, a pharmaceutical composition containing the compound and application of the compound and the pharmaceutical composition of the compound in preparing medicaments.

In one aspect, the invention relates to a compound of formula (I) or formula (I '), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I) or formula (I'), or a prodrug thereof,

wherein: each R^1a、R^1b、R^1c、R^1d、R^1e、R^1f、R^1g、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸X, Y and Z have the same meanings asThe meaning of the invention is described.

In one embodiment, X is CR^xOr N.

In one embodiment, Y is S, O or NH.

In one embodiment, Z is CH or N.

In one embodiment, R^1a、R^1b、R^1c、R^1d、R^1e、R^1fAnd R^xEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In one embodiment, R^1gIs H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆Alkyl radical

In one embodiment, R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R⁴Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R⁵Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R⁶And R⁷Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R⁸Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R^1a、R^1b、R^1c、R^1d、R^1e、R^1fAnd R^xEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In another embodiment, R^1a、R^1b、R^1c、R^1d、R^1e、R^1fAnd R^xEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-OCH₃Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In one embodiment, R^1gIs H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R^1gIs H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R²And R³Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R⁴Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R⁴Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃A methoxy group,Ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R⁵Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R⁵Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R⁶And R⁷Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R⁶And R⁷Each independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R⁸Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R⁸Is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one aspect, the present invention relates to a compound of formula (II) or formula (II'), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

wherein: each R^1a、R^1b、R^1c、R^1d、R^1e、R^1f、R^1g、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸X, Y and Z have the meanings as described in the invention.

In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of the compound having one of the following structures, or a prodrug thereof:

in yet another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein.

In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

In another embodiment, the present invention relates to a pharmaceutical composition further comprising an additional treatmentAn agent, wherein the additional therapeutic agent is nalmefene, risperidone, rivastigmine, memantine, mirtazapine, venlafaxine, desmopramine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline, tacrine, donepezil, galantamine, rivastigmine, vitamin E, fibrates, nicotinic acid, nicotinic receptor agonists, nicotinic acetylcholine receptor agonists, cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, promoters of alpha secretase activity, glycogen synthase kinase beta inhibitors, inhibitors of amyloid aggregation, gamma secretase inhibitors, gamma secretase modulators, histamine H3 antagonists, histone deacetylase inhibitors, PDE-4 inhibitors, PDE-10 inhibitors, mGluR1 receptor modulators or antagonists, mGluR5 receptor modulators or antagonists, mGluR2/3 antagonists, 5-HT₄Agonists, 5-HT₆Receptor antagonists or GABA_AAn inverse agonist.

In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for inhibiting BACE-1 and thereby inhibiting the production of A β.

In a further aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a disorder associated with beta-amyloid.

In one embodiment, the beta-amyloid associated disease is dementia, senile dementia, dementia associated with alzheimer's disease, parkinson's disease and/or down's syndrome, attention deficit symptoms associated with alzheimer's disease, parkinson's disease and/or down's syndrome, memory loss associated with parkinson's disease, memory loss associated with alzheimer's disease, stroke, neurodegeneration, amyloidosis, beta-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, hemodialysis complications, glaucoma, type II diabetes, amyloidogenesis associated with diabetes, traumatic brain injury, bovine spongiform encephalopathy, mild cognitive impairment or alzheimer's disease.

In another embodiment, the disease associated with β -amyloid is alzheimer's disease.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I), (I '), (II) or (II').

Biological test results show that the compound inhibits the generation of A beta by inhibiting BACE-1 and can be used as a better BACE-1 inhibitor.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

The term "chiral molecule" is a molecule having the property of not overlapping its mirror image; and "achiral molecule" refers to a molecule that can overlap with its mirror image.

The term "enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers, which mixture lacks optical activity.

The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.

"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, Br, I, N₃、-CN、-NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂-C (═ O) -alkyl, -C (═ O) -alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a particular substituent. Unless otherwise indicated, a substituent may be substituted at any reasonable position in the group that it may be substituted for. When more than one position in a given formula can be substituted with one or more particular substituents selected from the group, then the substituents may be substituted identically or differently at each of the possible positions in the formula.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

The term "D" denotes a single deuterium atom.

The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) And so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)₃) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) And so on.

The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein.

Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH)₃) Ethylthio (EtS, -SCH)₂CH₃) 1-propylthio (n-PrS, n-propylthio, -SCH)₂CH₂CH₃) 2-propylthio (i-PrS, i-propylthio, -SCH (CH)₃)₂) 1-butylthio (n-BuS, n-butylthio, -SCH)₂CH₂CH₂CH₃) 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH)₂CH(CH₃)₂) 2-butylthio (s-BuS, s-butylthio, -SCH (CH)₃)CH₂CH₃) 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC (CH)₃)₃) And so on.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like. The alkylamino group is optionally substituted with one or more substituents described herein.

The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.

The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CHFCH₃、-CH₂CH₂F、-CF₂CH₃、-CH₂CF₂CHF₂And the like. In one embodiment, C₁-C₆The haloalkyl group containing a fluorine-substituted C₁-C₆An alkyl group; in another embodiment, C₁-C₄The haloalkyl group containing a fluorine-substituted C₁-C₄An alkyl group; in yet another embodiment, C₁-C₂The haloalkyl group containing a fluorine-substituted C₁-C₂An alkyl group.

The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCHFCH₃、-OCH₂CH₂F、-OCF₂CH₃、-OCH₂CF₂CHF₂And the like. In one embodiment, C₁-C₆Haloalkoxy comprises fluorine substituted C₁-C₆An alkoxy group; in another embodiment, C₁-C₄Haloalkoxy comprises fluorine substituted C₁-C₄An alkoxy group; in yet another embodiment, C₁-C₂Haloalkoxy comprises fluorine substituted C₁-C₂An alkoxy group.

The term "n-member" or "n-member" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is 6-atom heterocyclyl or 6-membered heterocyclyl, and cyclohexyl is 6-atom cycloalkyl or 6-membered cycloalkyl.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system can include fused, bridged, and spiro rings. Wherein one or more atoms of the ring are independently replaced by a heteroatom having the meaning as described herein. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂Of (2) aA bolus); in another embodiment, heterocyclyl is a bicyclic heterocyclyl consisting of 7 to 12 ring atoms (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give the same SO, SO₂，PO，PO₂The group of (1). The heterocyclyl group is optionally substituted with one or more substituents described herein.

The ring atoms of the heterocyclic group may be carbon-based or heteroatom-based. Wherein, is cyclic-CH₂The group is optionally replaced by-C (═ O) -, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl

Radical, diaza

Radical, S-N-aza

Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH₂Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like. Said heterocyclyl group being optionally substitutedSubstituted with one or more substituents as described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, indenyl, naphthyl and anthryl. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene et al, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I), (I '), (II) or (II'). Such conversion is mediated by a prodrug in the bloodHydrolysis in liquid or enzymatic conversion to the parent structure in blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyratesCamphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumerate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodiate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, embonate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C₁-C₈Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.

The term "treating" any disease or condition, in some embodiments refers to ameliorating the disease or condition (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).

The term "additional therapeutic agent" refers to a therapeutic agent that is used as an adjunct therapy or in combination.

The iminothiadiazine dioxide derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof, which can inhibit the production of Abeta by inhibiting BACE-1, have potential application in the treatment of diseases related to beta-amyloid protein ('Abeta'), especially Alzheimer disease.

Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the present invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

The compounds of formula (I), (I '), (II) or (II') may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt need not be a pharmaceutically acceptable salt, but may be an intermediate useful in the preparation and/or purification of a compound of formula (I), (I '), (II) or (II') and/or in the isolation of an enantiomer of a compound of formula (I), (I '), (II) or (II').

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I), (I '), (II) or (II').

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound of formula (I), (I '), (II) or (II') or an individual stereoisomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

A method of treatment comprising administering a compound or pharmaceutical composition of the invention, further comprising administering to the patient an additional therapeutic agent (combination therapy), wherein the additional therapeutic agent is nalmefene, risperidone, rivastigmine, memantine, mirtazapine, venlafaxine, descumin, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentoxifylline, tacrine, donepezil, galantamine, rivastigmine, vitamin E, fibrates, nicotinic acid, nicotinic receptor agonists, nicotinic acetylcholine receptor agonists, cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, promoters of alpha secretase activity, glycogen synthase kinase beta inhibitors, inhibitors of amyloid aggregation, gamma secretase inhibitors, gamma secretase modulators, histamine H3 antagonists, histone deacetylase inhibitors, PDE-4 inhibitors, PDE-10 inhibitors, mGluR1 receptor modulators or antagonists, mGluR5 receptor modulators or antagonists, mGluR2/3 antagonists, 5-HT₄Agonists, 5-HT₆Receptor antagonists and GABA_AAn inverse agonist, or any combination thereof.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting a compound of the invention from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

For the preparation of pharmaceutical compositions using the compounds described herein, the pharmaceutically acceptable carrier can be a solid or liquid carrier. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5 to about 95% active ingredient. Suitable solid carriers are known in the artFor example magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing the various compositions can be found in: gennaro (ed.), Remington's Pharmaceutical Sciences,18^th ed.,1990,Mack Publishing Company Co.,Easton,Pennsylvania。

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

The compounds of the invention may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

The pharmaceutical compositions provided herein can be administered by rectal suppository by mixing the drug with a suitable non-irritating excipient (e.g., cocoa butter, glycerol esters synthesized with polyethylene glycol), which is solid at ordinary temperatures, and then liquefying or dissolving in the rectal cavity to release the drug. Because of individual variation, the severity of symptoms can vary widely, and each drug has its unique therapeutic properties, the precise mode of administration, dosage form and treatment regimen for each individual should be determined by the practitioner.

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate symptoms of the disease is administered or allowed to equilibrate in vivo. The effective amount required for a particular treatment regimen will depend on a variety of factors including the condition being treated, the severity of the condition, the activity of the particular drug employed, the mode of administration, the clearance rate of the particular drug, the duration of the treatment, the drug combination, the age, body weight, sex, diet and patient health, etc. Other factors that may be considered in The art for a "therapeutically effective amount" are described in Gilman et al, eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics,8^thed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17^th ed.,Mack Publishing Company,Easton,Pa.,1990。

One skilled in the art (e.g., an attending physician, pharmacist, or other technician) can readily determine the appropriate dosage of a compound of the present invention to be administered to a patient and will vary with the patient's health, age, weight, frequency of administration, use of other active ingredients, and/or the indication of the compound being administered. The dosage of the compounds of the present invention may range from about 0.001 to 500mg/kg body weight/day. In one embodiment, the dose of a compound of the invention or a pharmaceutically acceptable salt or solvate of said compound is from about 0.01 to about 25mg/kg body weight/day. In another embodiment, the amount of active compound in a unit dose of the formulation may be varied or adjusted from about 1mg to about 100mg, preferably from about 1mg to about 50mg, more preferably from about 1mg to about 25mg, depending on the particular application. In another embodiment, for oral administration, a suggested typical daily dosing regimen may range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, given in two to four divided doses.

The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pellets, troches, injections, sterile or non-aqueous solutions, suspensions, emulsions, patches and the like. The active ingredient is compounded with non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, pulvis Talci, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

The preferred route of administration will vary with clinical characteristics, the dosage will necessarily vary depending upon the condition of the patient being treated, and the physician will determine the appropriate dosage for the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiology and the selected vaccination regimen. The weight of the compound per unit dose, excluding the weight of the carrier (vehicle included in the drug), refers to the weight of the compound per administration.

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

In one embodiment, the treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present invention encompass the treatment of the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.

In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered orally. In another embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered by inhalation. In yet another embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered intranasally.

In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen, including the duration of the regimen, of the compound of the invention or of the pharmaceutical composition containing the compound of the invention depends on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The compounds of the present invention may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition. This is selected by the person skilled in the art according to the physical circumstances of the patient, such as health, age, weight, etc. If formulated as a fixed dose, such combination products employ the compounds of the present invention (within the dosage ranges described herein) and the other pharmaceutically active agents (within their dosage ranges).

Accordingly, in one aspect, the present invention includes a combination comprising an amount of at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more of the additional therapeutic agents described above.

In addition, the compounds of the present invention may be administered in the form of a prodrug. In the present invention, a "prodrug" of a compound of the present invention is a functional derivative that, when administered to a patient, is ultimately released in vivo from the compound of the present invention. When administering the compounds of the present invention in prodrug form, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Use of the Compounds and pharmaceutical compositions of the invention

The compounds and pharmaceutical compositions provided by the present invention are useful for the preparation of medicaments for inhibiting the production of a β by inhibiting BACE-1 and for the preparation of medicaments for the treatment of diseases associated with β -amyloid ("a β"), in particular alzheimer's disease.

In particular, the amount of compound in the compounds or pharmaceutical compositions of the invention is effective to detectably selectively inhibit A β production by inhibiting BACE-1.

The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or amelioration of diseases associated with beta-amyloid ("a β") protein by administering to a patient an effective amount of a compound or pharmaceutical composition of the present invention. The beta-amyloid ("a β") associated diseases further include, but are not limited to, dementia, senile dementia, dementia associated with alzheimer's disease, parkinson's disease and/or down's syndrome, attention deficit symptoms associated with alzheimer's disease, parkinson's disease and/or down's syndrome, memory loss associated with parkinson's disease, memory loss associated with alzheimer's disease, stroke, neurodegeneration, amyloidosis, beta-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, hemodialysis complications (from beta-amyloid₂Small globulin and, therefore, complications in hemodialysis patients), glaucoma, type II diabetes, diabetes-related amyloidogenesis, traumatic brain injury ("TBI"), bovine spongiform encephalopathy, corticobasal degeneration, progressive supranuclear palsy, microglial hyperplasia and encephalitis,alzheimer's disease, olfactory impairment associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, scrapie, Creutzfeld-Jakob disease, mild cognitive impairment ("MCI") or Alzheimer's disease.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the invention can be prepared by the processes described herein, wherein the substituents are as defined for formula (I), (I '), (II) or (II'), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), q (quatets, quartets), m (multiplets ), br (broadpededwideams), brs (broadpedsinglets, wideadlets), dd (doublets), ddd (doublets of doublets, doublets), dt (doublets of doublets, triplets), td (triplet of doublets ). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

CH₂Cl₂DCM dichloromethane μ g microgram

CDC1₃Deuterated chloroform mg

DMSO dimethyl sulfoxide g

DMSO-d₆Deuterium substituted dimethyl sulfoxide mL, mL

EtOAc, EA ethyl acetate μ L, μ L

CH₃Nanoliter of OH, MeOH methanol nL, nL

CD₃OD deuterated methanol min

PE petroleum ether (60-90 ℃) for h

RT, RT, r.t. Room temperature nM, nmol/L nanomole per liter

Boc₂O, Boc Di-tert-butyl dicarbonate acid anhydride mu M, mu mol/L micromol per liter

PIPES piperazine-1, 4-diethylsulfonic acid mmol, mM mmol

Tris-HCl Tris (hydroxymethyl) aminomethane-hydrochloric acid M, mol/L mol per liter

Glycerol Glycerol KF potassium fluoride

The following synthetic schemes describe the steps for preparing the compounds disclosed herein, wherein each R is, unless otherwise indicated^1a、R^1b、R^1c、R^1d、R^1e、R^1f、R⁴And X has the definitions stated in the present invention.

Synthesis scheme 1

Wherein PMB is 4-methoxybenzyl

Ph is phenyl

Formula (A), (B) and16) The compound shown can be prepared by the following steps: formula (A), (B) and1) A compound of the formula2) The compound is reacted to obtain the compound of the formula (A)3) A compound shown in the specification; then formula (A), (B), (C), (3) A compound of the formula4) The compound is reacted to obtain the compound of the formula (A)5) The compounds shown. Formula (A), (B) and5) Removing the protecting group of the compound to obtain a compound of the formula (I)6) A compound shown in the specification; then formula (A), (B), (C), (6) The compound and benzoyl isothiocyanate are reacted to obtain the compound of the formula (A)7) The compounds shown. Formula (A), (B) and7) Removing benzoyl from the compound shown in the formula (I)8) The compounds shown. Formula (A), (B) and8) The ring closing reaction of the shown compound is carried out to obtain a compound of the formula (A)9) A compound shown in the specification; formula (A), (B) and9) The protecting group on the compound shown is obtained by the formula (I)10) The compounds shown. Formula (A), (B) and10) The nitro group on the compound is reduced to obtain a compound of the formula11) The compounds shown. Formula (A), (B) and11) Reacting the compound with benzoyl isothiocyanate to obtain a compound shown in a formula (I)12) A compound shown in the specification; formula (A), (B) and12) Removing benzoyl from the compound shown in the formula (I)13) A compound shown in the specification; formula (A), (B) and13) A compound of the formula14) The compound shown in the formula (I) is reacted to obtain15) A compound shown in the specification; formula (A), (B) and15) Removing the protecting group of the compound to obtain a compound of the formula (I)16) The target product shown.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

Example 1 Synthesis of (R) -5- (2-fluoro-5- ((4- (quinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

Step 1) (Synthesis of) (R, E) -N- (1- (2-fluoro-5-nitrophenyl) ethylene) -2-methylpropane-2-sulfinamide

1- (2-fluoro-5-nitro-phenyl) ethanone (5g,27.3mmol), (R) - (+) -tert-butylsulfinamide (3.8g,31mmol) and anhydrous tetrahydrofuran (25mL) were charged to a 100mL single-neck round-bottom flask, tetraethyltitanate (13.7g,60.1mmol) was added, and the reaction was carried out under nitrogen at 70 ℃ for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (50mL), filtered, the filter cake was washed with dichloromethane (40mL × 2), the organic phases were combined, dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 20/1 to 5/1) to give the title compound as a yellow solid (7.1g, 91.0%).

MS(ESI,pos.ion)m/z:287.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm)8.59-8.51(m,1H),8.31(dd,J＝14.9,12.1Hz,1H),7.30(dd,J＝16.0,6.5Hz,1H),2.81(s,3H),1.33(s,9H).

Step 2) (R) -2- ((R) -1, 1-Dimethylethylsulfinamide) -2- (2-fluoro-5-nitrophenyl) -N- (4-methyl) Synthesis of oxybenzyl) -N-methylpropane-1-sulfonamide

Placing N- (4-methoxybenzyl) -N-methylmethanesulfonamide (1.60g,6.98mmol) in a 100mL two-neck flask, adding anhydrous tetrahydrofuran (20mL) under the protection of nitrogen, cooling at-30 ℃ for 10 minutes at a low temperature, then slowly adding N-butyllithium (4.5mL,1.6M), and stirring for 0.5 hour; then (R, E) -N- (1- (2-fluoro-5-nitrophenyl) ethylene) -2-methylpropane-2-sulfinamide (1.00g,3.49mmol, dissolved in 5mL of tetrahydrofuran) was added slowly and the reaction was continued for 0.5 h. Quenched by addition of saturated aqueous ammonium chloride (5mL), followed by addition of water (50mL), extraction with ethyl acetate (100mL × 2), collection of the organic phase, spin-drying under reduced pressure, and purification by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow oil (0.85g, 47%).

MS(ESI,pos.ion)m/z:516.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.59(dd,J＝6.8,2.7Hz,1H),8.26(dt,J＝8.4,3.3Hz,1H),7.28(d,J＝6.1Hz,1H),7.23(d,J＝8.3Hz,2H),6.88(d,J＝8.5Hz,2H),6.04(s,1H),4.32-4.18(m,2H),3.99-3.84(m,2H),3.82(d,J＝6.7Hz,3H),2.81-2.70(m,3H),1.95(s,3H),1.38(s,9H).

Step 3 synthesis of (R) -2-amino-2- (2-fluoro-5-nitro-phenyl) -N-methyl-propane-1-sulfonamide

(R) -2- ((R) -1, 1-Dimethylethylsulfinamide) -2- (2-fluoro-5-nitrophenyl) -N- (4-methoxybenzyl) -N-methylpropane-1-sulfonamide (5.85g,11.3mmol), dichloromethane (90mL), and methanol (30mL) were added to a 500mL single neck round bottom flask at 25 deg.C, concentrated hydrochloric acid (10mL) was added, and the reaction was allowed to continue stirring for 1.5 hours; stopping reaction, and performing reduced pressure spin-drying; then adding trifluoroacetic acid (15mL) and 1, 3-dimethoxybenzene (10mL), and continuing stirring for reacting for 16 hours; the reaction was stopped, water (100mL) and ethyl acetate (100mL) were added, the mixture was separated, the aqueous phase was collected, a sodium carbonate solid was added to adjust pH to 10, dichloromethane (100mL) was added for extraction, the mixture was separated, the organic phase was collected, spin-dried under reduced pressure, and column chromatography separation and purification (dichloromethane/methanol (v/v) ═ 40/1) gave the title compound as a yellow solid (2.28g, 69%).

MS(ESI,pos.ion)m/z:292.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.66(dd,J＝6.9,2.7Hz,1H),8.27-8.18(m,1H),7.22(dd,J＝10.7,9.2Hz,1H),4.18(t,J＝10.9Hz,1H),3.89(d,J＝14.4Hz,1H),3.46(d,J＝14.4Hz,1H),2.72(d,J＝5.2Hz,3H),1.67(s,3H).

Step 4) (R) -N- ((2- (2-fluoro-5-nitrophenyl) -1- (N-methylsulfamoyl) propan-2-yl) thionine Formyl) benzamide synthesis

(R) -2-amino-2- (2-fluoro-5-nitro-phenyl) -N-methyl-propane-1-sulfonamide (0.34g,1.17mmol) and dichloromethane (5mL) were added to a 100mL single neck round bottom flask at 25 deg.C, benzoyl isothiocyanate (0.300g,1.84mmol) was added dropwise, and the reaction was allowed to continue stirring for 10 hours; the organic phase was spin-dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (0.5g, 94.3%).

MS(ESI,pos.ion)m/z:455.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)11.67(d,J＝37.2Hz,1H),9.01(s,1H),8.30(dd,J＝6.8,2.5Hz,1H),8.25-8.16(m,1H),7.88(d,J＝7.7Hz,2H),7.64(t,J＝7.4Hz,1H),7.52(t,J＝7.6Hz,2H),7.21(dd,J＝11.1,9.1Hz,1H),4.84(dd,J＝26.0,9.6Hz,2H),3.76(t,J＝17.6Hz,1H),2.87(d,J＝5.1Hz,3H),2.27(s,3H).

Step 5 Synthesis of (R) -2- (2-fluoro-5-nitrophenyl) -N-methyl-2-thioropropane-1-sulfonamide

(R) -N- ((2- (2-fluoro-5-nitrophenyl) -1- (N-methylsulfamoyl) propan-2-yl) thiocarbamoyl) benzamide (7.8g,17.2mmol) and methanol (100mL) were added to a 500mL single neck round bottom flask at 25 deg.C, sodium carbonate (1.80g,17.0mmol) was added, and the reaction was stirred for an additional 0.5 h. Ammonium chloride (1.00g,18.7mmol) was added, the organic phase was spin dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (4.3g, 71.5%).

MS(ESI,pos.ion)m/z:351.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.25-8.16(m,2H),8.07(s,1H),7.46-7.39(m,1H),7.18(s,1H),7.06(d,J＝4.8Hz,1H),4.05-4.02(m,1H),3.82(d,J＝14.1Hz,1H),2.61(d,J＝4.8Hz,3H),1.96(s,3H).

Step 6) (R) -5- (2-fluoro-5-nitrophenyl) -3-imino-2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-bis Synthesis of oxo compounds

(R) -2- (2-fluoro-5-nitrophenyl) -N-methyl-2-thiouronopropane-1-sulfonamide (0.5g,1.43mmol) and ethanol (20mL) were charged to a 100mL single neck round bottom flask at 25 deg.C, iodomethane (0.608g,4.28mmol) was added, and the reaction was continued for 12 hours. Then, the reaction was warmed to 70 ℃ and reacted for 3 hours, the reaction was stopped, the reaction was spin-dried under reduced pressure, water (20mL) was added, ethyl acetate was extracted (50mL), the mixture was separated, the organic phase was spin-dried under reduced pressure, and column chromatography was performed to separate and purify the title compound (dichloromethane/methanol (v/v) ═ 40/1) as a yellow solid (0.298g, 66%).

MS(ESI,pos.ion)m/z:317.1[M+H]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm)8.45(dt,J＝13.3,6.7Hz,1H),8.30-8.19(m,1H),7.35(dd,J＝11.2,9.0Hz,1H),3.34-3.31(m,2H),3.17(s,3H),1.74(s,3H).

Step 7) (R) -tert-butyl (5- (2-fluoro-5-nitrophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadi Synthesis of oxazin-3-methylene) carbamates

(R) -5- (2-fluoro-5-nitrophenyl) -3-imino-2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide (0.47g,1.49mmol), triethylamine (0.3g,2.96mmol) and dichloromethane (10mL) were added to a 100mL single neck round bottom flask at 25 deg.C, followed by Boc anhydride (0.500g,2.29mmol) and the reaction was allowed to continue stirring for 12 hours; the reaction was stopped, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give the title compound as a white solid (0.5g, 81%).

MS(ESI,pos.ion)m/z:361.0[M+H-56]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.28(s,1H),6.91(dd,J＝11.9,8.5Hz,1H),6.61(dt,J＝9.4,2.7Hz,2H),4.29(dd,J＝14.1,2.1Hz,1H),3.68(d,J＝14.1Hz,1H),3.27(s,3H),1.88(s,3H),1.57(s,9H).

Step 8) (R) -tert-butyl (5- (5-amino-2-fluorophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thia-dia-ne Synthesis of oxazin-3-methylene) carbamates

(R) -tert-butyl (5- (2-fluoro-5-nitrophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (0.5g,1.2mmol), palladium on charcoal (150mg) and methanol (15mL) were added to a 100mL single-neck round-bottom flask at 25 deg.C, and the reaction was stirred under a hydrogen balloon for 24 hours. The reaction was stopped, filtered, the filtrate was spin-dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a white solid (0.424g, 91.4%).

MS(ESI,pos.ion)m/z:387.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.28(s,1H),6.91(dd,J＝11.9,8.5Hz,1H),6.61(dt,J＝9.4,2.7Hz,2H),4.29(dd,J＝14.1,2.1Hz,1H),3.68(d,J＝14.1Hz,1H),3.27(s,3H),1.88(s,3H),1.57(s,9H).

Step 9) (R) -tert-butyl (5- (5- (3-benzoylthioureido) -2-fluorophenyl) -2, 5-dimethyl-1, 1-dioxygen Synthesis of substituted-1, 2, 4-thiadiazine-3-methylene) carbamate

(R) -tert-butyl (5- (5-amino-2-fluorophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (0.27g,0.70mmol) and dichloromethane (5mL) were added to a 100mL single-neck round-bottom flask at 25 deg.C, benzoyl isothiocyanate (0.228g,1.4mmol) was added dropwise, and the reaction was stirred for an additional 10 hours; the organic phase was spin-dried under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a pale yellow solid (0.19g, 49%).

MS(ESI,pos.ion)m/z:550.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)9.11(s,1H),8.00(dd,J＝7.3,2.6Hz,1H),7.94-7.86(m,2H),7.69(t,J＝7.4Hz,1H),7.63(ddd,J＝8.5,3.9,2.8Hz,1H),7.58(t,J＝7.7Hz,2H),7.18(dd,J＝11.4,8.8Hz,1H),4.34(d,J＝14.1,1H),3.72(d,J＝14.1Hz,1H),3.27(s,3H),1.95(s,3H),1.58(s,9H).

Step 10) (R) -tert-butyl (5- (2-fluoro-5-thioalkylphenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thia-ne Synthesis of diazine-3-methylene) carbamate

(R) -tert-butyl (5- (5- (3-benzoylthioureido) -2-fluorophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (1.07g,1.95mmol) and methanol (20mL) were added to a 100mL single-neck round-bottom flask at 25 deg.C, sodium carbonate (0.2g,1.89mmol) was added, and the reaction was stirred for an additional 0.5 hour. Ammonium chloride (0.1g,1.9mmol) was added, the organic phase was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (823mg, 94.9%).

MS(ESI,pos.ion)m/z:446.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.68(s,1H),7.92(s,1H),7.28-7.18(m,3H),4.22(d,J＝13.7Hz,1H),3.63(d,J＝14.2Hz,1H),3.27(s,3H),1.96(s,3H),1.57(s,9H)。

Step 11) (R) -tert-butyl (5- (2-fluoro-5- ((4- (quinolin-2-yl) thiazol-2-yl) amino) phenyl) -2,5- Synthesis of dimethyl-1, 1-dioxo-1, 2, 4-thiadiazine-3-methylene) carbamate

(R) -tert-butyl (5- (2-fluoro-5-thionophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (190mg,0.43mmol), 2-bromo-1- (quinolin-2-yl) ethanone (150mg,0.6mmol) and ethanol (10mL) were added to a 100mL single-neck round-bottom flask at 25 deg.C and the reaction was stirred for an additional 2 hours. Saturated sodium bicarbonate solution (15mL) and dichloromethane (30mL) were added, the layers were separated, the organic phase was spin-dried under reduced pressure, and column chromatography separation and purification (petroleum ether/ethyl acetate (v/v) ═ 6/1) gave the title compound as a white solid (0.21g, 82.5%). MS (ESI, pos. ion) M/z 597.1[ M + H ]]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.26(d,J＝8.6Hz,1H),8.13-8.08(m,2H),7.84(d,J＝7.9Hz,1H),7.77-7.68(m,2H),7.65(s,1H),7.54(t,J＝7.5Hz,1H),7.34(dd,J＝6.9,2.8Hz,1H),7.16(dd,J＝11.6,8.8Hz,1H),4.39(dd,J＝14.1,1.8Hz,1H),3.70(d,J＝14.1Hz,1H),3.28(s,3H),1.94(d,J＝12.7Hz,3H),1.50(s,9H).

Step 12) (R) -5- (2-fluoro-5- ((4- (quinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, synthesis of 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

(R) -tert-butyl (5- (2-fluoro-5- ((4- (4-fluorophenyl) thiazol-2-yl) amino) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (230mg,0.38mmol) and dichloromethane (5mL) were added to a 50mL single-neck flask at 25 ℃, an ethyl hydrogen chloride solution (2mL,4M) was added, and the reaction was stirred for 2 hours; the reaction was stopped, dried under reduced pressure, saturated sodium bicarbonate solution (20mL) was added, followed by extraction with dichloromethane (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate (2g), filtered, the filtrate was dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (0.152g, 79.4%).

MS(ESI,pos.ion)m/z:497.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.12(d,J＝8.6Hz,1H),8.07(d,J＝8.5Hz,1H),8.01(d,J＝8.6Hz,1H),7.75(d,J＝8.0Hz,1H),7.68(t,J＝7.6Hz,1H),7.61(d,J＝4.5Hz,1H),7.49(t,J＝7.4Hz,1H),7.42(d,J＝7.8Hz,2H),6.98(dd,J＝11.5,8.8Hz,1H),3.93(d,J＝13.8Hz,1H),3.64(d,J＝14.0Hz,1H),3.17(s,3H),1.70(s,3H).

Example 2 Synthesis of (R) -5- (2-fluoro-5- ((4- (6-chloroquinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

Step 1) (R) -tert-butyl (5- (2-fluoro-5- ((4- (6-chloroquinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, synthesis of 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazine-3-methylene) carbamate

This title compound was prepared as described in example 1, step 11 by reacting (R) -tert-butyl (5- (2-fluoro-5-thionophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (200mg,0.45mmol) and 2-bromo-1- (6-chloroquinolin-2-yl) ethanone (171mg,0.6mmol) in ethanol (10mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give the title compound as a white solid (0.235g, 83%).

MS(ESI,pos.ion)m/z:631.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.27(d,J＝8.4Hz,1H),8.15-8.09(m,2H),7.76-7.69(m,2H),7.65(s,1H),7.53(t,J＝7.4Hz,1H),7.36-7.33(m,1H),7.17(dd,J＝11.6,8.8Hz,1H),4.36(d,J＝14.1Hz,1H),3.71(d,J＝14.1Hz,1H),3.28(s,3H),1.81(s,3H),1.60(s,9H).

Step 2) (R) -5- (2-fluoro-5- ((4- (6-chloroquinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imido- Synthesis of 2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

This step was prepared by the method described in example 1, step 12, using (R) -tert-butyl (5- (2-fluoro-5- ((4- (6-chloroquinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (230mg,0.37mmol), ethyl hydrogen chloride acetate solution (2mL,4M) in dichloromethane (5mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (0.167g, 85%).

MS(ESI,pos.ion)m/z:531.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.12(d,J＝8.6Hz,1H),8.06(d,J＝8.4Hz,1H),8.01(d,J＝8.6Hz,1H),7.75(d,J＝8.0Hz,1H),7.61(d,J＝4.5Hz,1H),7.49-7.46(m,1H),7.41(d,J＝7.8Hz,2H),6.98-6.95(m,1H),3.91(d,J＝11.4Hz,1H),3.73(d,J＝14.0Hz,1H),3.23(s,3H),1.80(s,3H).

Example 3 Synthesis of (R) -5- (2-fluoro-5- ((4- (6-bromoquinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

Step 1) (R) -tert-butyl (5- (2-fluoro-5- ((4- (6-bromoquinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylidene) aminoSynthesis of formic acid esters

This title compound was prepared as described in example 1, step 11 by reacting (R) -tert-butyl (5- (2-fluoro-5-thionophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (200mg,0.45mmol) and 2-bromo-1- (6-bromoquinolin-2-yl) ethanone (165mg,0.5mmol) in ethanol (10mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give the title compound as a white solid (231mg, 76%).

MS(ESI,pos.ion)m/z:675.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.26(d,J＝8.4Hz,1H),8.17-8.09(m,2H),7.78-7.70(m,2H),7.65(s,1H),7.54(m,1H),7.35-7.33(m,1H),7.17(dd,J＝11.6,8.8Hz,1H),4.33(d,J＝14.1Hz,1H),3.70(d,J＝14.1Hz,1H),3.29(s,3H),1.81(s,3H),1.59(s,9H).

Step 2) (R) -5- (2-fluoro-5- ((4- (6-bromoquinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imido- Synthesis of 2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

This step was prepared by the method described in example 1, step 12, using (R) -tert-butyl (5- (2-fluoro-5- ((4- (6-bromoquinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (220mg,0.32mmol), ethyl hydrogen chloride acetate solution (2mL,4M) in dichloromethane (5mL), and the crude product was isolated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (167mg, 91%).

MS(ESI,pos.ion)m/z:575.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.13(d,J＝8.4Hz,1H),8.07-8.05(m,1H),8.02(d,J＝8.6Hz,1H),7.73(d,J＝8.0Hz,1H),7.62(d,J＝4.6Hz,1H),7.48-7.46(m,1H),7.41(d,J＝8.0Hz,2H),6.98-6.94(m,1H),3.92(d,J＝11.4Hz,1H),3.73(d,J＝14.0Hz,1H),3.24(s,3H),1.80(s,3H).

Example 4 Synthesis of (R) -5- (3- ((4- (quinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

Step 1) Synthesis of (R, E) -2-methyl-N- (1- (3-nitrophenyl) ethylene) propane-2-sulfinamide

The title compound was prepared as described in example 1, step 1, by reacting m-nitroacetophenone (8.0g,48.4mmol), (R) - (+) -tert-butylsulfinamide (6.5g,54mmol) and tetraethyltitanate (21mL,99.16mmol) in tetrahydrofuran (65mL) and purifying the crude by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 10/1) to give the title compound as a yellow solid (11g, 85%).

MS(ESI,pos.ion)m/z:269.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.68(s,1H),8.33(dd,J＝8.2,1.1Hz,1H),8.20(d,J＝7.7Hz,1H),7.63(t,J＝8.0Hz,1H),2.83(s,3H),1.34(s,9H).

Step 2) (R) -2- ((R) -1, 1-dimethylethylsulfenamide) -N- (4-methoxybenzyl) -N-methyl-2- (3- Synthesis of nitrophenyl) propane-1-sulfonamide

The title compound was prepared as described in example 1, step 2 by reacting N- (4-methoxybenzyl) -N-methylmethanesulfonamide (687mg,2.99mmol), N-butyllithium (1.2mL,3.0mmol,2.5M) and (R, E) -2-methyl-N- (1- (3-nitrophenyl) ethylene) propane-2-sulfinamide (402mg,1.49mmol) in tetrahydrofuran (10mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (364mg, 48.8%).

MS(ESI,pos.ion)m/z:498.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.40(s,1H),8.18(dd,J＝8.2,1.3Hz,1H),7.83(d,J＝7.8Hz,1H),7.57(t,J＝8.0Hz,1H),7.22(d,J＝8.6Hz,2H),6.87(d,J＝8.6Hz,2H),5.90(s,1H),4.24(dd,J＝31.9,14.3Hz,2H),3.80(s,3H),3.77(d,J＝14.2Hz,1H),3.56(d,J＝14.1Hz,1H),2.75(s,3H),1.93(s,3H),1.36(s,9H).

Step 3 Synthesis of (R) -2-amino-N-methyl-2- (3-nitrophenyl) propane-1-sulfonamide

This title compound was prepared as described in example 1, step 3 by reacting (R) -2- ((R) -1, 1-dimethylethylsulphenamide) -N- (4-methoxybenzyl) -N-methyl-2- (3-nitrophenyl) propane-1-sulphonamide (2.50g,5.02mmol), concentrated hydrochloric acid (6.0mL), trifluoroacetic acid (15mL) and metaxylylene ether (4.70mL,35.2mmol) in dichloromethane (30mL) and methanol (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 40/1) to give the title compound as a yellow oil (1g, 73%).

MS(ESI,pos.ion)m/z:274.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.42(s,1H),8.14(dd,J＝8.1,1.2Hz,1H),7.91(d,J＝7.9Hz,1H),7.56(t,J＝8.0Hz,1H),3.52(d,J＝14.4Hz,1H),3.40(d,J＝14.3Hz,1H),2.68(d,J＝5.1Hz,3H),1.73(s,3H).

Step 4) (R) -N- ((1- (N-methylsulfamoyl) -2- (3-nitrophenyl) propan-2-yl) thiocarbamoyl) Synthesis of benzamide

The title compound was prepared as described in example 1, step 4 by reacting (R) -2-amino-N-methyl-2- (3-nitrophenyl) propane-1-sulfonamide (1g,3.66mmol) and benzoyl isothiocyanate (657mg,4.02mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow solid (1.56g, 97.7%).

MS(ESI,pos.ion)m/z:437.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)11.67(s,1H),8.93(s,1H),8.25-8.08(m,2H),7.94-7.79(m,2H),7.74-7.59(m,2H),7.55(dd,J＝13.3,7.6Hz,3H),4.89(d,J＝14.2Hz,1H),3.71(d,J＝14.2Hz,1H),2.85(t,J＝5.4Hz,3H),2.14(s,3H).

Step 5 Synthesis of (R) -N-methyl-2- (3-nitrophenyl) -2-thioropropane-1-sulfonamide

The title compound was prepared as described in example 1, step 5, by reacting (R) -N- ((1- (N-methylsulfamoyl) -2- (3-nitrophenyl) propan-2-yl) thiocarbamoyl) benzamide (1.56g,3.57mmol) and sodium carbonate (379mg,3.57mmol) in methanol (35mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a yellow solid (1.12g, 94%).

MS(ESI,pos.ion)m/z:333.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.13(s,1H),8.11-8.00(m,2H),7.79(d,J＝7.8Hz,1H),7.60(t,J＝8.0Hz,1H),7.15(s,1H),6.99-6.93(m,1H),4.03(d,J＝7.1Hz,1H),3.86(d,J＝14.1Hz,1H),3.33(s,4H),1.81(s,3H).

Step 6) preparation of (R) -3-imino-2, 5-dimethyl-5- (3-nitrophenyl) -1,2, 4-thiadiazine 1, 1-dioxo Synthesis of

The title compound was prepared as described in example 1, step 6 by reacting (R) -N-methyl-2- (3-nitrophenyl) -2-thioropropane-1-sulfonamide (1.12g,3.37mmol) and iodomethane (0.64mL,10mmol) in ethanol (30mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 40/1) to give the title compound as a yellow solid (718mg, 71.4%).

MS(ESI,pos.ion)m/z:299.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.37(d,J＝1.8Hz,1H),8.23-8.06(m,1H),7.76(d,J＝7.8Hz,1H),7.53(t,J＝8.0Hz,1H),3.58(q,J＝13.8Hz,2H),3.24(s,3H),1.75(s,3H).

Step 7) (R) -tert-butyl (2, 5-dimethyl-5- (3-nitrophenyl) -1, 1-dioxo-1, 2, 4-thiadiazine-3- Methylene) carbamate synthesis

This step title compound was prepared as described in example 1, step 7 by reacting (R) -3-imino-2, 5-dimethyl-5- (3-nitrophenyl) -1,2, 4-thiadiazine 1, 1-dioxo (718mg,2.41mmol), triethylamine (0.67mL,4.8mmol) and Boc anhydride (0.84mL,3.6mmol) in dichloromethane (20mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give the title compound as a white solid (880mg, 91.8%).

MS(ESI,pos.ion)m/z:343.0[M+H-56]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.74(s,1H),8.27-8.17(m,2H),7.77-7.69(m,1H),7.62(t,J＝7.9Hz,1H),3.96(d,J＝14.1Hz,1H),3.75(d,J＝14.1Hz,1H),3.26(s,3H),1.93(s,3H),1.55(s,9H).

Step 8) (R) -tert-butyl (5- (3-aminophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazine-3- Methylene) carbamate synthesis

The title compound was prepared as described in example 1, step 8 by reacting (R) -tert-butyl (2, 5-dimethyl-5- (3-nitrophenyl) -1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (867mg,2.176mmol) and palladium on charcoal (180mg) in methanol (15mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a white solid (680mg, 84.8%).

MS(ESI,pos.ion)m/z:369.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)10.49(s,1H),7.18(t,J＝7.8Hz,1H),6.71(d,J＝8.0Hz,1H),6.68-6.56(m,2H),3.81(d,J＝14.0Hz,1H),3.66(d,J＝14.0Hz,1H),3.27(s,3H),1.87(s,3H),1.53(s,9H).

Step 9) (R) -tert-butyl (5- (3- (3-benzoylthiourea) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, synthesis of 4-thiadiazine-3-methylene) carbamate

This step title compound was prepared as described in example 1, step 9 by reacting (R) -tert-butyl (5- (3-aminophenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (1.93g,5.24mmol) and benzoyl isothiocyanate (0.94g,5.8mmol) in dichloromethane (20mL) and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 4/1) to give the title compound as a yellow solid (2.7g, 96.8%).

MS(ESI,pos.ion)m/z:532.1[M+H]⁺；

Step 10) (R) -tert-butyl (2, 5-dimethyl-1, 1-dioxo-5- (3-thiothiophenyl) -1,2, 4-thiadiazine- Synthesis of 3-methylene) carbamates

The title compound was prepared as described in example 1, step 10, by reacting (R) -tert-butyl (5- (3- (3-benzoylthiourea) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazine-3-methylene) carbamate (2.7g,5.08mmol) and sodium carbonate (0.717g,6.76mmol) in methanol (30mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (2.0g, 92.1%).

MS(ESI,pos.ion)m/z:428.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)10.23(s,1H),9.77(s,1H),7.46(s,1H),7.36(d,J＝4.8Hz,2H),7.23-7.18(m,1H),4.56(d,J＝14.3Hz,1H),4.35(d,J＝14.3Hz,1H),3.03(s,3H),1.76(s,3H),1.60(s,9H).

Step 11) (R) -tert-butyl (5- (3- ((4- (quinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-dimethyl Synthesis of 1, 1-dioxo-1, 2, 4-thiadiazine-3-methylene) carbamate

This step title compound was prepared as described in example 1, step 11 by reacting (R) -tert-butyl (2, 5-dimethyl-1, 1-dioxo-5- (3-thionophenyl) -1,2, 4-thiadiazin-3-methylene) carbamate (214mg,0.5mmol) and 2-bromo-1- (quinolin-2-yl) ethanone (150mg,0.6mmol) in ethanol (10mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give the title compound as a yellow solid (246mg, 85%).

MS(ESI,pos.ion)m/z:579.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.25(d,J＝8.4Hz,1H),8.15-8.09(m,2H),7.84(d,J＝8.0Hz,1H),7.78-7.68(m,2H),7.65(s,1H),7.46(s,1H),7.36(d,J＝4.8Hz,2H),7.23-7.18(m,1H),3.91(d,J＝14.0Hz,1H),3.70(d,J＝14.0Hz,1H),3.27(s,3H),1.92(s,3H),1.60(s,9H).

Step 12) (R) -5- (3- ((4- (quinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5-dimethyl Synthesis of 1,2, 4-thiadiazine 1, 1-dioxides

This step was prepared by the method described in example 1, step 12, using (R) -tert-butyl (5- (3- ((4- (quinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (230mg,0.4mmol), ethyl hydrogen chloride in ethyl acetate (2mL,4M) in dichloromethane (10mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a yellow solid (0.17g, 89%).

MS(ESI,pos.ion)m/z:479.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.27(d,J＝8.2Hz,1H),8.15-8.09(m,2H),7.82(d,J＝8.0Hz,1H),7.78(d,J＝8.6Hz,1H),7.71-7.68(m,1H),7.63-7.59(m,1H),7.46(s,1H),7.36(d,J＝4.8Hz,2H),7.23-7.18(m,1H),3.92(d,J＝14.1Hz,1H),3.73(d,J＝14.0Hz,1H),3.24(s,3H),1.78(s,3H).

Example 5 Synthesis of (R) -5- (3- ((4- (6-chloroquinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

Step 1) (R) -tert-butyl (5- (3- ((4- (6-chloroquinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-di Methyl-1, 1-dioxo-1, 2, 4-thiadiazine-3-methyleneGroup) synthesis of carbamates

This title compound was prepared as described in example 1, step 11 by reacting (R) -tert-butyl (2, 5-dimethyl-1, 1-dioxo-5- (3-thionophenyl) -1,2, 4-thiadiazin-3-methylene) carbamate (200mg,0.47mmol) and 2-bromo-1- (6-chloroquinolin-2-yl) ethanone (170mg,0.6mmol) in ethanol (5mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give the title compound as a white solid (262mg, 91%).

MS(ESI,pos.ion)m/z:613.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.25(d,J＝8.4Hz,1H),8.15-8.09(m,2H),7.84(d,J＝8.0Hz,1H),7.78-7.68(m,1H),7.65(s,1H),7.46(s,1H),7.36(d,J＝4.8Hz,2H),7.23-7.18(m,1H),3.91(d,J＝14.0Hz,1H),3.70(d,J＝14.0Hz,1H),3.27(s,3H),1.92(s,3H),1.60(s,9H).

Step 2) (R) -5- (3- ((4- (6-chloroquinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5- Synthesis of dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

The title compound was prepared as described in example 1, step 12 by reacting (R) -tert-butyl (5- (3- ((4- (6-chloroquinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (250mg,0.41mmol), ethyl hydrogen chloride acetate solution (2mL,4M) in dichloromethane (5mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (0.18g, 86%).

MS(ESI,pos.ion)m/z:513.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.26(d,J＝8.2Hz,1H),8.15-8.12(m,1H),8.10-8.07(m,1H),7.83(d,J＝8.0Hz,1H),7.79-7.67(m,1H),7.66(s,1H),7.47(s,1H),7.38(d,J＝4.6Hz,2H),7.23-7.18(m,1H),3.91(d,J＝14.0Hz,1H),3.65(brs,1H),3.09(s,3H),1.72(s,3H).

Example 6 Synthesis of (R) -5- (3- ((4- (6-bromoquinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5-dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

Step 1) (R) -tert-butyl (5- (3- ((4- (6-bromoquinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-di Synthesis of methyl-1, 1-dioxo-1, 2, 4-thiadiazine-3-methylene) carbamate

This title compound was prepared as described in example 1, step 11 by reacting (R) -tert-butyl (2, 5-dimethyl-1, 1-dioxo-5- (3-thionophenyl) -1,2, 4-thiadiazin-3-methylene) carbamate (200mg,0.47mmol) and 2-bromo-1- (6-bromoquinolin-2-yl) ethanone (165mg,0.5mmol) in ethanol (5mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 6/1) to give the title compound as a white solid (251mg, 81%).

MS(ESI,pos.ion)m/z:657.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.25(d,J＝8.2Hz,1H),8.17-8.14(m,1H),8.11-8.08(m,1H),7.83(d,J＝8.4Hz,1H),7.77-7.68(m,1H),7.65(s,1H),7.47(s,1H),7.37(d,J＝4.8Hz,2H),7.22-7.18(m,1H),3.91(d,J＝14.0Hz,1H),3.72(d,J＝14.1Hz,1H),3.27(s,3H),1.93(s,3H),1.59(s,9H).

Step 2) (R) -5- (3- ((4- (6-bromoquinolin-2-yl) thiazol-2-yl) amino) phenyl) -3-imino-2, 5- Synthesis of dimethyl-1, 2, 4-thiadiazine 1, 1-dioxide

The title compound was prepared as described in example 1, step 12 by reacting (R) -tert-butyl (5- (3- ((4- (6-bromoquinolin-2-yl) thiazol-2-yl) amino) phenyl) -2, 5-dimethyl-1, 1-dioxo-1, 2, 4-thiadiazin-3-methylene) carbamate (230mg,0.35mmol), ethyl hydrogen chloride acetate solution (2mL,4M) in dichloromethane (5mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (0.181g, 93%).

MS(ESI,pos.ion)m/z:557.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.27(d,J＝8.2Hz,1H),8.13-8.07(m,2H),7.84(d,J＝8.2Hz,1H),7.78-7.71(m,1H),7.65(s,1H),7.48(s,1H),7.38(d,J＝4.8Hz,2H),7.23-7.19(m,1H),3.92(d,J＝14.1Hz,1H),3.65(brs,1H),3.10(s,3H),1.73(s,3H).

Biological assay

Example A: method for evaluating activity of BACE-1 inhibitor enzyme level in vitro

Experimental methods

1.1X assay buffer and test Compound formulation

(1)1X assay buffer(20nM PIPES,pH5.0；0.1％Brij-35；10％Glycerol)

(2) Test Compound preparation

Test compound was diluted to 1mM and control compound MK-8931 was diluted to 100. mu.M in 100% DMSO, respectively. mu.L of a 1mM test compound solution and 100. mu.M MK-8931 solution were added to an Echo 384-well plate (Labcyte, P-05525), respectively. Test compounds were diluted 9 times with a 3-fold dilution gradient. 100nL of test compound solution was transferred from the starting plate to a test plate (PerkinElmer, Cat. No.6008289) by Echo 550(Labcyte Echo 550 sonic pipetting system apparatus). To control wells, 100nL DMSO was added. The final DMSO concentration in all wells was 1%.

Preparation of BACE-1 enzyme solution

(1) A BACE-1 enzyme solution is prepared by adopting 1X assay buffer, the concentration is two times of the final concentration, and the final concentration is 3 nM.

(2) Add 5. mu.L of BACE-1 enzyme solution to each well of the test plate using an electric multichannel pipettor and the solution was centrifuged rapidly.

(3) Incubate at room temperature for 15 min.

3.2 preparation of substrate solution for APP

(1) Preparing APP substrate solution by adopting 1X assay buffer, wherein the concentration of the solution is twice of the final concentration of the test.

Final concentration: Biotin-APP substrate-K25 nM; non-biotinylated and non-labeled APP substrate 5 μ M.

(2) The reaction was started by adding 5 μ L of APP substrate solution per well in the test plate using an electric multi-channel pipette.

(3) The solution was centrifuged rapidly.

4. Reaction of

After sealing the test plate, incubate for 4h at 28 ℃.

Detection of Homogeneous Time-Resolved Fluorescence (HTRF)

(1) Preparation of 2X detection buffer (25mM Tris-HCl, pH 8.0; 0.0005% Brij-35; 250mM KF)

(2) The Streptavidin-XLent solution was prepared at 2X detection buffer, at a concentration 2-fold the final concentration tested (10. mu.g/mL).

(3) The reaction was stopped by adding 10. mu.L of Streptavidin-XLent solution to each well of the test plate using an electric multi-channel pipette.

(4) Quickly mixing, and balancing at 25 deg.C for 60 min.

6. Collecting data

Data were collected in the EnVison software.

7. Data analysis

(1) HTRF fluorescence ratios (665nm/615nm 10000) were copied from Envison software.

(2) The HTRF fluorescence ratio was converted to a percent inhibition value. For maximum and minimum processing: values above Avg ± 3SD are considered as deviations.

The proportion of deletion of the deviation value is controlled within 20 percent.

a. Inhibition rate (sample ratio-min)/(max-min) × 100

b. The minimum value is the HTRF fluorescence ratio of the BACE-1 enzyme and the APP substrate, and the maximum value is the HTRF ratio of the assay buffer and the APP substrate.

(3) Data are presented in Excel tabular form, curves fitted with GraphPad Prism 5.

(4) Each compound IC₅₀Values were calculated using a GraphPad Prism 5 four parameter fit model:

Y＝Bottom+(Top-Bottom)/(1+(IC₅₀/X) HillSlope), Y is the percent inhibition rate, and X is the compound concentrationAnd (4) degree.

The results are shown in Table A.

TABLE A results of in vitro inhibition of BACE-1 enzyme levels by the compounds of the present invention

Example No.2	IC50(μM)	Example No.2	IC50(μM)
				Example 1	B	Example 3	A
Example 2	A	Example 5	A

Remarking: a is 1 mu M<IC₅₀<10μM；B:10μM<IC₅₀<50μM。

The experimental result shows that the compound has better BACE-1 inhibition effect.

In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (10)

1. A compound of formula (I) or formula (I '), or a pharmaceutically acceptable salt of a compound of formula (I) or formula (I'),

wherein:

x is CR^xOr N;

y is S, O or NH;

z is CH or N;

R^1a、R^1b、R^1d、R^1e、R^1fand R^xEach independently is H or D;

R^1cis H, D, F, Cl, Br, I or C₁-C₆An alkyl group;

R^1gis H or D;

R²and R³Each independently is H or D;

R⁴is H, D, F, Cl, Br, I or C₁-C₆An alkyl group;

R⁵is C₁-C₆An alkyl group;

R⁶and R⁷Each independently is H or D; and

R⁸is C₁-C₆An alkyl group.

2. The compound of claim 1, wherein R^1cIs H, D, F, Cl, Br, I or C₁-C₄An alkyl group.

3. The compound of claim 1 or 2, wherein R^1cH, D, F, Cl, Br, I, methyl, ethyl, n-propyl or isopropyl.

4. The compound of claim 1, wherein

R⁴Is H, D, F, Cl, Br, I or C₁-C₄An alkyl group;

R⁵is C₁-C₄An alkyl group;

R⁸is C₁-C₄An alkyl group.

5. The compound of claim 1 or 4, wherein

R⁴H, D, F, Cl, Br, I, methyl, ethyl, n-propyl or isopropyl;

R⁵is methyl, ethyl, n-propyl or isopropyl;

R⁸is methyl, ethyl, n-propyl or isopropyl.

6. The compound of claim 1, which is a compound of formula (II) or formula (II '), or a pharmaceutically acceptable salt of a compound of formula (II) or formula (II'),

7. the compound of claim 1 or 6, which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:

8. a pharmaceutical composition comprising a compound of any one of claims 1-7; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

9. The pharmaceutical composition of claim 8, optionally further comprising an additional therapeutic agent, wherein the additional therapeutic agent is a fibrate, a nicotinic receptor agonist, an acetylcholine receptor agonist, a cholinesterase inhibitor, an N-methyl-D-aspartate receptor antagonist, a promoter of alpha secretase activity, a glycogen synthase kinase beta inhibitor, an inhibitor of amyloid aggregation, a gamma secretase modulator, a histamine H3 antagonist, a histone deacetylase inhibitor, a PDE-4 inhibitor, a PDE-10 inhibitor, an mGluR1 receptor modulator, an mGluR5 receptor modulator, an mGluR2/3 antagonist, 5-HT receptor modulator, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof₄Agonists, 5-HT₆Receptor antagonists or GABA_AAn inverse agonist.

10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 8 to 9 in the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a disorder associated with β -amyloid;

wherein the beta-amyloid associated disease is dementia, Down's syndrome, attention deficit symptoms, memory loss, stroke, neurodegeneration, amyloidosis, beta-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, hemodialysis complications, glaucoma, type II diabetes, diabetes-related amyloidogenesis, traumatic brain injury, bovine spongiform encephalopathy, mild cognitive impairment or Alzheimer's disease.