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CN119654326A - Novel heterocyclic compounds - Google Patents

Novel heterocyclic compounds Download PDF

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Publication number
CN119654326A
CN119654326A CN202380058308.9A CN202380058308A CN119654326A CN 119654326 A CN119654326 A CN 119654326A CN 202380058308 A CN202380058308 A CN 202380058308A CN 119654326 A CN119654326 A CN 119654326A
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azaspiro
methyl
heptane
hexahydropyrido
carbonyl
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约尔格·本兹
莫德·吉鲁
乌韦·迈克尔·格莱瑟
伯德·库茵
阿丽娜·李乐克
芬恩·苏珊娜·奥哈拉
马丁·里特尔
迪迪埃·罗姆巴赫
菲利普·克劳迪奥·施密德
马蒂亚斯·比特·威特韦尔
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention provides novel heterocyclic compounds having the general formula (I) wherein A, B, R 1、R2、R4 and R 5 are as described herein, compositions comprising the compounds, methods of making the compounds, and methods of using the compounds.

Description

Novel heterocyclic compounds
Technical Field
The present invention relates to organic compounds useful in the treatment or prevention of mammalian diseases and conditions associated with MAGL, such as neuroinflammation, neurodegenerative diseases, pain, cancer, psychotic disorders, multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain and/or a Monoacylglycerollipase (MAGL) inhibitor of kidney disease, in particular, to a pharmaceutical composition useful in the treatment or prevention of diseases and conditions associated with MAGL in a mammal.
Background
Endogenous Cannabinoids (ECs) are lipid signals that exert their biological effects by interacting with the cannabinoid receptors (CBR), CB1 and CB 2. They regulate a variety of physiological processes including neuroinflammation, neurodegenerative diseases and tissue regeneration (Iannotti, f.a. et al, progress IN LIPID RESEARCH2016,62,107-28.). In the brain, the major endogenous cannabinoid 2-arachidonyl glycerol (2-AG) is produced by diacylglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase (MAGL). MAGL can hydrolyze 85% of 2-AG and the remaining 15% is hydrolyzed by ABHD6 and ABDH (Nomura, D.K. et al, science 2011,334,809). MAGL is expressed throughout the brain and in most brain Cell types, including neurons, astrocytes, oligodendrocytes and microglia (Chanda, P.K. et al, molecular pharmacology 2010,78,996; viader, A. Et al, cell reports 2015,12,798.). 2-AG hydrolyzes to form Arachidonic Acid (AA), a precursor of Prostaglandins (PG) and Leukotrienes (LT). AA oxidative metabolism in inflamed tissues increases. The inflammatory process involves two major enzymatic pathways for arachidonic acid oxidation, namely the cyclooxygenase that produces PG and the 5-lipoxygenase that produces LT. Among the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important products. These products have been detected at sites of inflammation (e.g., in the cerebrospinal fluid of patients with neurodegenerative diseases) and are thought to contribute to the inflammatory response and disease progression. 2-AG hydrolase activity was significantly reduced in the nervous system of mice lacking MAGL (Mgll-/-) while 2-AG levels were elevated, while other arachidonic acid-containing phosphate and neutral lipids (including arachidonic Acid Ethanolamine (AEA) and other free fatty acids) remained unchanged. In contrast, the levels of prostaglandins and other eicosanoids, including prostaglandin E2 (PGE 2), D2 (PGD 2), F2 (PGF 2) and thromboxane B2 (TXB 2), derived from AA and AA derivatives are greatly reduced. Phospholipase a 2(PLA2) has been considered as the major source of AA, but the AA level in the brain of cPLA 2 deficient mice is unchanged, enhancing the key role of MAGL in the brain in the regulation of AA production and encephalitis processes.
Neuroinflammation is a common pathological change characteristic of brain diseases including, but not limited to, neurodegenerative diseases (e.g., multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, and psychiatric disorders such as anxiety and migraine). In the brain, the production of eicosanoids and prostaglandins controls the neuroinflammatory process. The pro-inflammatory Lipopolysaccharide (LPS) resulted in a stable time-dependent increase in eicosanoids in the brain, a phenomenon that was significantly attenuated in Mgll-/-mice. LPS treatment also resulted in a generalized elevation of proinflammatory cytokines (including interleukin-1-a (IL-1-a), IL-1b, IL-6) and tumor necrosis factor-a (TNF-a) (inhibited in Mgll-/-mice).
Neuroinflammation is characterized by activation of innate immune cells, microglia and astrocytes of the central nervous system. Anti-inflammatory agents have been reported to inhibit activation of glial cells and progression of diseases including alzheimer's disease and multiple sclerosis in preclinical models (Lleo a., cell Mol Life sci.2007,64,1403). Importantly, genetic and/or pharmacological disruption of MAGL activity also blocks LPS-induced activation of microglial cells in the brain (Nomura, D.K. et al, science2011,334, 809.).
Furthermore, genetic and/or pharmacological disruption of MAGL activity has been shown to have protective effects in animal models of a variety of neurodegenerative diseases, including but not limited to Alzheimer's disease, parkinson's disease and multiple sclerosis. For example, irreversible MAGL inhibitors have been widely used in preclinical models of neuroinflammatory and neurodegenerative diseases (Long, J.Z. et al Nature chemical biology, 2009,5,37.). Systemic injection of such inhibitors can reproduce the Mgll-/-mouse phenotype in the brain, including elevated 2-AG levels, reduced AA levels, and associated eicosanoid production, and prevent cytokine production and microglial activation following LPS-induced neuroinflammation (Nomura, d.k. et al, science 2011,334,809.), completely confirming that MAGL is a drug target.
With genetic and/or pharmacological disruption of MAGL activity, endogenous levels of the natural substrate 2-AG of MAGL in the brain are elevated. 2-AG has been reported to exhibit beneficial effects on pain, for example, analgesic effects on mice (Ignatowska-Jankowska b. Et al, j. Pharmacol. Exp. Thor. 2015,353, 424), and also beneficial effects on mental disorders (e.g., depression in chronic stress models) (Zhong p. Et al, neuropsychopharmacology 2014,39,1763).
In addition, oligodendrocytes (OL), myelin cells of the central nervous system, and their precursors (OPC) express cannabinoid receptor 2 (CB 2) on their membranes. 2-AG is an endogenous ligand for CB1 and CB2 receptors. Pharmacological inhibition of both cannabinoids and MAGL has been reported to attenuate the excitotoxic onset weaknesses of OL and OPC and thus may have neuroprotective effects (Bernal-Chico, A. Et al, glia2015,63, 163.). In addition, pharmacological inhibition of MAGL increases the number of mouse brain myelin sheath OL, suggesting that MAGL inhibition may promote OPC differentiation in vivo myelin sheath OL (Alpar, A. Et al, nature communications 2014,5,4421.). Inhibition of MAGL also promotes remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu A. Et al, journal of Neuroscience 2017,37 (35), 8385.).
In recent years, metabolism, particularly lipid metabolism, has received great attention in cancer research. Researchers believe that de novo synthesis of fatty acids plays an important role in tumor progression. Many studies have shown that endogenous cannabinoids have anti-tumor effects, including antiproliferative, apoptosis-inducing, and anti-metastatic effects. MAGL acts as an important lytic enzyme in the lipid metabolism and endogenous cannabinoid system and as a component of gene expression profile, affecting different aspects of tumorigenesis (Qin, H., et al, cell Biochem.Biophys.2014,70,33;Nomura DK et al, cell 2009,140 (1), 49-61; nomura DK et al, chem. Biol.2011,18 (7), 846-856; jinlong Yin et al, nature Communications 2020,11,2978).
The endogenous cannabinoid system is also involved in many gastrointestinal physiological and pathophysiological roles (Marquez, surrez et al 2009). All of these effects are driven primarily via the cannabinoid receptors (CBR), CB1 and CB 2. CB1 receptors are present throughout the GI tract of animals and healthy humans, particularly in the intestinal nervous system (ENS) and in the epithelial lining and smooth muscle cells of blood vessels in the colon wall (Wright, rooney et al 2005), (Duncan, davison et al 2005). Activation of CB1 produces anti-emetic, anti-peristaltic and anti-inflammatory effects and helps regulate pain (PERISETTI, rimu et al 2020). CB2 receptors are expressed in immune cells such as plasma cells and macrophages in the lamina propria of the GI tract (Wright, rooney et al 2005) and act primarily on human colon tissue epithelium associated with Inflammatory Bowel Disease (IBD). Activation of CB2 exerts an anti-inflammatory effect by reducing pro-inflammatory cytokines. MAGL expression in colonic tissue of UC patients is increased (Marquez, suarez et al 2009), and 2-AG levels in plasma of IBD patients are increased (Grill, hogenauer et al 2019). Several animal studies demonstrate the potential of MAGL inhibitors for symptomatic treatment of IBD. MAGL inhibits the prevention of TNBS-induced mouse colitis via CB1/CB2 MoA and reduces local circulatory inflammation markers (Marquez, suarez et al 2009). In addition, MAGL inhibits MoA driven by CB1 to improve intestinal wall integrity and intestinal permeability (Wang, zhang et al 2020).
In summary, inhibition of the action and/or activation of MAGL is a promising novel therapeutic strategy for the treatment or prevention of various diseases and disorders.
WO2020104494 discloses certain MAGL inhibitors. However, it was found that while those MAGL inhibitors have properties that make them particularly useful for treating CNS indications, such as multiple sclerosis, some properties (e.g., high permeability) mean that they are less suitable if different exposures across tissues are required. This may make them less suitable for treating certain conditions that may benefit from achieving higher exposures in the target tissue than other parts of the body.
Thus, there remains a highly unmet need for novel MAGL inhibitors, particularly for novel MAGL inhibitors having unique properties that allow for different exposures in different tissues.
Disclosure of Invention
Surprisingly, starting from the compounds disclosed in WO2020104494, many chemical modifications lead to a significant decrease in passive permeability (P app) while maintaining high cellular potency and excellent overall drug-like properties. The compounds of the invention find particular use in indications that benefit from different levels of MAGL inhibition in different tissues, particularly indications that benefit from higher levels of MAGL inhibition in the periphery than in the brain.
In a first aspect, the present invention provides a compound of formula (I)
Wherein A, B, R 1、R2、R4 and R 5 are as described herein.
In one aspect, the present invention provides a process for the manufacture of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, which process comprises:
(a) Allowing an amine of formula 1B, wherein R 1、R2、R4、R5, A and B are as described herein,
With 6- (1, 2, 4-triazole-1-carbonyl) -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (2),
In the presence of a base, or
(B) 4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one (2 b)
And a compound of formula 1c, wherein R 1、R2、R4、R5, A and B are as described herein,
In the presence of a base, and reacting,
To form said compound of formula (I).
In another aspect, the invention provides a compound of formula (I) as described herein, produced according to the methods described herein.
In another aspect, the present invention provides a compound of formula (I) as described herein for use as a therapeutically active substance.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.
In another aspect, the invention provides a compound of formula (I) as described herein for use in the treatment or prevention of diseases and conditions associated with MAGL.
Detailed Description
Definition of the definition
Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
The term "alkyl" refers to a monovalent or multivalent (e.g., monovalent or divalent) straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms ("C 1-C6 -alkyl") (e.g., 1,2,3, 4,5, or 6 carbon atoms). In some embodiments, the alkyl group contains 1 to 3 carbon atoms, for example 1,2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2, 2-dimethylpropyl. A particularly preferred but non-limiting example of an alkyl group is methyl.
The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Unless otherwise indicated, an alkoxy group contains 1 to 6 carbon atoms ("C 1-C6 -alkoxy"). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, but non-limiting example of an alkoxy group is methoxy.
The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferably, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl) or bromine (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).
As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C 3-10 -cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. A preferred, but non-limiting example of cycloalkyl is cyclopropyl.
As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic system having 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, the remaining ring atoms being carbon. Some non-limiting examples of heterocyclyl groups include azetidine, pyrrolidine, piperidine, piperazinyl, and morpholine. One preferred, but non-limiting example of a heterocyclic group is azetidine.
The term "cyano" refers to a-CN (nitrile) group.
The term "oxo" refers to an oxygen atom (=o) bonded to the parent molecule through a double bond.
The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced with a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by halogen atoms, most preferably fluorine. A particularly preferred, but non-limiting, example of a haloalkyl group is trifluoromethyl (CF 3).
The term "haloalkylcycloalkyl" refers to a cycloalkyl group in which at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a haloalkyl group, preferably CF 3. Preferably, "haloalkylcycloalkyl" refers to a cycloalkyl group in which 1, 2 or 3 hydrogen atoms (particularly 1 hydrogen atom) of the cycloalkyl group have been replaced by a haloalkyl group, most preferably CF 3. One particularly preferred, but non-limiting, example of a haloalkylcycloalkyl group is trifluoromethyl cyclopropyl.
The term "haloalkyl heterocyclyl" refers to a heterocyclyl group in which at least one of the hydrogen atoms of the heterocyclyl group has been replaced by a haloalkyl group, preferably CF 3. Preferably, "haloalkyl heterocyclyl" refers to a heterocyclyl group in which 1,2 or 3 hydrogen atoms (particularly 1 hydrogen atom) of the heterocyclyl group have been replaced by a haloalkyl group, most preferably CF 3. One particularly preferred, but non-limiting, example of a haloalkyl heterocyclyl is 3- (trifluoromethyl) azetidine.
The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which 1,2 or 3 hydrogen atoms of the alkoxy group have been replaced by halogen atoms, most preferably fluorine. A particularly preferred, but non-limiting, example of a haloalkoxy group is trifluoromethoxy (-OCF 3).
The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effect and properties of the free base or free acid, which are not undesirable in biological or other respects. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like (particularly hydrochloric acid) and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimide resins, and the like). The specific pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.
As used herein, the term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a multifunctional compound so as to selectively chemically react at another unprotected reactive site typically associated therewith in synthetic chemistry. The protecting group may be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxyl protecting groups. Specific protecting groups are t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further specific protecting groups are t-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is t-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in t.w. greene and p.g. m.wutts, protective Groups in Organic Chemistry, 5 th edition, 2014,John Wiley&Sons,N.Y.
The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (e.g. racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. In a preferred embodiment, the compounds of formula (I) according to the invention are cis-enantiomers of formula (Ia) or (Ib), respectively, as described herein.
The asymmetric carbon atom may be in the "R" or "S" configuration, depending on Cahn-Ingold-Prelog Convention.
The abbreviation "MAGL" refers to monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.
The term "treating" as used herein includes (1) inhibiting the state, disorder or condition of at least one clinical or sub-clinical symptom of the disease (e.g., preventing, alleviating or delaying the progression of the disease or its recurrence in the case of maintenance therapy), and/or (2) alleviating the condition (i.e., causing regression of the state, disorder or condition of the disease or at least one clinical or sub-clinical symptom). The benefit to the patient to be treated is statistically significant or at least perceptible to the patient or physician. However, it should be appreciated that when a drug is administered to a patient to treat a disease, the result may not always be an effective treatment.
The term "preventing" as used herein includes preventing or delaying the appearance of clinical symptoms of a state, disorder or condition that develops in a mammal, particularly a human, that may have or be susceptible to the state, disorder or condition but has not undergone or exhibited clinical or subclinical symptoms of the state, disorder or condition.
As used herein, the term "neuroinflammation" refers to acute and chronic inflammation of nervous tissue, which is the major tissue component of two parts of the nervous system, the brain and spinal cord of the Central Nervous System (CNS), and the branched peripheral nerves of the Peripheral Nervous System (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as alzheimer's disease, parkinson's disease and multiple sclerosis. Acute neuroinflammation generally occurs immediately after injury to the central nervous system, for example, by Traumatic Brain Injury (TBI).
As used herein, the term "traumatic brain injury" ("TBI", also referred to as "intracranial injury") relates to brain injury caused by external mechanical forces such as rapid acceleration or deceleration, impact, shock wave, or projectile penetration.
As used herein, the term "neurodegenerative disease" relates to a disease associated with progressive loss of structure or function of neurons, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, alzheimer's disease, parkinson's disease, and amyotrophic lateral sclerosis.
As used herein, the term "psychotic disorder" (also referred to as psychosis or mental illness) relates to a behavioral or mental pattern that may cause suffering or poor lifestyle. Such features may be persistent, recurrent, or palliative, or may be individual events. Examples of psychotic disorders include, but are not limited to, anxiety and depression.
As used herein, the term "pain" refers to the unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain (including chemotherapy-induced neuropathy), phantom pain, and psychogenic pain. One specific example of pain is neuropathic pain, which is caused by injury or disease affecting any part of the nervous system (i.e., somatosensory system) that involves physical sensation. In one embodiment, the "pain" is neuropathic pain resulting from amputation or open chest surgery. In one embodiment, "pain" is chemotherapy-induced neuropathy.
As used herein, the term "neurotoxicity" refers to toxicity of the nervous system. This occurs when exposed to natural or artificial toxic substances (neurotoxins) that alter the normal activity of the nervous system, thereby causing damage to the nervous tissue. Examples of neurotoxicity include, but are not limited to, neurotoxicity caused by exposure to chemotherapy, radiation therapy, drug therapy, substances used in drug abuse and organ transplantation, exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics and some natural substances.
As used herein, the term "cancer" refers to a disease characterized by the presence of neoplasms or tumors due to abnormal uncontrolled growth of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, colon carcinoma, and ovarian cancer.
The term "mammal" as used herein includes humans and non-humans, and includes, but is not limited to, humans, non-human primates, dogs, cats, mice, cows, horses, and pigs. In a particularly preferred embodiment, the term "mammal" refers to a human.
Compounds of the invention
In a first aspect, the present invention provides a compound of formula (I)
Or a pharmaceutically acceptable salt thereof, wherein:
(i) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1, 2-dihydropyridinyl, [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyrazine, 1, 2-benzoxazole, 1H-indazole, 1H-imidazo [1,2-c ] pyrimidin-5-one, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,2-a ] pyrimidine, 2H-pyrazolo [3,4-c ] pyridine, 7H-pyrrolo [2,3-d ] pyrimidine, [1,2,4] triazolo [1,5-b ] pyrimidine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [4,3-b ] pyridine, 1H-imidazo [4,5-b ] pyridine, 3H-imidazo [4,5-b ] pyridine, 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine, 1H-pyrazolo [3,4-b ] pyridine, 1H-imidazo [1,2-a ] pyrimidin-5-one and 2H-indazole;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halo-C 1-6 -alkyl) - (3-to 6-membered heterocyclyl) -, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-, and groups
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
r 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl, and 4-to 6-membered heterocyclyl, wherein the 4-to 6-membered heterocyclyl is optionally substituted with a halo-C 1-6 -alkyl substituent;
x is selected from O and NH, or
(Ii) A is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-, and groups
R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl and 4-to 6-membered heterocyclyl, wherein the 4-to 6-membered heterocyclyl is optionally substituted with a halo-C 1-6 -alkyl substituent, and
X is selected from O and NH, or
(Iii) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl and 4-to 6-membered heterocyclyl, wherein the 4-to 6-membered heterocyclyl is optionally substituted with a halo-C 1-6 -alkyl substituent, and
X is selected from O and NH;
R 4 and R 5 are each independently selected from hydrogen, halogen and C 1-6 -alkyl, and
B is selected from:
in another aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein:
a is a 9 membered bicyclic heteroaryl group comprising 1 to 5 heteroatoms selected from N, O and S, the remaining ring atoms being carbon;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-, and groups
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl;
x is selected from O and NH, or
R 4 and R 5 are each independently selected from hydrogen, halogen and C 1-6 -alkyl, and
B is selected from:
in one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Ii) A is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-, and groups
R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Iii) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1, 2-dihydropyridinyl, [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine, [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyridine, and indazole-1, 2H-b ] pyridine;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-, and groups
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl;
x is selected from O and NH;
R 4 and R 5 are each independently selected from hydrogen, halogen and C 1-6 -alkyl, and
B is selected from:
In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia)
Wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Ii) A is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Iii) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1, 2-dihydropyridinyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, and
B is selected from:
in one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl and (halo-C 1-6 -alkyl) - (4-to 6-membered heterocyclyl), and
X is selected from O and NH, or
(Ii) A is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, halo-C 1-6 -alkyl and cyano;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Iii) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1, 2-dihydropyridinyl, [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyrazine, 1, 2-benzoxazole, 1H-indazole, 1H-imidazo [1,2-c ] pyrimidin-5-one, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,2-a ] pyrimidine, 2H-pyrazolo [3,4-c ] pyridine, 7H-pyrrolo [2,3-d ] pyrimidine, [1,2,4] triazolo [1,5-b ] pyrimidine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [4,3-b ] pyridine, 1H-imidazo [4,5-b ] pyridine, 3H-imidazo [4,5-b ] pyridine, 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine, 1H-pyrazolo [3,4-b ] pyridine, 1H-imidazo [1,2-a ] pyrimidin-5-one and 2H-indazole;
R 1 is selected from the group consisting of C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halo-C 1-6 -alkyl) - (3-to 6-membered heterocyclyl) -, halo-C 1-6 -alkoxy and a group
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Ii) A is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, halo-C 1-6 -alkyl and cyano;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Iii) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1, 2-dihydropyridinyl, [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine, [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyridine, and indazole-1, 2H-b ] pyridine;
R 1 is selected from the group consisting of C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, and groups
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is halo-C 1-6 -alkyl, and
X is selected from O and NH.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Ii) A is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, halo-C 1-6 -alkyl and cyano;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Iii) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1, 2-dihydropyridinyl, [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine, [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyridine, and indazole-1, 2H-b ] pyridine;
R 1 is selected from the group consisting of C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, and groups
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Ii) A is pyridyl;
R 1 is selected from halogen, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-, and groups
R 2 is selected from hydrogen, halogen, and cyano;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Iii) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1, 2-dihydropyridinyl;
R 1 is selected from halo-C 1-6 -alkyl and halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, and
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
r 1 is selected from (C 1-6 -alkyl) 2 PO-, groups And a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3a is halo-C 1-6 -alkyl, and
R 3b is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, or
(Ii) A is pyridyl;
R 1 is selected from halogen, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-, groups And a group
R 2 is selected from hydrogen, halogen, and cyano;
R 3a is halo-C 1-6 -alkyl, and
R 3b is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, or
(Iii) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1, 2-dihydropyridinyl;
R 1 is selected from halo-C 1-6 -alkyl and halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, and
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is O or
(Ii) A is pyridyl;
r 1 is selected from halogen and halo-C 1-6 -alkyl;
r 2 is selected from hydrogen and halogen, or
(Iii) A is selected from pyrazinyl and pyrazolyl;
R 1 is halo-C 1-6 -alkyl, and
R 2 is hydrogen.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (CH 3)2 PO-and radicals
R 2 is selected from hydrogen, fluorine and CF 3;
R 3 is selected from methyl and CF 3, and
X is O or
(Ii) A is pyridyl;
R 1 is selected from fluorine and CF 3;
r 2 is selected from hydrogen and fluorine, or
(Iii) A is selected from pyrazinyl and pyrazolyl;
R 1 is CF 3, and
R 2 is hydrogen.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is O or
(Ii) A is pyridyl;
r 1 is selected from halogen and halo-C 1-6 -alkyl;
r 2 is selected from hydrogen and halogen, or
(Iii) A is selected from pyrazinyl and pyrazolyl;
R 1 is halo-C 1-6 -alkyl, and
R 2 is hydrogen, and
B is selected from:
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (CH 3)2 PO-and radicals
R 2 is selected from hydrogen, fluorine and CF 3;
R 3 is selected from methyl and CF 3, and
X is O or
(Ii) A is pyridyl;
R 1 is selected from fluorine and CF 3;
r 2 is selected from hydrogen and fluorine, or
(Iii) A is selected from pyrazinyl and pyrazolyl;
R 1 is CF 3, and
R 2 is hydrogen, and
B is selected from:
in one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, halo-C 1-6 -alkyl and cyano;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1, 2-dihydropyridinyl, [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyrazine, 1, 2-benzoxazole, 1H-indazole, 1H-imidazo [1,2-c ] pyrimidin-5-one, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,2-a ] pyrimidine, 2H-pyrazolo [3,4-c ] pyridine, 7H-pyrrolo [2,3-d ] pyrimidine, [1,2,4] triazolo [1,5-b ] pyrimidine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [4,3-b ] pyridine, 1H-imidazo [4,5-b ] pyridine, 3H-imidazo [4,5-b ] pyridine, 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine, 1H-pyrazolo [3,4-b ] pyridine, 1H-imidazo [1,2-a ] pyrimidin-5-one and 2H-indazole;
R 1 is selected from the group consisting of C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halo-C 1-6 -alkyl) - (3-to 6-membered heterocyclyl) -, halo-C 1-6 -alkoxy and a group
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1, 2-dihydropyridinyl, [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine, [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyridine, and indazole-1, 2H-b ] pyridine;
R 1 is selected from the group consisting of C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, and groups
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1, 2-dihydropyridinyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is pyridyl;
R 1 is selected from halogen, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-,
And a group
R 2 is selected from hydrogen, halogen, and cyano;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1, 2-dihydropyridinyl;
R 1 is selected from halo-C 1-6 -alkyl and halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, and
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl;
r 1 is selected from (C 1-6 -alkyl) 2 PO-, groups And a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3a is halo-C 1-6 -alkyl, and
R 3b is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is pyridyl;
R 1 is selected from halogen, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-, groups And a group
R 2 is selected from hydrogen, halogen, and cyano;
R 3a is halo-C 1-6 -alkyl, and
R 3b is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is O.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is pyridyl;
R 1 is selected from halogen and halo-C 1-6 -alkyl, and
R 2 is selected from hydrogen and halogen.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is selected from pyrazinyl and pyrazolyl;
R 1 is halo-C 1-6 -alkyl, and
R 2 is hydrogen.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl;
R 1 is selected from (CH 3)2 PO-and radicals
R 2 is selected from hydrogen, fluorine and CF 3;
R 3 is selected from methyl and CF 3, and
X is O.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is pyridyl;
r 1 is selected from fluorine and CF 3, and
R 2 is selected from hydrogen and fluorine.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
a is selected from pyrazinyl and pyrazolyl;
R 1 is CF 3, and
R 2 is hydrogen.
In a preferred embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein a is a 9 membered bicyclic heteroaryl group comprising 1 to 5 heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein a is a 9 membered bicyclic heteroaryl group containing 1 to 5 nitrogen atoms, the remaining ring atoms being carbon.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein a is a 9 membered bicyclic heteroaryl group containing 1 to 5 nitrogen atoms, the remaining ring atoms being carbon.
In a particularly preferred embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine, [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyrazine, 1, 2-benzoxazole, 1H-indazole and 2H-indazole.
In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from:
In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from:
In a preferred embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein B is
In a preferred embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein B is
In a preferred embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein B is
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
r 4 is selected from hydrogen, halogen and C 1-6 -alkyl, and
R 5 is selected from hydrogen and halogen.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
R 4 and R 5 are both hydrogen, or
R 4 and R 5 are both halogen, or
R 4 is C 1-6 -alkyl and R 5 is hydrogen.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
R 4 and R 5 are both hydrogen, or
R 4 and R 5 are both fluorine, or
R 4 is methyl and R 5 is hydrogen.
In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are both hydrogen.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are both fluoro.
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl and R 5 is hydrogen.
In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl and (halo-C 1-6 -alkyl) - (4-to 6-membered heterocyclyl), and
X is selected from O and NH, or
(Ii) A is pyridyl;
R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO-and groups
R 2 is selected from hydrogen, halogen, halo-C 1-6 -alkyl and cyano;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is selected from O and NH, or
(Iii) A is selected from the group consisting of 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 4-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1, 2-dihydropyridinyl, [1,2,4] triazolo [4,3-a ] pyridine, [1,2,4] triazolo [1,5-a ] pyridine, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, 2H-pyrazolo [3,4-b ] pyridine, 2H-pyrazolo [4,3-c ] pyridine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [3,4-d ] pyrimidine [1,2,4] triazolo [1,5-a ] pyrimidine, imidazo [1,2-a ] pyrazine, 1, 2-benzoxazole, 1H-indazole, 1H-imidazo [1,2-c ] pyrimidin-5-one, 1H-pyrrolo [2,3-b ] pyridine, imidazo [1,2-a ] pyrimidine, 2H-pyrazolo [3,4-c ] pyridine, 7H-pyrrolo [2,3-d ] pyrimidine, [1,2,4] triazolo [1,5-b ] pyrimidine, pyrazolo [1,5-a ] pyrimidine, 2H-pyrazolo [4,3-b ] pyridine, 1H-imidazo [4,5-b ] pyridine, 3H-imidazo [4,5-b ] pyridine, 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine, 1H-pyrazolo [3,4-b ] pyridine, 1H-imidazo [1,2-a ] pyrimidin-5-one and 2H-indazole;
R 1 is selected from the group consisting of C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halo-C 1-6 -alkyl) - (3-to 6-membered heterocyclyl) -, halo-C 1-6 -alkoxy and a group
R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;
r 3 is halo-C 1-6 -alkyl;
x is selected from O and NH;
R 4 and R 5 are both hydrogen, or
R 4 and R 5 are both halogen, or
R 4 is C 1-6 -alkyl and R 5 is hydrogen, and
B is selected from:
in a preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (C 1-6 -alkyl) 2 PO-and a group
R 2 is selected from hydrogen, halogen, and halo-C 1-6 -alkyl;
R 3 is selected from the group consisting of C 1-6 -alkyl and halo-C 1-6 -alkyl, and
X is O or
(Ii) A is pyridyl;
r 1 is selected from halogen and halo-C 1-6 -alkyl;
r 2 is selected from hydrogen and halogen, or
(Iii) A is selected from pyrazinyl and pyrazolyl;
R 1 is halo-C 1-6 -alkyl, and
R 2 is hydrogen;
r 4 and R 5 are both hydrogen, and
B is selected from:
In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:
(i) A is phenyl;
R 1 is selected from (CH 3)2 PO-and radicals
R 2 is selected from hydrogen, fluorine and CF 3;
R 3 is selected from methyl and CF 3, and
X is O or
(Ii) A is pyridyl;
R 1 is selected from fluorine and CF 3;
r 2 is selected from hydrogen and fluorine, or
(Iii) A is selected from pyrazinyl and pyrazolyl;
R 1 is CF 3, and
R 2 is hydrogen;
r 4 and R 5 are both hydrogen, and
B is selected from:
in one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethylsulfonyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (3, 5-difluoro-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-fluoro-3-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (4-fluoro-2-methylsulfonyl-phenyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (3-methylsulfonylphenyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (2-fluoro-4-methylsulfonyl-phenyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 3-dimethylphosphoryl-5- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
5- [ [2- [ (4 ar,8 as) -3-oxo-4, 4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazine-6-carbonyl ] -2-azaspiro [3.3] heptan-6-yl ] methyl ] -3- (trifluoromethyl) pyridine-2-carbonitrile;
5- [ [2- [ (4 ar,8 as) -3-oxo-4, 4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazine-6-carbonyl ] -2-azaspiro [3.3] heptan-6-yl ] methyl ] -2- (trifluoromethyl) pyridine-3-carbonitrile;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethylsulfonyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethylsulfonyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 ar,8 as) -6- [6- [ [5- (trifluoromethyl iminosulfonyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,3, 4-oxadiazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1H-1,2, 4-triazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- [1- (trifluoromethyl) cyclopropyl ] pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 3-fluoro-5- (trifluoromethyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- (trifluoromethoxy) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethoxy) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 2-oxo-4- (trifluoromethyl) -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 2-oxo-5- (trifluoromethyl) -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-methylsulfonyl-3-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-methylsulfonyl-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-dimethylphosphoryl-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1,2, 4-thiadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 2-methyl-5- (trifluoromethyl) triazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 1-methyl-5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 2-methyl-5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 1-methyl-3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (2, 2-trifluoroethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 1-methyl-4- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 5-methyl-3- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [1- (2, 2-trifluoroethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) pyrimidin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- (trifluoromethyl) pyrimidin-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) pyrimidin-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1,2, 4-oxadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) triazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-1,2, 4-triazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) oxazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (difluoromethyl) -5-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (difluoromethyl) -3-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-chloro-3-fluoro-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (3-chloro-5-fluoro-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (difluoromethyl) -1H-pyrazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-chloro-3-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-chloro-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-fluoro-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 3-fluoro-5- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 ar,8 as) -6- [6- [ [ 3-fluoro-5- (trifluoromethyiiminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
rac- (4 ar,8 as) -6- [6- [ [ 2-fluoro-4- (trifluoromethyiiminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 ar,8 as) -6- [6- [ [2- (methyliminosulfonyl) -4- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
rac- (4 ar,8 as) -6- [6- [ [4- (methyliminosulfonyl) -3- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 ar,8 as) -6- [6- [ [3- (methyliminosulfonyl) -5- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ 3-dimethylphosphoryl-5- (trifluoromethyl) benzyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- ([ S (R) ] -trifluoromethyl iminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- ([ S (S) ] -trifluoromethyl iminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- ([ S (S) ] -trifluoromethyl iminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- ([ S (R) ] -trifluoromethyl iminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- ([ S (R) ] -trifluoromethyl iminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- ([ S (S) ] -trifluoromethyl iminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- ([ S (S) ] -trifluoromethyl iminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- ([ S (R) ] -trifluoromethyl iminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 ar,8 as) -6- [6- [ [ 4-fluoro-2- (methyliminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (3-dimethylphosphoryl-5-fluoro-phenyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 ar,8 as) -6- [6- [ [4- (methyliminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 ar,8 as) -6- [6- [ [3- (methyliminosulfonyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (3-dimethylphosphorylphenyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ [5- (trifluoromethyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ (3, 5-difluoro-2-pyridinyl) methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ (5-fluoro-2-pyridinyl) methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ [6- (difluoromethoxy) -3-pyridinyl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
5- [ [ (6S) -2- [ (4 ar,8 as) -3-oxo-4, 4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazine-6-carbonyl ] -2-azaspiro [3.4] oct-6-yl ] methyl ] -2- (trifluoromethyl) pyridine-4-carbonitrile;
5- [ [ (6R) -2- [ (4 ar,8 as) -3-oxo-4, 4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazine-6-carbonyl ] -2-azaspiro [3.4] oct-6-yl ] methyl ] -2- (trifluoromethyl) pyridine-4-carbonitrile;
(4 ar,8 as) -6- [ (6S) -6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [ (6R) -6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [ (6R) -6- [ [4- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [ (6R) -6- [ [3- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [5- (trifluoromethyl) pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [6- (trifluoromethoxy) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [ 2-oxo-4- (trifluoromethyl) -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [5- (trifluoromethylsulfonyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [4- (trifluoromethyl) oxazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [4- (trifluoromethyl) imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [3- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ (3-chloro-5-fluoro-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ (5-chloro-3-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [7- [ (5-fluoro-2-pyridinyl) methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [7- [ [5- (trifluoromethyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) imidazo [1,2-a ] pyrazin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [4,3-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-indazol-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [4,3-c ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-indazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) imidazo [1,5-a ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [1- (trifluoromethyl) indazol-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) benzo [ d ] isoxazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) imidazo [1,2-a ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 3-methoxy-5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 1-methyl-3- (trifluoromethyl) pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (4-trifluoromethylsulfonylpyrazol-1-yl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-7-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 1-cyclopropyl-3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 ar,8 as) -6- [6- [ [4- (trifluoromethyiminosulfonyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) - [1,2,4] triazolo [1,5-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (2, 2-trifluoroethyl) triazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 2-methyl-4- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) thiazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [1- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ 3-methanesulfonyl-5- (trifluoromethyl) benzyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [1- (2-hydroxyethyl) -3- (trifluoromethyl) pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 as,8 ar) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,3, 4-oxadiazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [ 2-methoxy-6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (1R) -1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (1S) -1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [2- (trifluoromethyl) -4-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [2- (trifluoromethyl) pyrimidin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) - [1,2,4] triazolo [1,5-a ] pyridin-7-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-c ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) imidazo [1,2-a ] pyridin-7-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [4- [3- (trifluoromethyl) azetidin-1-yl ] sulfonylbenzyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- [1- (trifluoromethyl) cyclopropyl ] -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- [1- (trifluoromethyl) cyclopropyl ] -4-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [6- (trifluoromethoxy) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [1- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ 3-methanesulfonyl-4- (trifluoromethyl) benzyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) imidazo [1,2-a ] pyrimidin-7-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [ 2-methoxy-5- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [3- (trifluoromethyl) azetidin-1-yl ] pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) benzo [ d ] isoxazol-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 2-keto-4- [1- (trifluoromethyl) cyclopropyl ] -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-keto-1H-imidazo [1,2-c ] pyrimidin-7-yl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [5- (trifluoromethyl) pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [1- (2, 2-trifluoroethyl) -1,2, 4-triazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ difluoro- [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 2-oxo-5- [1- (trifluoromethyl) cyclopropyl ] -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 5-oxo-1- (2, 2-trifluoroethyl) imidazo [1,2-a ] pyrimidin-7-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) - [1,2,4] triazolo [1,5-b ] pyridazin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) imidazo [1,2-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ [2- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ [2- (trifluoromethyl) imidazo [1,2-a ] pyrazin-6-yl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ [3- (trifluoromethyl) -1H-pyrazolo [4,3-c ] pyridin-6-yl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [7- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [2- [ [3- (trifluoromethyl) -1H-pyrazolo [4,3-b ] pyridin-5-yl ] methyl ] -7-azaspiro [3.5] nonane-7-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [2- [ [3- (trifluoromethyl) -1H-pyrazolo [4,3-c ] pyridin-6-yl ] methyl ] -7-azaspiro [3.5] nonane-7-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [2- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl ] methyl ] -7-azaspiro [3.5] nonane-7-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [2- [ [2- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-6-yl ] methyl ] -7-azaspiro [3.5] nonane-7-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) -3H-imidazo [4,5-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) -1H-imidazo [4,5-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- (1H-pyrazolo [4,3-b ] pyridin-5-ylmethyl) -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (5-methoxypyrrolo [2,3-c ] pyridin-1-yl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 1-methyl-3- (trifluoromethyl) pyrazolo [3,4-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
Rac- (4 aR,8 aS) -6- [7- [ [2- (trifluoromethyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.5] nonane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one, and
(4 Ar,8 as) -6- [6- [ [4- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a preferred embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:
(4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (3, 5-difluoro-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ (2-fluoro-4-methylsulfonyl-phenyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [ 3-dimethylphosphoryl-5- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [ (6R) -6- [ [4- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one;
(4 aR,8 aS) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one, and
(4 Ar,8 as) -6- [ (6R) -6- [ [3- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 aR,8 aS) -6- [6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 ar,8 as) -6- [6- [ (3, 5-difluoro-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 aR,8 aS) -6- [6- [ [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 ar,8 as) -6- [6- [ (2-fluoro-4-methylsulfonyl-phenyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 aR,8 aS) -6- [6- [ [ 3-dimethylphosphoryl-5- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 aR,8 aS) -6- [ (6R) -6- [ [4- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 aR,8 aS) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 aR,8 aS) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particularly preferred embodiment, the invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4 aR,8 aS) -6- [ (6R) -6- [ [3- (trifluoromethylsulfonyl) phenyl ] methyl ] -2-azaspiro [3.4] octane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one.
In a particular embodiment, the present invention provides pharmaceutically acceptable salts, especially hydrochloride salts, of the compounds of formula (I) as described herein. In another particular embodiment, the present invention provides a compound of formula (I) as described herein.
In some embodiments, the compounds of formula (I) are isotopically labeled by wherein one or more atoms are replaced by atoms having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to 2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I and 125 I, respectively. Certain isotopically-labeled compounds of formula (I) (e.g., those containing a radioisotope) are useful in pharmaceutical and/or matrix tissue distribution studies. The radioactive isotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this because they are easy to incorporate and detection means are off-the-shelf. For example, the compound of formula (I) may be enriched in 1,2, 5, 10, 25, 50, 75, 90, 95 or 99% of a given isotope.
Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
Substitution with positron emitting isotopes such as 11C、18F、15 O and 13 N can be used in Positron Emission Tomography (PET) studies for examination of substrate receptor occupancy. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using suitable isotopically-labelled reagents in place of the non-labelled reagents previously used, analogous to those described in the examples as set forth below.
Preparation process
The preparation of the compounds of formula (I) according to the invention can be carried out sequentially or in a concurrent synthetic route. The synthesis of the present invention is shown in the following general scheme. The skills required to perform the reaction and purify the resulting product are known to those skilled in the art. Unless indicated to the contrary, substituents and indices used in the following process descriptions have the meanings provided herein.
If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, the introduction of appropriate protecting groups can be applied prior to the critical step by methods well known in the art (as described in "Protective Groups in Organic Chemistry" by t.w.greene and p.g.m.wutts, 5 th edition, 2014, john Wiley & Sons, n.y.). Such protecting groups can be removed later in the synthesis using standard methods described in the literature.
If the starting material or intermediate contains a stereogenic center, the compounds of formula (I) may be obtained as diastereomers or mixtures of enantiomers, which may be separated by methods well known in the art (e.g., chiral HPLC, chiral SFC, or chiral crystallization). The racemic compounds can be separated, for example, by diastereomeric salts into the corresponding counterparts by crystallization with optically pure acids, or by specific chromatography using chiral adsorbents or chiral eluents to separate the enantiomers. Starting materials and intermediates containing stereogenic centers can also be isolated to provide diastereomerically/enantiomerically enriched starting materials and intermediates. The use of such diastereomerically/enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally result in the corresponding diastereomerically/enantiomerically enriched compounds of formula (I).
Those skilled in the art will recognize that in the synthesis of the compounds of formula (I), if not desired, an "orthogonal protecting group strategy" will be applied which allows cleavage of multiple protecting groups at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been reported in the literature (e.g., barany and R.B.Merrifield, J.Am.Chem.Soc.1977,99,7363;H.Waldmann et al, angel. Chem. Int. Ed. Engl.1996,35,2056).
Those skilled in the art will recognize that the order of the reactions may vary depending on the reactivity and nature of the intermediates.
In more detail, the compounds of formula (I) may be manufactured by the methods given below, by the methods given in the examples or by similar methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. Also, the reaction conditions reported in the literature that affect the reaction are described, for example, in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2 nd edition, richard c.larock. John Wiley & Sons, new York, ny.1999. It is convenient to carry out the reaction in the presence or absence of a solvent. The nature of the solvent used is not particularly limited as long as it does not adversely affect the reaction or the reagents involved and can dissolve the reagents at least to some extent. The reactions described can occur over a wide temperature range and the exact reaction temperature is not critical to the invention. The above reaction can be conveniently carried out in a temperature range of-78 ℃ to reflux. The time required for the reaction may also vary widely, depending on many factors, in particular the reaction temperature and the nature of the reagents. But generally requires a period of 0.5 hours to several days to obtain the intermediates and compounds. The reaction sequence is not limited to the sequence shown in the scheme, but the sequence of the reaction steps may be freely changed depending on the starting materials and their corresponding reactivities.
If the starting materials or intermediates are not commercially available or their synthesis is not reported in the literature, they can be prepared using existing preparation methods similar to the close analogs or as outlined in the experimental section.
The following abbreviations are used in this text:
Acoh=acetic acid, acn=acetonitrile, bn=benzyl, binap= (2, 2 '-bis (diphenylphosphino) -1,1' -binaphthyl), boc=tert-butoxycarbonyl, CAS rn=chemical abstracts accession number, cbz=benzyloxycarbonyl, cs 2CO3 =cesium carbonate, co=carbon monoxide, cucl=cuprous chloride (I), cucn=cuprous cyanide (I), cui=cuprous iodide (I), dabco=1, 4-diazabicyclo [2.2.2] octane; triethylene diamine, dast= (diethylamino) sulfur trifluoride, dbu=1, 8-diazabicyclo [5,4,0] undec-7-ene, dce=1, 2-dichloroethane, dead=diethyl azodicarboxylate, diad=diisopropyl azodicarboxylate, DIBAL-h=diisobutylaluminum hydride, dmap=4-dimethylaminopyridine, dme=dimethoxyethane, dmea=n, N '-dimethylethylenediamine, dmf=n, N-dimethylformamide, dipea=n, N-diisopropylethylamine, dppf=1, 1-bis (diphenylphosphino) ferrocene, edc.hcl=n- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, ei=electron bombardment, esi=electrospray ionization, etoac=ethyl acetate, etoh=h=hour, fa=formic acid, H 2 o=water, esi=sulfuric acid, HATU = 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N, N' -tetramethyl-uronium-hexafluoro-phosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-1H-benzotriazole; HPLC = high performance liquid chromatography, iPrMgCl = isopropyl magnesium chloride, i2 = iodine, IPA = 2-propanol, ISP = ion spray positive (mode), ISN = ion spray negative (mode), K 2CO3 = potassium carbonate, KHCO 3 = potassium bicarbonate, KI = potassium iodide, KOH = potassium hydroxide, K 3PO4 = tripotassium phosphate, liAlH 4 or LAH = lithium aluminum hydride, liHMDS = lithium bis (trimethylsilyl) amide, liOH = lithium hydroxide, mCPBA = m-chloroperoxybenzoic acid, mgSO 4 = magnesium sulfate, min = minutes, mL = milliliters, MPLC = medium pressure liquid chromatography, MS = mass spectrometry, MTBE = tert-butyl methyl ether, nBuLi = N-butyl lithium, naBH 3 CN = cyano sodium borohydride, naH = sodium hydride, NBS = N-bromosuccinimide, naHCO 3, sodium bicarbonate, no 2 = sodium nitrite, naBH (OAc) 3 = sodium triacetoxyborohydride, naOH = sodium hydroxide, sodium carbonate, na = 2CO3 sodium hydroxide, na = sodium sulfonate, na = 2SO4 = sodium sulfonate, na = sodium sulfonate = sodium 6857, NH 4 cl=ammonium chloride, nmp=n-methyl-2-pyrrolidone, oac=acetoxy, T3 p=propylphosphonic anhydride, pe=petroleum ether, pg=protecting group, pd—c=palladium on activated carbon, pdCl2 (dppf) -CH 2Cl2 =1, 1 '-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex, pd 2(dba)3 =tris (dibenzylideneacetone) dipalladium (0), pd (OAc) 2 =palladium (II) acetate, pd (OH) 2 =palladium hydroxide, pd (PPh 3)4 =tetrakis (triphenylphosphine) palladium (0), pmp=1, 2, 6-pentamethylpiperidine, ptsa=p-toluenesulfonic acid, r=any group, rp=reverse phase, rt=room temperature, sfc=supercritical fluid chromatography, S-phos=2-dicyclohexylphosphino-2', 6 '-dimethoxybiphenyl, tbai=tetrabutylammonium iodide, tea=triethylamine, tfa=trifluoroacetic acid, thf=tetrahydrofuran, tmeda=n, N' -tetramethyl ethylenediamine, TS-tpp=triphenylphosphine-polymer bonding, znCl 2 =zinc chloride, hal=halogen, preparative tlc=preparative thin layer chromatography.
The compounds of formula I of the present invention can be prepared by reacting an activated intermediate of formula 2 with nucleophilic spiro cyclic amine 1 in the presence of a base such as DIPEA in a solvent such as DMF or CH 3 CN with heating. (scheme 1). Alternatively, an activated intermediate may be formed on the other coupling partner (1), which will produce the urea of formula I.
Scheme 1
The activated intermediate 2 may be formed instantaneously in the reaction mixture or by reacting the amine 3 with a coupling agent such as bis (1H-1, 2, 4-triazol-1-yl) methanone (4) in the presence of a base such as DIPEA in a solvent such as acetonitrile (scheme 2). Alternatively, the same strategy as in schemes 1 and 2 can be used, but prior to coupling with amine 3, the activation intermediate is first built on spiro amine 1.
Scheme 2
The structural unit of formula 1 can be produced by a Suzuki reaction (e.g. Pd (dppf) Cl 2、K2CO3, dioxane/H 2 O), (X=Br, I), followed by hydrogenation (e.g. Pd/C, H 2) and deprotection (e.g. using TsOH or TFA when PG=Boc) (scheme 3). The desired borate intermediate 5 can be produced by reacting a ketone with 4, 5-tetramethyl-2- [ (tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methyl ] -1,3, 2-dioxapentaborane (LiTMP, THF, -78 ℃). In the case of a=n linked heteroaryl, a Chan-Lam type coupling can be used instead of the Suzuki reaction (e.g. Cu (OAc) 2 under an oxygen atmosphere) followed by hydrogenation/deprotection. A similar sequence can also be used to generate structural units in which, for example, R 4 = Me and R 5 = H starting from a suitably functionalized borate 5 (in which there is an additional Me group on the alkene carbon with the borate). In some cases, where a = heteroaryl group with a free N-H group (e.g., N-H pyrazole or fused N-H pyrazole), it is beneficial to use an additional protecting group on the N-H group (e.g., SEM protection, which can be introduced using standard techniques, and which can typically be deprotected in a final deprotection step under acidic conditions).
Scheme 3
Alternatively, a building block of formula 1 (wherein a=n linked heteroaryl) can be prepared by reacting a nucleophilic heterocycle a (8) with a suitably protected building block 9 (x=leaving group, such as OMs, I, br) in the presence of a base such as Cs 2CO3, followed by deprotection under standard conditions (e.g., using TsOH when pg=boc) (scheme 4). Typically, mesylate building block 9 (x=oms) is used, which can be conveniently formed from hydroxy analogs by reaction with MsCl in the presence of a weak base such as Et 3 N.
Scheme 4
Alternatively, the building block of formula 1 (wherein a=n linked heteroaryl) can be prepared by Mitsunobu-type reaction of heterocycle a (8) with hydroxy building block 10 (e.g. using diisopropyl azodicarboxylate and triphenylphosphine, or Tsunoda reagent (cyanomethylene tributylphosphine)), followed by deprotection under standard conditions (e.g. using TsOH when pg=boc). (scheme 5) alternatively, the structural unit of formula 1 can be prepared by converting the hydroxy structural unit 10 to a mesylate (e.g., using MsCl, et 3 N), followed by S N reaction with heterocycle a (8) in the presence of a base such as NaH.
Scheme 5
Alternatively, the structural unit of formula 1 (wherein a is a C-linked heteroaryl group) may be generated using standard heterocyclic synthesis techniques, for example starting from a suitable carboxylic acid (11) or ester, nitrile (12) or diketone (13) derivative. The nitrile derivative can be produced from the hydroxy derivative (10) via conversion to a mesylate (e.g., using MsCl, et 3 N) followed by S N 2 substitution of the mesylate group with cyanide (e.g., using KCN). The diketone derivative can be formed from the ester derivative (14). (scheme 6)
Scheme 6
The (hetero) aryltrifluoromethyl cyclopropyl structural unit 15 is generally not available but is generated from the halide structural unit 16 (x= I, br) via a Suzuki reaction with 1- (trifluoromethyl) vinylboronic acid to give 17. Cyclopropanation with diphenyl (methyl) sulfonium tetrafluoroborate and LiHMDS gives the desired structural unit 15. (scheme 7) this sequence can also be carried out between the steps of other synthetic schemes, for example for N-linked heteroaryl ring a, these functionalization steps can also be carried out simultaneously with the preparation of the structural unit of formula 1, after the Chan-Lam coupling/hydrogenation sequence but before the final deprotection (see scheme 3). Alternatively, the (hetero) aryltrifluoromethyl cyclopropyl building block can be generated from a commercial building block via standard heterocyclic synthesis techniques.
Scheme 7
The structural unit of formula 18, wherein R 4＝R5 = F, can be generated via deoxofluorination of the appropriate ketone 20 (e.g., using DAST (diethylaminosulfur trifluoride)) followed by appropriate deprotection (e.g., using TsOH or TFA, wherein PG = Boc). The ketone can be generated using oxidation of the benzyl CH 2 group on the appropriate intermediate 19 (generated in scheme 3) (e.g., using SeO 2), or alternatively via nucleophilic attack of Weinreb amine 23 by a suitable metallized anionic derivative of (hetero) aryl 22. Intermediate 22 can be formed from a suitable halo (hetero) aryl derivative 21 (x=br, I, cl) via metallization (e.g., using nBuLi).
(Scheme 8)
Scheme 8
In some cases, where a = fused (hetero) aryl, the introduction of a suitably substituted monocyclic a-ring is introduced as detailed above (e.g., scheme 3), followed by the introduction of a fused (hetero) aryl ring using standard heterocyclic synthesis techniques (e.g., substituted (hetero) aryl ring a with both ketone and o-fluoro groups may be cyclized to fused oxazole using hydroxylamine hydrochloride), the introduction of a fused (hetero) aryl typically occurs in the middle of an existing synthesis step, most commonly prior to deprotection of structural unit 1.
In some cases, the compounds of formula I may be further functionalized to give other compounds of formula I. For example, compounds of formula I carrying a (hetero) aryl bromide or iodide may be further functionalized with other groups (e.g., amines, or alkyl groups) using metal catalyzed cross coupling conditions such as Buchwald or Suzuki reactions.
In some cases, building blocks can be formed from commercially available fragments using standard functional group interconversion techniques (e.g., installing halides (e.g., using NIS or NBS), removing halides (e.g., under hydrogenation conditions), converting halides to other groups (e.g., small amines, small alkyl groups) using metal catalyzed cross-coupling conditions such as Buchwald or Suzuki reaction, converting iodides to trifluoromethyl groups using trifluoromethyl reagents (e.g., diphenyl (trifluoromethyl) sulfonium triflate), installing and removing protecting groups, hydrolyzing esters to acids, generating amides from acids and small amines, converting boron-containing groups to hydroxyl groups using alkaline peroxide conditions, cycloaddition of azido trimethylsilane to nitriles to tetrazoles, obtaining bromides by Sandmeyer reaction of aniline, oxidizing sulfides to sulfones, oxidizing sulfides to sulfoxides using PhI (OAc) 2 and NH 2COONH4, alkylating hydroxyl or amine groups via S N reaction or reductive amination, alkylating hydroxyl or amine groups using carbonyl or sulfonium triflate groups, coupling with a boronic acid-base such as methyl iodide or an aromatic ring-base such as in place of the place of a boronic acid-base such as in the case of p-N-35 m 4 or a cyclic alkyl or a boronic acid-base such as methyl-35 m-37, or a 4-base-methyl-4-or a coupling condition such as in place of a boronic acid-base-to a base-methyl-p-N-propyl group. Such techniques can also be used to elaborate commercially available fragments before, after, or in the middle of the above-described synthetic sequence reactions.
In one aspect, the present invention provides a process for the manufacture of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, which process comprises:
(a) Allowing an amine of formula 1B, wherein R 1、R2、R4、R5, A and B are as described herein,
With 6- (1, 2, 4-triazole-1-carbonyl) -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (2),
In the presence of a base, or
(B) 4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one (2 b)
And a compound of formula 1c, wherein R 1、R2、R4、R5, A and B are as described herein,
In the presence of a base, and reacting,
To form said compound of formula (I).
In one embodiment, the present invention provides a process for the manufacture of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein, comprising:
(a) Allowing an amine of formula 1, wherein R 1、R2, A and B are as described herein,
With 6- (1, 2, 4-triazole-1-carbonyl) -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (2),
In the presence of a base, or
(B) 4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one (2 a)
And a compound of formula 1a, wherein R 1、R2, A and B are as described herein,
In the presence of a base, and reacting,
To form said compound of formula (I).
In one embodiment, the base is DIPEA.
In one embodiment, the steps (a) or (b) are performed in a solvent, preferably DMF or CH 3 CN.
In one embodiment, the amine of formula 1 is obtained by
(C) Allowing a compound of formula 6, wherein R 1、R2 and a are as defined herein, and wherein X is bromo or iodo;
and a borate of formula 5, wherein B is as defined herein and R is C 1-6 -alkyl;
Suzuki coupling in the presence of a base and a palladium catalyst to form a compound of formula (7) wherein R 1、R2, A and B are as defined herein and PG is a suitable amino protecting group,
Subsequently:
(d) Hydrogenating the compound of formula 7 to obtain a compound of formula 7a,
And
(E) Removing the amino protecting group PG from the compound of formula 7a to give the compound of formula 1.
In one embodiment, the palladium catalyst in step (c) is selected from PdCl (crotyl) (PtBu 3) and Pd (dppf) Cl 2.
In one embodiment, the base in step (c) is K 2CO3.
In one embodiment, the Suzuki coupling of step (c) is performed in a solvent mixture comprising dioxane and water.
In one embodiment, the suitable amino protecting group is t-Butoxycarbonyl (BOC).
In one embodiment, the hydrogenation in step (d) is performed under a hydrogen atmosphere using palladium on carbon as catalyst.
In one embodiment, the hydrogenation in step (d) is performed at an elevated hydrogen pressure, preferably about 22800 mmHg.
In one embodiment, the hydrogenation in step (d) is performed in ethyl acetate.
In one embodiment, the suitable amino protecting group PG is BOC and is removed in step (e) using p-toluene sulfonic acid.
In one embodiment, the amine of formula 1 is obtained by
(C1) Allowing the amine of 8
With an alcohol of formula 9, wherein PG is a suitable amino protecting group
Carrying out a Mitsunobu type reaction in the presence of a phosphine and a dialkyl azodicarboxylate;
to form a compound of formula 10 wherein PG is a suitable amino protecting group;
And
(D1) Removing the amino protecting group PG from the compound of formula 10 to obtain the compound of formula 1.
In one embodiment, the phosphine is triphenylphosphine.
In one embodiment, the dialkyl azodicarbonate is selected from the group consisting of DEAD and DIAD.
In one embodiment, the Mitsunobu-type reaction is carried out in a solvent, preferably THF.
In one embodiment, the suitable amino protecting group PG is BOC and is removed in step (d 1) using p-toluene sulfonic acid.
In one aspect, the present invention provides a compound of formula (I) as described herein, produced according to any one of the methods described herein.
MAGL inhibitory Activity
The compounds of the invention are MAGL inhibitors. Accordingly, in one aspect, the present invention provides the use of a compound of formula (I) as described herein for inhibiting mamgl in a mammal.
In another aspect, the invention provides a compound of formula (I) as described herein for use in a method of inhibiting mamgl in a mammal.
In another aspect, the invention provides the use of a compound of formula (I) as described herein for the manufacture of a medicament for inhibiting maml MAGL.
In another aspect, the invention provides a method for inhibiting MAGL in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.
The inhibitory activity of the compounds of formula (I) according to the invention on MAGL is analyzed by determining the enzymatic activity after hydrolysis of the natural substrate 2-arachidonoyl glycerol to give arachidonic acid, which can be subsequently analyzed by mass spectrometry. This assay is hereinafter abbreviated as "2-AG assay".
The 2-AG assay was performed in 384 well assay plates (PP, greiner catalog number 784201) in a total volume of 20. Mu.L. In polypropylene plates, compound dilutions were prepared in 100% DMSO (VWR CHEMICALS 23500.297) using a 3-fold dilution step to give final concentrations ranging from 12.5 μm to 0.8pM. mu.L of compound dilution (100% DMSO) was added to 9. Mu.L of MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1mM EDTA (Fluka, 03690-100 ml), 0.01% (v/v) Tween). After shaking, the plates were incubated for 15min at RT. mu.L of the assay buffer solution of 2-arachidonyl glycerol was added to start the reaction. The final concentrations in this assay were 50pM MAGL and 8. Mu.M 2-arachidonyl glycerol. After shaking and incubation for 30 minutes at RT, the reaction was quenched by the addition of 40. Mu.L of acetonitrile containing 4. Mu. M d 8-arachidonic acid. The arachidonic acid content was tracked using an online SPE system (AGILENT RAPIDFIRE) in combination with a triple quadrupole mass spectrometer (Agilent 6460). In the acetonitrile/water liquid position, a C18SPE cartridge (G9205A) was used. The mass spectrometer was operated in a negative electrospray mode with a mass ion pair of arachidonic acid of 303.1→259.1 and a mass ion pair of d 8-arachidonic acid of 311.1→ 267.0. The activity of the compounds was calculated based on the intensity ratio of [ arachidonic acid/d 8-arachidonic acid ].
TABLE 1
In one aspect, the invention provides a compound of formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, wherein the compound of formula (I) and pharmaceutically acceptable salts or esters thereof has a MAGL inhibition IC 50 of less than 25 μm, preferably less than 10 μm, more preferably less than 5 μm, as measured in the MAGL assay described herein.
In one embodiment, the compounds of formula (I) and pharmaceutically acceptable salts or esters thereof as described herein have an IC 50 (MAGL inhibition) value between 0.000001 μm and 25 μm, the specific compound has an IC 50 value between 0.000005 μm and 10 μm, further the specific compound has an IC 50 value between 0.00005 μm and 5 μm, as measured in the MAGL assay described herein.
P app (passive permeability measurement) was obtained as part of a unidirectional P-gp screen
Description of the experiment
It is generally determined that transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human or mouse P-gp are used, cultured on 96 Kong Bantou filter plates, where they form polarized monolayers with tight junctions and act as barriers between the apical and basal compartments.
P-gp is expressed in a monolayer of apical membrane.
The compactness of the cell monolayer and the functional activity of P-gp were confirmed by the addition of the cell impermeable markers, fluorescence yellow and reference P-gp substrate Ai Duosha class, respectively.
The assay was fully automated on a Tecan liquid handling robot.
Data analysis and interpretation
For the substrate test, the assay determines the one-way permeability of the test compound by administration to the apical (i.e., donor compartment) side of the cell monolayer in the absence and presence of (P app a > B equation 1), measuring the movement of the compound into the basolateral (i.e., receiver) compartment in the presence and absence of the specific P-gp inhibitor zosuquidar, and incubating for 3 hours at 37 ℃. The effect of P-gp was measured by expressing the top-end efflux rate (AP-ER, equation 2). The average permeability (P app) was determined by zosuquidar conditions in the absence of P-gp. The extent of excretion and permeability characteristics of the compounds were then classified using AP-ER and average P app (Table 2).
Equation 1.P app, A, C0 and dQ/dt represent apparent permeability, filter surface area, initial concentration and delivery per time period, respectively. The P app value is calculated from a single point in time.
Equation 2. The top-end outflow rate (AP-ER) was calculated. Papp, inh (A > B) is the permeability value from the tip to the basolateral direction in the presence of inhibitor, and Papp (A > B) is the permeability value from the tip to the basolateral direction in the absence of inhibitor.
Results
The compounds of the present invention surprisingly show reduced P app compared to the compounds disclosed in WO2020104494, while retaining overall drug-like properties. Thus, the passive permeability (P app) of the compounds disclosed in WO2020104494 is typically in the range of 250nm/s to 350nm/s (table 2), at which time setting the exposure gradient across the tissue becomes extremely challenging. In contrast, the passive permeability of the compounds of the invention is typically in the range of 30nm/s to 250nm/s (Table 3), more preferably in the range of 50nm/s to 200nm/s, which when combined with other suitable properties is capable of setting an exposure gradient across the tissue.
TABLE 2
WO2020104494 Papp(nm/s)
Example 49 253
Example 51 258
Example 72 262
Example 50 267
Example 53 274
Example 71 300
Example 25 293
EXAMPLE 23 265
TABLE 3 Table 3
A reduction in P app is also observed due to the novel combination of heteroaryl groups with CR 4R5 linkers, compared to the heteroaryl analogs disclosed in WO2020104494 (where l=o), wherein R 4 and R 5 are as defined herein. Comparing example 25 of pair WO2020104494 with inventive example 3, P app surprisingly decreases from 293nm/s to 133nm/s.
Use of the compounds of the invention
In one aspect, the present invention provides a compound of formula (I) as described herein for use as a therapeutically active substance.
In another aspect, the invention provides a compound of formula (I) as described herein for use in the treatment or prevention of diseases and conditions associated with MAGL.
In another aspect, the invention provides a method for treating or preventing diseases and conditions associated with MAGL, comprising administering to a mammal an effective amount of a compound of formula (I) as described herein.
In another aspect, the invention provides the use of a compound of formula (I) as described herein for the treatment or prophylaxis of diseases and conditions associated with MAGL.
In another aspect, the invention provides the use of a compound of formula (I) as described herein in the manufacture of a medicament for the treatment or prophylaxis of diseases and conditions associated with MAGL.
In one embodiment, the diseases and conditions associated with MAGL are selected from the group consisting of neuroinflammation, neurodegenerative diseases, pain, cancer, psychotic disorders, multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, gut motility, visceral pain, fibromyalgia, endometriosis, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and/or kidney disease.
In one embodiment, the diseases and conditions associated with MAGL are selected from neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders.
In one embodiment, the diseases and conditions associated with MAGL are selected from multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, gut motility, visceral pain, fibromyalgia, endometriosis, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, rheumatoid arthritis, osteoarthritis, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, and/or kidney disease.
In a preferred embodiment, the diseases and conditions associated with MAGL are selected from inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, visceral pain, fibromyalgia, endometriosis, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and/or kidney disease.
In a preferred embodiment, the diseases and conditions associated with MAGL are selected from inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, abdominal pain, and/or abdominal pain associated with irritable bowel syndrome.
In a preferred embodiment, the diseases and conditions associated with MAGL are selected from visceral pain, endometriosis, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.
In a preferred embodiment, the diseases and conditions associated with MAGL are selected from endometriosis, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.
In a particularly preferred embodiment, the disease and condition associated with MAGL is endometriosis.
In a particularly preferred embodiment, the disease and condition associated with MAGL is pain associated with rheumatoid arthritis.
In a particularly preferred embodiment, the disease and condition associated with MAGL is pain associated with osteoarthritis.
In a particularly preferred embodiment, the diseases and conditions associated with MAGL are inflammatory bowel diseases.
In a particularly preferred embodiment, the diseases and conditions associated with MAGL are symptoms associated with inflammatory bowel disease.
In a particularly preferred embodiment, the diseases and conditions associated with MAGL are intestinal motility.
In a particularly preferred embodiment, the disease and condition associated with MAGL is abdominal pain.
In a particularly preferred embodiment, the disease and condition associated with MAGL is abdominal pain associated with irritable bowel syndrome.
Pharmaceutical composition and administration
In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.
The compounds of formula (I) and pharmaceutically acceptable salts and esters thereof are useful as medicaments (e.g., in the form of pharmaceutical formulations). The pharmaceutical formulations may be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays) or intrarectally (e.g., in the form of suppositories). But may also be administered parenterally, such as intramuscularly or intravenously (e.g., in the form of injection solutions).
The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants to form tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof (talc, stearic acid or its salts etc.) can be used, for example, as such adjuvants for tablets, dragees and hard gelatine capsules.
Suitable auxiliaries for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols etc.
Suitable adjuvants for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
Suitable auxiliaries for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.
Suitable auxiliaries for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.
In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffer masks or antioxidants. They may also contain other therapeutically valuable substances.
The dosage may vary within wide limits and will of course be adapted to the various requirements in each particular case. In general, a daily dose of about 0.1 to 20mg per kg body weight, preferably about 0.5 to 4mg per kg body weight (e.g. about 300mg per person) for oral administration should be suitable, which is preferably divided into 1-3 separate doses (which may consist of e.g. the same amount). It will be apparent that the upper limit set forth herein may be exceeded when shown as indicated.
Tablet formulation (wet granulation)
Preparation procedure
1. Items 1,2, 3 and 4 were mixed and granulated with purified water.
2. The pellets were dried at 50 ℃.
3. The particles are passed through a suitable milling apparatus.
4. Add item 5 and mix for three minutes and press on a suitable press.
Capsule preparation
Preparation procedure
1. Items 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.
2. Items 4 and 5 were added and mixed for 3 minutes.
3. Filled into suitable capsules.
Examples
The invention will be more fully understood by reference to the following examples. However, the claims should not be construed as being limited to the scope of the examples.
In the case of preparation examples obtained as mixtures of enantiomers, the pure enantiomers may be separated by methods described herein or by methods known to the person skilled in the art, such as chiral chromatography (e.g. chiral SFC) or crystallization.
All reaction examples and intermediates were prepared under argon atmosphere, if not otherwise stated.
Examples were generated using urea coupling between structural units A.X and P.X. The structural units a.1 and a.2 may be used interchangeably as the free base or as a suitable salt (e.g. hydrochloride, tartrate) as shown in the representative examples below.
Example 1
(4 Ar,8 as) -6- [6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one
To a solution of (4 aR,8 aS) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-6-ium-3-one, (2S, 3S) -2, 3-bis [ (4-methylbenzoyl) oxy ] butanedioic acid, (2S, 3S) -4-hydroxy-2, 3-bis [ (4-methylbenzoyl) oxy ] -4-oxo-butanoic acid ester, hydrate (structural unit A.1;56mg,0.06mmol,1eq, CAS 2626262663-49-9) and DIEA (54 mg,0.42mmol,7 eq) in acetonitrile (1 mL) was added bis (1, 2, 4-triazol-1-yl) methanone (13mg,0.078mmol,1.3eq,CAS 41864-22-6). The reaction mixture was stirred at 30 ℃ for 2h. After addition of p-toluenesulfonic acid, 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane (structural unit P.1;36mg,0.06mmol,1 eq) stirring was continued at 50℃overnight. The crude material was purified by preparative HPLC (YMC-Triart C, 12nm,5 μm,100X 30mm, ACN/water+0.1% HCOOH). The product was concentrated in vacuo to give (4 ar,8 as) -6- [6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (11 mg,100% purity, 41% yield) as a colorless gum. MS (ESI) m/z=440.2 [ M+H ] +.
Example 12
(4 Ar,8 as) -6- [6- [ [5- (trifluoromethylsulfonyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one
To a solution of (4 aR,8 aS) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one (10 mg, 64. Mu. Mol,1eq, CAS 2377107-31-6) and DIEA (24 mg,33uL, 192. Mu. Mol,3 eq) in DMF (500 uL) was added bis (1, 2, 4-triazol-1-yl) methanone (10 mg, 64. Mu. Mol,1eq, CAS 41864-22-6). The mixture was stirred at 35 ℃ for 1h. DIEA (24 mg,33uL, 192. Mu. Mol,3 eq) and p-toluene sulfonic acid; 6- [ (5-trifluoromethanesulfonyl-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane (31 mg, 64. Mu. Mol,1 eq) were added. The reaction mixture was stirred at 70 ℃ for 15h. The crude material was purified by preparative HPLC (YMC-Triart C, 12nm,5 μm,100X 30mm, ACN/water+0.1% TEA). The product was concentrated in vacuo to give (4 ar,8 as) -6- [6- [ (5-trifluoromethylsulfonyl-2-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (12 mg, 35%) as a white solid. MS (ESI) m/z=503.2 [ M+H ] +.
Example 35
(4 AR,8 aS) -6- [6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2 ]
Carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one
To a solution of (4 aR,8 aS) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one (10 mg, 64. Mu. Mol,1eq, CAS 2377107-31-6) and DIEA (24 mg,33uL, 192. Mu. Mol,3 eq) in DMF (500 uL) was added bis (1, 2, 4-triazol-1-yl) methanone (10 mg, 64. Mu. Mol,1eq, CAS 41864-22-6). The mixture was stirred at 35 ℃ for 1h. DIEA (24 mg,33uL, 192. Mu. Mol,3 eq) and 6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane were added, p-toluenesulfonic acid (27 mg, 64. Mu. Mol,1 eq). The reaction mixture was stirred at 70 ℃ for 15h. The crude material was purified by preparative HPLC (Gemini NX,12nm,5 μm,100x 30mm, acn/water+0.1% HCOOH). The product was concentrated in vacuo to give (4 ar,8 as) -6- [6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (21 mg, 70%) as a colorless amorphous oil. MS (ESI) m/z=442.3 [ m+h ] +.
Example 113
(4 Ar,8 as) -6- [6- [ [2- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one
To a solution of (4 aR,8 aS) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one, hydrochloride (35 mg, 149. Mu. Mol,1eq, CA 2411577-59-6) in DMF (836 uL) was added DIEA (134 mg,181uL,1.04mmol,7 eq) and bis (1, 2, 4-triazol-1-yl) methanone (27 mg, 163. Mu. Mol,1.1eq, CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30min. 6- (2-azaspiro [3.3] heptan-6-ylmethyl) -2- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidine, 2-trifluoroacetic acid (134 mg, 163. Mu. Mol,1.1 eq) was added. The reaction mixture was stirred at 50 ℃ for 18h. The reaction mixture was purified by SFC to give (4 ar,8 as) -6- [6- [ [2- (trifluoromethyl) pyrazolo [1,5-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (62 mg, 78% yield) as a white solid. MS (ESI) m/z=479.2 [ M+H ] +.
Example 114
(4 Ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one
To a solution of (4 aR,8 aS) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one; hydrochloride (35 mg, 149. Mu. Mol,1eq, CA 2411577-59-6) in DMF (836 uL) was added DIEA (134 mg,182uL,1.04mmol,7 eq) and bis (1, 2, 4-triazol-1-yl) methanone (27 mg, 163. Mu. Mol,1.1eq, CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30min. 6- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridine and p-toluenesulfonic acid (105 mg, 163. Mu. Mol,1.1 eq) were added. The reaction mixture was stirred at 50 ℃ for 18h. The reaction mixture was purified by reverse phase HPLC to give (4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (37 mg, yield 49%) as a white solid. MS (ESI) m/z=479.2 [ M+H ] +.
Example 118
(4 Ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one
To a solution of (4 aR,8 aS) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one; hydrochloride (35 mg, 149. Mu. Mol,1eq, CA 2411577-59-6) in DMF (836 uL) was added DIEA (134 mg,182uL,1.04mmol,7 eq) and bis (1, 2, 4-triazol-1-yl) methanone (27 mg, 163. Mu. Mol,1.1eq, CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30min. 5- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridine and p-toluenesulfonic acid (76 mg, 163. Mu. Mol,1.1 eq) were added. The reaction mixture was stirred at 50 ℃ for 18h. The reaction mixture was purified by reverse phase HPLC to give (4 ar,8 as) -6- [6- [ [3- (trifluoromethyl) -1H-pyrazolo [3,4-b ] pyridin-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (29 mg, 39% yield) as a white solid. MS (ESI) m/z=479.2 [ M+H ] +.
Example 133
(4 Ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one
To a solution of (4 ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one (85 mg,180 μmol,1eq, cas 2626262663-49-9) in DMF (1 mL) was added DIEA (148 mg,200ul,1.15mmol,7 eq) and bis (1, 2, 4-triazol-1-yl) methanone (29.58 mg,180 μmol,1.1eq, cas 41864-22-6). The reaction mixture was stirred at room temperature for 30min. Para-toluene sulfonic acid, 6- [ [6- [1- (trifluoromethyl) cyclopropyl ] -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane (105 mg, 163. Mu. Mol,1 eq) was added. The reaction mixture was stirred at 50 ℃ for 18h. The reaction mixture was purified by reverse phase SFC to give (4 ar,8 as) -6- [6- [ [6- [1- (trifluoromethyl) cyclopropyl ] -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carbonyl ] -4,4a,5,7,8 a-hexahydropyrido [4,3-b ] [1,4] oxazin-3-one as a colorless gum. MS (ESI) m/z=479.1 [ M+H ] +.
Similar to the examples described above, the examples in the following tables are generated using the corresponding structural units A.X and P.X.
Synthesis of building blocks
Structural units A.1 and A.2
Building blocks A.1 and A.2 are commercially available or have been reported in the scientific literature, for example as the free base (A.1 free base: CAS2377107-31-6; A.2 free base: CAS 1821824-68-3), hydrochloride (A.1 HCl: CAS2411577-59-6; A.2HCl: CA 2361608-82-2) or tartrate (A.1 tartrate: CAS 2624363-49-9) salts, and are used interchangeably. In some cases, the racemic commercial product is purchased and separated into the corresponding stereoisomers.
(+) - (4 Ar,8 as) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one
And
(-) - (4 AS,8 aR) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one
Enantiomers (500 mg,2.18mmol, cas 262966-65-8,ChemBridge Corporation) of rac- (4 ar,8 as) -hexahydro-2H-pyrido [4,3-b ] [1,4] oxazin-3 (4H) -one dihydrochloride were separated by preparative chiral HPLC (ReprosilChiral NR column) using EtOH (containing 0.05% NH 4 OAc): n-heptane (30:70) in an isocratic mixture.
The first eluted enantiomer, (+) - (4 aR,8 aS) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one (A.1). Yellow solid (0.150 g; 44.0%). MS (ESI) m/z=157.1 [ M+H ] +.
The second eluted enantiomer, (-) - (4 aS,8 aR) -4a,5,6,7,8 a-hexahydro-4H-pyrido [4,3-b ] [1,4] oxazin-3-one (A.2). Yellow solid (0.152 g; 44.6%). MS (ESI) m/z=157.1 [ M+H ] +.
Structural unit P.1, 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane, p-toluenesulfonic acid
Step 1 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A mixture of 2, 6-tetramethylpiperidine (95.9 mL, 618 mmol) in THF (750 mL) was cooled to-30℃under an atmosphere of N 2. n-BuLi (227 mL, 618 mmol) was added dropwise and the reaction mixture was stirred at the same temperature for 30min. Next, the reaction was cooled to-60 ℃ and a solution of 4, 5-tetramethyl-2- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methyl ] -1,3, 2-dioxaborolan (136 g,506 mmol) in THF (750 mL) was added dropwise. After stirring for 30min, a solution of tert-butyl 6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (100 g,473 mmol) in THF (300 mL) was added dropwise at-60 ℃. The reaction mixture was slowly warmed to 25 ℃ and stirred at 25 ℃ for 12h. To this mixture H 2 O (8 0 ml) was slowly added and then purified together with another batch of the same size by a silica gel column (PE/ea=1:0 to 3:1 gradient) to give the title compound (220 g, 650 mmol, yield of about 69% per batch) as a white solid, confirmed by 1 H NMR (400 MHz, chloroform-d) δ=5.21-5.16 (m, 1H), 3.99-3.89 (m, 4H), 3.13-2.90 (m, 4H), 1.46-1.41 (m, 9H), 1.26-1.20ppm (m, 13H).
Step 2 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A solution of 6- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1 g,3mmol,1eq, CAS 2763647-64-7), 2-bromo-5- (trifluoromethyl) pyrazine (812 mg,3.6mmol,1.2eq, CAS 1196152-38-1) and tripotassium phosphate (1.27 g,6mmol,2 eq) in 1, 4-dioxane (20 mL), water (2 mL) was degassed with argon. Palladium (II) chloride (crotyl) (tri-t-butylphosphine) (59 mg,0.15mmol,0.05eq, CAS 1334497-00-5) was added. The mixture was stirred at 70 ℃ for 4h. The reaction mixture was poured into EtOAc and washed with water, saturated NaCl. The organic layer was dried over Na 2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40g, etOAc in heptane 0% to 30%) to give tert-butyl 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (593 mg,97% purity, 54% yield) as a white solid. MS (ESI) M/z= [ M-C 4H8+H]+ ].
Step 3 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A solution of tert-butyl 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (0.59 g,1.66mmol,1 eq) in tetrahydrofuran (10 mL), methanol (30 mL) was degassed with argon. Pd/C10% (176 mg,0.166mmol,0.1 eq) was added. The mixture was stirred at room temperature under a balloon of H 2 for 30min. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (588 mg,95% purity, 94% yield) as an off-white solid. MS (ESI) M/z= [ M-C 4H8+H]+ ].
Step 4 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane; p-toluenesulfonic acid
To a solution of tert-butyl 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (183 mg,0.51mmol,1 eq) in ethyl acetate (1.2 mL) was added 4-methylbenzenesulfonic acid monohydrate (102 mg,0.54mmol,1.05 eq). The mixture was stirred at 80 ℃ for 16h. The reaction mixture was concentrated in vacuo to give 6- [ [5- (trifluoromethyl) pyrazin-2-yl ] methyl ] -2-azaspiro [3.3] heptane, p-toluenesulfonic acid (228 mg,94% purity, 98% yield) as a pale brown solid. MS (ESI) m/z=258.2 [ M+H ] +.
Similar to structural unit p.1, the following structural units are generated in step 2 using the relevant (hetero) aryl bromide, chloride or iodide structural units for the Suzuki coupling. In some cases, alternative salts (e.g., trifluoroacetate, xylene sulfonate, hydrochloride) are also used. To introduce a different spiro system, an alternative building block was used in step 2 instead of tert-butyl 6- [ (4, 5-tetramethyl-1, 3, 2-dioxapenta-borane-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate, for example 7- [ (4, 5-tetramethyl-1, 3, 2-dioxapenta-borane-2-yl) methylene ] -2-azaspiro [3.5] nonane-2-carboxylate (CAS 2763648-39-9) for P.84, (6Z) -6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (CAS 2763648-54-8) for P.92 or 2- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (C.184) for P.184.
Structural unit P.14 [6- (2-azaspiro [3.3] heptane-6-ylmethyl) -3-pyridinyl ] -imino-oxo- (trifluoromethyl) -lambda 6 -sulfane, 4-methylbenzenesulfonic acid
Step 1 2-bromo-5- (trifluoromethylsulfanyl) pyridine
To a solution of 2-bromo-5-iodopyridine (0.5 g,1.76mmol,1 eq) in ACN (10 mL) was added 2,2' -bipyridine (275mg,1.76mmol,1eq,CAS 366-18-7), silver (I) trifluormethanethiol (441mg,2.1mmol,1.2eq,CAS 811-68-7), and CuI (335 mg,1.76mmol,1 eq) at 20 ℃. The mixture was stirred at 90 ℃ for 12h. The reaction mixture was filtered to give 2-bromo-5- (trifluoromethylthio) pyridine (400 mg,1.55mmol, 88% yield). The crude product was used directly in the next step.
Step 2 6- [ [5- (trifluoromethylsulfanyl) -2-pyridinyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (4.2 g,12.5mmol,1eq, cas 2763647-64-7), 2-chloro-5- (trifluoromethylthio) pyridine (2.67 g,12.5mmol,1eq, cas 1204234-94-5) and potassium carbonate (3.46 g,25mmol,2 eq) in 1, 4-dioxane (25 mL) and water (5 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.02g,1.25mmol,0.1eq,CAS 95464-05-4). The mixture was stirred at 80 ℃ under an atmosphere of N 2 for 12h. The crude material was purified by silica gel chromatography (heptane/EtOAc 3:1) to give tert-butyl 6- [ [5- (trifluoromethylsulfanyl) -2-pyridinyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (1.8 g, 37% yield) as a brown solid. MS (ESI) m/z=331.0 [ M+H ] +.
Step 3 6- [ [5- (trifluoromethylsulfanyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [5- (trifluoromethylsulfanyl) -2-pyridinyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (1.7 g,4.4mmol,1 eq) in EtOAc (20 mL) at 20℃was added wet Pd/C10% (1.7 mg,0.44mmol,0.1 eq) and the mixture was stirred under H 2 atmosphere (balloon) for 6H at 20 ℃. The mixture was filtered and concentrated in vacuo to give tert-butyl 6- [ [5- (trifluoromethylsulfanyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.5 g,3.86mmol, yield 87%) as an off-white oil. MS (ESI) M/z= [ M+H ] +.
Step 4 6- [ [5- (trifluoromethylsulfinyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [5- (trifluoromethylsulfanyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1 g,2.57mmol,1 eq) in hexafluoroisopropanol (15 mL) was added PhI (OAc) 2 (3.48g,10.8mmol,4.2eq,CAS 3240-34-4) and ammonium carbamate (602 mg,7.72mmol,3 eq). The reaction mixture was stirred at 20 ℃ for 12h and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex luna C, 150 x 40mm x 15um, water (FA) -ACN) and lyophilized to give tert-butyl 6- [ [5- (trifluoromethylsulfinyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (200 mg,0.48mmol, 18% yield) as a brown oil. MS (ESI) m/z=333.0 [ M+H ] +.
Step 5 [6- (2-azaspiro [3.3] heptan-6-ylmethyl) -3-pyridinyl ] -imino-oxo- (trifluoromethyl) - λ6-sulfane, 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ [5- (trifluoromethyiiminosulfonyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (230 mg,0.55mmol,1 eq) in EtOAc (3 mL) was added p-toluenesulfonic acid (113 mg,0.66mmol,1.2 eq). The mixture was stirred at 80 ℃ for 12h. The reaction mixture was concentrated in vacuo, then deionized water was added and lyophilized to give [6- (2-azaspiro [3.3] heptane-6-ylmethyl) -3-pyridinyl ] -imino-oxo- (trifluoromethyl) - λ6-sulfane, 4-methylbenzenesulfonic acid (244 mg,0.5mmol, 85% yield) as a brown solid. MS (ESI) m/z=320.0 [ M+H ] +.
Similar to structural unit p.14, the following structural units are generated in step 1 using the relevant (hetero) aryl bromo-or iodo-compounds for the cross-coupling reaction.
Structural unit P.15 2- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- [1- (trifluoromethyl) cyclopropyl ] -1,3, 4-oxadiazole, 4-methylbenzenesulfonic acid
Step1 6- (2-hydrazino-2-keto-ethyl) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 2- (2-tert-butoxycarbonyl-2-azaspiro [3.3] heptan-6-yl) acetic acid (2.5 g,9.8mmol,1eq, cas 1251002-39-7) in tetrahydrofuran (30 mL) was added CDI (1.75 g,10.7mmol,1 eq). The mixture was stirred at 70 ℃ for 1.5h and cooled to 0 ℃. Hydrazine monohydrate (1.47 g,29.4mmol,3 eq) was added. The mixture was stirred at room temperature for 30min. The reaction mixture was poured into EtOAc/THF 2:1, washed with H2O, saturated NaCl, dried over Na 2SO4 and concentrated in vacuo to give tert-butyl 6- (2-hydrazino-2-keto-ethyl) -2-azaspiro [3.3] heptane-2-carboxylate (3.85 g,68% purity, 99% yield) as a white solid. MS (ESI) m/z=214.1 [ M-C 4H8+H]+.
Step 2 6- [ 2-keto-2- [ N' - [1- (trifluoromethyl) cyclopropanecarbonyl ] hydrazino ] ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 1- (trifluoromethyl) cyclopropanecarboxylic acid (1.5 g,9.7mmol,1eq, CAS 277756-46-4) in dichloromethane (30 mL) was added 1-chloro-N, N, 2-trimethylpropenamine (1.56 g,11.6mmol,1.2eq, CAS 26189-59-3). The mixture was stirred at room temperature for 2h. The formyl chloride solution was added dropwise to a solution of tert-butyl 6- (2-hydrazino-2-keto-ethyl) -2-azaspiro [3.3] heptane-2-carboxylate (3.85 g,9.7mmol,1 eq) and DIPEA (2.51 g,19.4mmol,2 eq) in tetrahydrofuran (20 mL) at room temperature. The mixture was stirred at room temperature for 2h. The reaction mixture was poured into EtOAc/THF 2:1 and washed with water, saturated NaCl. The organic layer was dried over Na 2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80g, methanol 0% to 5% in ch2cl 2) to give tert-butyl 6- [ 2-keto-2- [ N' - [1- (trifluoromethyl) cyclopropanecarbonyl ] hydrazino ] ethyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.49 g,95% purity, 84% yield) as a white solid. MS (ESI) m/z=350.1 [ M-C 4H8+H]+.
Step 3 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,3, 4-oxadiazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ 2-keto-2- [ N' - [1- (trifluoromethyl) cyclopropanecarbonyl ] hydrazino ] ethyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.49 g,8.61mmol,1 eq) in tetrahydrofuran (40 mL) was added Burgess reagent (4.1 g,17.2mmol,2eq, CA 29684-56-8). The mixture was stirred at 60 ℃ for 1h. The reaction mixture was poured into EtOAc/THF 3:1 and washed with water, saturated NaCl. The organic layer was dried over Na 2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80g, methanol 0% to 5% in ch2cl 2) to give tert-butyl 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,3, 4-oxadiazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.22 g,95% purity, 91% yield) as a white solid. MS (ESI) m/z=388.2 [ m+h ] +.
Step 4 2- (2-azaspiro [3.3] heptan-6-ylmethyl) -5- [1- (trifluoromethyl) cyclopropyl ] -1,3, 4-oxadiazole; 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,3, 4-oxadiazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.22 g,8.31mmol,1 eq) in isopropyl acetate (160 mL) was added p-toluenesulfonic acid monohydrate (1.9 g,9.97mmol,1.2 eq). The mixture was stirred at 85 ℃ for 4h and concentrated in vacuo to give 2- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- [1- (trifluoromethyl) cyclopropyl ] -1,3, 4-oxadiazole, 4-methylbenzenesulfonic acid (4.25 g,40% purity, 44% yield) as a white solid. MS (ESI) m/z=288.0 [ m+h ] +.
Structural unit P.16 4-methylbenzenesulfonic acid, 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
Step 16- [ (3-bromo-1, 2, 4-triazol-1-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 3-bromo-1H-1, 2, 4-triazole (2g,13.5mmol,1eq,CAS 7343-33-1) in DCE (40 mL) was added 6- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (6.8g,20.2mmol,1.5eq,CAS 2763647-64-7), pyridine (2.2 mL,27mmol,2 eq), boric acid (835 mg,13.5mmol,1 eq) and Cu (OAc) 2 (3.64 g,18.2mmol,1.35 eq). The mixture was stirred at 70 ℃ for 12h. The reaction mixture was poured into EtOAc and washed with water, saturated NaCl. The organic layer was dried over Na 2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12g, etOAc in heptane 0% to 50%) to give tert-butyl 6- [ (3-bromo-1, 2, 4-triazol-1-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (1.7 g, 35% yield) as a yellow solid. MS (ESI) m/z=354.9 [ M+H ] +.
Step 2 6- [ [3- [1- (trifluoromethyl) vinyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (3-bromo-1, 2, 4-triazol-1-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (500 mg,1.4mmol,1 eq) in THF (5 mL) was added 4, 6-trimethyl-2- [1- (trifluoromethyl) vinyl ] -1,3, 2-dioxaborolan (374mg,1.7mmol,1.2eq,CAS 1011460-68-6), 1.5M K 3PO4 aqueous solution (2.8 mL,4.2mmol,3 eq) and Ad2nBuP-Pd-G3 (162 mg,0.14mmol,0.1eq, cas 1651823-59-4). The mixture was stirred at 100 ℃ for 16h and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, etOAc 0% to 45% in heptane) to give tert-butyl 6- [ [3- [1- (trifluoromethyl) vinyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (450 mg, 85% yield) as an off-white solid. MS (ESI) m/z=317.1 [ M-C 4H8+H]+.
Step 3 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [3- [1- (trifluoromethyl) vinyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.1 g,3mmol,1 eq) in THF (11 mL) was added diphenyl (methyl) sulfonium tetrafluoroborate (851 mg,3mmol,1eq, CAS 10504-60-6). The suspension was cooled to 0 ℃ and a solution of NaHMDS1M in THF (4.7 ml,4.7mmol,1.6 eq) was added dropwise. The reaction mixture was stirred at 20 ℃ for 12h. The crude product was purified by preparative HPLC (Shim-pack C18 x 25 x 10um, water (0.225% fa) -ACN) to give tert-butyl 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (440 mg,1.14mmol, 38% yield). MS (ESI) M/z= [ M-C 4H8+H]+ ].
Step 4-Methylbenzenesulfonic acid 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
A solution of p-toluenesulfonic acid (256 mg,1.5mmol,1.2 eq) and tert-butyl 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (480 mg,1.24mmol,1 eq) in EtOAc (5 mL) was stirred at 80℃for 12h. The mixture was concentrated in vacuo. Deionized water was added to the residue and lyophilized to give 4-methylbenzenesulfonic acid, 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (551 mg, 96% yield) as a yellow oil. MS (ESI) m/z=287.0 [ M+H ] +.
Similar to structural unit p.16, the following structural units were generated in step 1 using the relevant heteroaryl compounds for Chan Lam type coupling.
Structural unit P.19:4-methylbenzenesulfonic acid, 6- [ [4- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
To a solution of tert-butyl 6- [ [4- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (700 mg,1.82mmol,1 eq) in EtOAc (14 mL) was added p-toluenesulfonic acid monohydrate (1036 mg,5.45mmol,3 eq). The reaction mixture was stirred at 30 ℃ for 72h, concentrated in vacuo and purified by FC to give 4-methylbenzenesulfonic acid, 6- [ [4- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (563 mg,0.89mmol, 46% yield) as a yellow solid. MS (ESI) m/z=286.2 [ M+H ] +. FC conditions are Interhim, 80g SiO2, MTBE/methanol (0% to 66% to 100%), flow = 60ml/min,13,8-14,9CV.
Step 1 6- [ (4-Bromoimidazol-1-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 4-bromo-1H-imidazole (1443 mg,9.82mmol,1.5eq, CAS 2302-25-2) in NMP (20 mL) was added NaH (471 mg,11.79mmol,1.8 eq) under nitrogen at 0 ℃. The resulting yellow solution was stirred at 0 ℃ for 30min. 6- (methylsulfonylmethyl) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (2g,6.55mmol,1eq,CAS 2740574-92-7) was added and stirred at 50℃for 12h. The mixture was diluted with 20ml of saturated aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC (0.01% fa: acn=100% to 0% in water, 220nm and 254 nm) and lyophilized to give tert-butyl 6- [ (4-bromoimidazol-1-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.1 g,3.09mmol, 47% yield) as a yellow solid. MS (ESI) m/z=358.1 [ M+H ] +.
Step 2 6- [ [4- [1- (trifluoromethyl) vinyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (4-bromoimidazol-1-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (5G, 14.03mmol,1 eq) and 4, 6-trimethyl-2- [1- (trifluoromethyl) vinyl ] -1,3, 2-dioxaborolan (3.74G, 16.84mmol,1.2eq, cas 1011460-68-6), K3PO4 (8.93G, 42.1mmol,3 eq) in THF (165 mL) and water (33 mL) was added APhos-Pd-G3 (891.35 mg,1.4mmol,0.1eq, cas 1820817-64-8). The mixture was degassed with N 2 and stirred under an atmosphere of N 2 at 60 ℃ for 12h. The crude material was purified by silica gel column (petroleum ether: ethyl acetate=1:1 to 0:1) and concentrated in vacuo to give tert-butyl 6- [ [4- [1- (trifluoromethyl) vinyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.2 g,8.62mmol, 61% yield) as a yellow oil. MS (ESI) m/z=372.2 [ M+H ] +.
Step 3 6- [ [4- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [4- [1- (trifluoromethyl) vinyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2 g,5.39mmol,1 eq) in THF (40 mL) was added diphenyl (methyl) sulfonium tetrafluoroborate (1.86 g,6.46mmol,1.2eq, CAS 10504-60-6) at 20 ℃. The suspension was cooled to 0 ℃ and NaHMDS/THF (8.62 ml,8.62mmol,1.6 eq) was added dropwise under N 2. The reaction mixture was stirred at room temperature for 12h. The reaction mixture was poured into saturated aqueous NH 4 Cl and extracted with EtOAc. The organic layer was dried over Na 2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2, petroleum ether: ethyl acetate=0:1) to give the crude product. The crude product was purified by preparative HPLC (column, [ Phenomenex luna C18.150 x 40mm x 15um ]; mobile phase: [ ACN ] and [ H 2 O ] (conditions: [ water (0.225% fa) -ACN ], B%:50% to 80%; detector, UV 254nm. Rt: [15min ]) and lyophilized to yield tert-butyl 6- [ [4- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (640 mg,1.67mmol, 31% yield) as a yellow oil MS (ESI): m/z=386.2 [ m+h ] +.
Structural unit P.23 1- (2-azaspiro [3.3] heptan-6-ylmethyl) -4- (trifluoromethyl) pyridin-2-one, 4-methylbenzenesulfonic acid
Step 1 6- [ [ 2-oxo-4- (trifluoromethyl) -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
4- (Trifluoromethyl) -1H-pyridin-2-one (5.34g,32.75mmol,1eq,CAS 50650-59-4) was added in small portions to a suspension of sodium hydride (60% in oil) (2.14 g,49.1mmol,1.5 eq) in DMF (100 mL) under argon at 0 ℃. The mixture was stirred at 0 ℃ for 10 minutes and at room temperature for 30 minutes. The reaction mixture was cooled to 0 ℃ and tert-butyl 6- (methylsulfonylmethyl) -2-azaspiro [3.3] heptane-2-carboxylate (10 g,32.7mmol,1eq, cas 2740574-92-7), sodium iodide (4.91 g,32.7mmol,1 eq) was added. The mixture was stirred at 0 ℃ for 1h and then at 80 ℃ for 18h. The reaction mixture was poured into EtOAc and washed with water, saturated NaCl. The organic layer was dried over Na 2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120g, tert-butyl methyl ether in heptane 0% to 100%) to give tert-butyl 6- [ [ 2-oxo-4- (trifluoromethyl) -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.6 g, 29% yield) as a yellow solid. MS (ESI) m/z=273.0 [ M+H ] +.
Step 21- (2-azaspiro [3.3] heptan-6-ylmethyl) -4- (trifluoromethyl) pyridin-2-one, 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ [ 2-oxo-4- (trifluoromethyl) -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (5 g,13.43mmol,1 eq) in ethyl acetate (150 mL) was added p-toluenesulfonic acid monohydrate (5.1 g,26.8mmol,2 eq) and stirred at 25 ℃ for 72h. The reaction mixture was filtered and washed with diethyl ether to give 1- (2-azaspiro [3.3] heptane-6-ylmethyl) -4- (trifluoromethyl) pyridin-2-one, 4-methylbenzenesulfonic acid (5.34 mg, yield 85%) as a pale yellow solid. MS (ESI) m/z=273.0 [ M+H ] +.
Structural unit P.24 1- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- (trifluoromethyl) pyridin-2-one, 4-methylbenzenesulfonic acid
In analogy to building block P.23, 5- (trifluoromethyl) -1H-pyridin-2-one (CAS 33252-63-0) was treated with sodium hydride, 6- (methylsulfonylmethyl) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester CAS 2740574-92-7 and sodium iodide in DMF. The resulting product was treated with p-toluenesulfonic acid monohydrate to give 1- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- (trifluoromethyl) pyridin-2-one, 4-methylbenzenesulfonic acid as a white solid. MS (ESI) m/z=273.0 [ M+H ] +.
Structural unit P.33 4-methylbenzenesulfonic acid, 6- [ [4- (2, 2-trifluoroethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
Step 16- [ [4- (2, 2-trifluoroethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a mixture of 4- (2, 2-trifluoroethyl) -1H-pyrazole (737 mg,4.9mmol,1eq, CAS 1211529-61-1), sodium iodide (1.47 g,9.8mmol,2 eq) and cesium carbonate (3.2 g,9.8mmol,2 eq) in acetonitrile (68 mL) was added tert-butyl 6- (methylsulfonylmethyl) -2-azaspiro [3.3] heptane-2-carboxylate (1.5 g,4.9mmol,1eq, CAS 2740574-92-7) at room temperature. The reaction mixture was stirred at 80 ℃ for 18h, filtered, and concentrated in vacuo. The crude material was purified by HPLC to give tert-butyl 6- [ [4- (2, 2-trifluoroethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (223 mg, yield 12%) as a pale yellow solid. MS (ESI) m/z=360 [ M+H ] +.
Step 2 4-Methylbenzenesulfonic acid 6- [ [4- (2, 2-trifluoroethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
To a solution of tert-butyl 6- [ [4- (2, 2-trifluoroethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (250 mg,0.7mmol,1 eq) in EtOAc (7.5 mL) was added p-toluenesulfonic acid monohydrate (330 mg,1.74mmol,2.5 eq) and stirred at 25 ℃ for 18h. The reaction mixture was concentrated in vacuo and purified by HPLC to give 4-methylbenzenesulfonic acid, 6- [ [4- (2, 2-trifluoroethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (198mg, 0.46mmol, 62% yield) as a pale brown gum. MS (ESI) m/z=260 [ M+H ] +.
Structural units p.35 and p.36:
4-Methylbenzenesulfonic acid, 6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (P.35)
4-Methylbenzenesulfonic acid, 6- [ [ 5-methyl-3- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (P.36)
Step 1 6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
And 6- [ [ 5-methyl-3- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- (hydroxymethyl) -2-azaspiro [3.3] heptane-2-carboxylate (6 g,26.4mmol,1eq, cas 1363381-93-4), triphenylphosphine (8.65 g,33mmol,1.25 eq) and 5-methyl-3- (trifluoromethyl) -1H-pyrazole (3.96 g,26.4mmol,1 eq) in THF (120 mL) was added diisopropyl azodicarboxylate (6.24 mL,31.7mmol,1.2 eq) dropwise. The mixture was stirred at room temperature for 24h. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 330g, MTBE 0% to 35% in heptane) to give
Tert-butyl 6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.3 g, 24% yield) was a white solid. MS (ESI) m/z=360.0 [ M+H ] +
And tert-butyl 6- [ [ 5-methyl-3- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.8 g, 40% yield) as a colorless oil. MS (ESI) m/z=360.0 [ M+H ] +.
Step 2 4-Methylbenzenesulfonic acid 6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (P.35)
To a solution of tert-butyl 6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.05 g,2.9mmol,1 eq) in EtOAc (10 mL) was added p-toluenesulfonic acid monohydrate (603 mg,3.51mmol,1.2 eq). The mixture was stirred at 80 ℃ for 12h. The reaction mixture was concentrated in vacuo and lyophilized to give 4-methylbenzenesulfonic acid, 6- [ [ 3-methyl-5- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (1.16 g, yield 89%) as a pale brown powder. MS (ESI) m/z=260.0 [ M+H ] +.
Step 2 4-Methylbenzenesulfonic acid 6- [ [ 5-methyl-3- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (P.36)
To a solution of tert-butyl 6- [ [ 5-methyl-3- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (700 mg,1.95mmol,1 eq) in EtOAc (7 mL) was added p-toluenesulfonic acid monohydrate (402 mg,2.34mmol,1.2 eq). The mixture was stirred at 80 ℃ for 2.5h. The reaction mixture was concentrated in vacuo and lyophilized to give 4-methylbenzenesulfonic acid, 6- [ [ 5-methyl-3- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (840 mg, yield 97%) as a pale brown powder. MS (ESI) m/z=260.0 [ M+H ] +.
Structural unit P.47 5- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- (trifluoromethyl) -1,2, 4-oxadiazole, 4-methylbenzenesulfonic acid
Step 1 6- [ [3- (trifluoromethyl) -1,2, 4-oxadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- (2-ethoxy-2-oxo-ethyl) -2-azaspiro [3.3] heptane-2-carboxylate (300 mg,1.06mmol,1eq, cas 2122433-35-4) in methanol (3 mL) was added sodium methoxide 5M (0.42 mL,2.1mmol,2 eq) and 2, 2-trifluoro-N' -hydroxy-acetamidine (271mg,2.1mmol,2eq,CAS 4314-35-6). The mixture was stirred at 60 ℃ for 12h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with water. The residue was purified by preparative HPLC (Shim-pack C18 x 25 x 10um, water (FA) -ACN,25 ml/min) and lyophilized to give tert-butyl 6- [ [3- (trifluoromethyl) -1,2, 4-oxadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (120 mg, 32% yield) as a yellow oil. MS (ESI) m/z=292.0 [ M-C 4H8+H]+.
Step 2 5- (2-azaspiro [3.3] heptan-6-ylmethyl) -3- (trifluoromethyl) -1,2, 4-oxadiazole, 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ [3- (trifluoromethyl) -1,2, 4-oxadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (118 mg,0.34mmol,1 eq) in EtOAc (2 mL) was added p-toluene sulfonic acid (70 mg,0.41mmol,1.2 eq). The reaction mixture was stirred at 80 ℃ for 12h and concentrated in vacuo. Deionized water was added to the residue and lyophilized to give 5- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- (trifluoromethyl) -1,2, 4-oxadiazole, 4-methylbenzenesulfonic acid (125 mg,0.3mmol, 84% yield) as a white solid. MS (ESI) m/z=248.1 [ M+H ] +.
Structural unit P.48 3- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- (trifluoromethyl) -1,2, 4-oxadiazole, 4-methylbenzenesulfonic acid
Step 1 6- [ (2Z) -2-amino-2-hydroxyimino-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
TEA (3.42 g,33.8mmol,2 eq) was added to a mixture of hydroxylamine, hydrochloride (2.35 g,33.8mmol,2 eq) in ethanol (25 mL) at 25 ℃. After 1h, 6- (cyanomethyl) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (4g,16.9mmol,1eq,CAS 1374658-94-2) was added. The mixture was stirred at 50 ℃ for 12h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with water. The organic layer was dried over Na 2SO4 and concentrated in vacuo to give tert-butyl 6- [ (2Z) -2-amino-2-hydroxyimino-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylate (4.5 g, 98% yield) as a colorless oil. MS (ESI) m/z=270.1 [ M+H ] +.
Step 2 6- [ [5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (2Z) -2-amino-2-hydroxyimino-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylate (800 mg,2.97mmol,1 eq) in methanol (20 mL) was added sodium methoxide 5M (1.19 mL,5.94mmol,2 eq) and ethyl trifluoroacetate (2.11 g,14.85mmol,5 eq) at 30 ℃. The mixture was stirred at 50 ℃ for 12h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with water. The residue was purified by preparative HPLC (Shim-pack C18 x25 x 10um, water (FA) -ACN,25 ml/min) and lyophilized to give tert-butyl 6- [ [5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (360 mg, 36% yield) as a colorless oil. MS (ESI) m/z=292.0 [ M+H ] +.
Step 3- (2-azaspiro [3.3] heptan-6-ylmethyl) -5- (trifluoromethyl) -1,2, 4-oxadiazole; 4-methylbenzenesulfonic acid
A mixture of tert-butyl 6- [ [5- (trifluoromethyl) -1,2, 4-oxadiazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (350 mg,1mmol,1 eq) and p-toluenesulfonic acid (208 mg,1.2mmol,1.2 eq) in EtOAc (10 mL) was stirred at 80℃for 12h.
The reaction mixture was concentrated in vacuo. The residue was dissolved in ACN (2 mL), water (20 mL) and lyophilized to give 3- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- (trifluoromethyl) -1,2, 4-oxadiazole, 4-methylbenzenesulfonic acid (410 mg, 90% yield) as a white solid. MS (ESI) m/z=248.0 [ M+H ] +.
Structural unit P.50 4-methylbenzenesulfonic acid, 6- [ [4- (trifluoromethyl) triazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane
Step 1 6- [ [4- (trifluoromethyl) triazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a mixture of 4- (trifluoromethyl) -1H-triazole (2.69 g,19.65mmol,1eq, CAS 1267573-04-5), lithium bromide (3.41 g,39.3mmol,2 eq) in acetonitrile (300 mL) was added tert-butyl 6- (methylsulfonylmethyl) -2-azaspiro [3.3] heptane-2-carboxylate (6 g,19.65mmol,1eq, CAS 2740574-92-7). The reaction mixture was stirred at 50 ℃ for 18h, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220g, MTBE 0% to 100% in heptane) to give tert-butyl 6- [ [4- (trifluoromethyl) triazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.5 g, 36% yield) as a pale yellow solid. MS (ESI) m/z=247.0 [ M-C 4H8+H]+.
Step 2 4-Methylbenzenesulfonic acid 6- [ [4- (trifluoromethyl) triazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane
To a solution of tert-butyl 6- [ [4- (trifluoromethyl) triazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.5 g,7.2mmol,1 eq) in EtOAc (100 mL) was added p-toluenesulfonic acid monohydrate (4.12 g,21.6mmol,3 eq). The reaction mixture was stirred at 25 ℃ for 18h, filtered and washed with diethyl ether to give 4-methylbenzenesulfonic acid, 6- [ [4- (trifluoromethyl) triazol-2-yl ] methyl ] -2-azaspiro [3.3] heptane (3.63 g, yield 81%) as a white powder. MS (ESI) m/z=247.2 [ M+H ] +.
During the synthesis of structural unit P.50, the positionally isomeric compound 6- [ [4- (trifluoromethyl) triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Formed as a small by-product in step 1, which is subsequently converted to 4-methylbenzenesulfonate of 6- [ [4- (trifluoromethyl) triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane following the procedure described in step 2 for the synthesis of structural unit p.50.
Structural unit P.51 4-methylbenzenesulfonic acid, 6- [ [5- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
Step 1 4-Methylbenzenesulfonic acid 6- [ [5- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
Sodium hydride (60% in oil) was added (146 mg,3.65mmol,1.8 eq) to a solution of 3- (trifluoromethyl) -1H-1,2, 4-triazole (417mg,3mmol,1.5eq,CAS 60406-75-9) in NMP (6 mL) at 0deg.C. The mixture was stirred at 0 ℃ for 0.5h. At 20℃tert-butyl 6- (methylsulfonylmethyl) -2-azaspiro [3.3] heptane-2-carboxylate (620 mg,2mmol,1eq, CAS 2740574-92-7) was added. The reaction mixture was stirred at 50 ℃ for 12h. The crude product was purified by HPLC (Welch Ultimate XB-SiOH 250 x 50 x 10um, hexane-EtOH) and concentrated in vacuo to give 4-methylbenzenesulfonic acid, 6- [ [5- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (55 mg, 8% yield) as a pale yellow oil. MS (ESI) m/z=291.1 [ M-C 4H8+H]+.
Step 2 4-Methylbenzenesulfonic acid 6- [ [5- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
To a solution of tert-butyl 6- [ [5- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (45 mg,0.13mmol,1 eq) in EtOAc (0.5 mL) was added p-toluenesulfonic acid (29 mg,0.17mmol,1.3 eq). The reaction mixture was stirred at 80 ℃ for 12h and concentrated in vacuo. To the residue was added water and lyophilized to give 4-methylbenzenesulfonic acid, 6- [ [5- (trifluoromethyl) -1,2, 4-triazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (47 mg, yield 86%) as an off-white solid. MS (ESI) m/z=247.2 [ M+H ] +.
Similar to structural unit P.51, the following structural units were generated in step 1 using the relevant commercial structural units for the S N reaction. In some cases, the alternative salt trifluoroacetate salt is also used.
Structural unit P.54 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid
Step 1 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Copper diacetate (2.38 g,12mmol,2 eq) was added to a solution of 4- (trifluoromethyl) -1H-pyrazole (2.43 g,18mmol,3 eq), 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (2 g,6mmol,1eq, CAS 2763647-64-7) and pyridine (1.45 mL,18mmol,3 eq) in DMSO (80 mL) under an O 2 atmosphere, followed by stirring at 100℃for 12H under O 2 (balloon). The aqueous phase was extracted with EtOAc (200 mL. Times.3). The combined organic phases were washed with brine (200 ml x 3), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (0.1% FA conditions) to give tert-butyl 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (640 mg, 31% yield) as a brown solid. MS (ESI) m/z=288.1 [ M-C 4H8+H]+.
Step 2 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (460 mg,2 mmol) in EtOAc (7 mL) was added Pd/C10% (230 mg,0.2 mmol). The reaction mixture was stirred under an atmosphere of H 2 (balloon) at 25 ℃ for 2H. The mixture was filtered and concentrated in vacuo to give tert-butyl 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (690 mg, 99% yield) as a yellow solid. MS (ESI) m/z=346.1 [ M+H ] +.
Step 3 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane; 4-methylbenzenesulfonic acid
A solution of tert-butyl 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (675mg, 1.95 mmol) and p-toluenesulfonic acid (404 mg,2.35 mmol) in EtOAc (6 mL) was stirred at 80℃for 12h. The reaction mixture was concentrated in vacuo. Deionized water was added to the residue, and the mixture was lyophilized to give 6- [ [4- (trifluoromethyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane; 4-methylbenzenesulfonic acid (794 mg, 96% yield) as a white solid. MS (ESI) m/z=246.2 [ M+H ] +.
Similar to structural unit p.54, the following structural units were generated in step 1 using the relevant heteroaryl compounds for Chan Lam type coupling.
Structural units p.58 and p.59:
6- [ [3- (difluoromethyl) -5-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid (P.58)
6- [ [5- (Difluoromethyl) -3-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid (P.59)
Step 1 6- [ [3- (difluoromethyl) -5-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
And 6- [ [5- (difluoromethyl) -3-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- (hydroxymethyl) -2-azaspiro [3.3] heptane-2-carboxylate (6 g,26.4mmol,1eq, cas 1363381-93-4) in toluene (100 mL) was added 5- (difluoromethyl) -3-methyl-1H-pyrazole (4.18g,31.7mmol,1.2eq,CAS 934759-09-8) and 2- (tributylphosphoranylidene) acetonitrile (9.56 g,39.6mmol,1.5eq, cas 157141-27-0). The mixture was stirred at 100 ℃ for 12h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (neutral condition, welch Ultimate XB-CN 250 x 50 x 10um, hexane-EtOH) and concentrated in vacuo to give tert-butyl 6- [ [3- (difluoromethyl) -5-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.7 g,7.91mmol, 30% yield) as a pale yellow powder. MS (ESI) m/z=286.0 [ M-C ] 4H8+H]+
And tert-butyl 6- [ [5- (difluoromethyl) -3-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.6 g,10.54mmol, 40% yield) as a pale yellow oil. MS (ESI) m/z=286.0 [ M-C 4H8+H]+.
Step 2 6- [ [3- (difluoromethyl) -5-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane; 4-methylbenzenesulfonic acid (P.58)
To a solution of tert-butyl 6- [ [3- (difluoromethyl) -5-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.85 g,8.35mmol,1 eq) in EtOAc (15 mL) was added p-toluenesulfonic acid (1.72 g,10mmol,1.2 eq). The mixture was stirred at 80 ℃ for 2h. The reaction mixture was concentrated in vacuo to give 6- [ [3- (difluoromethyl) -5-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane; 4-methylbenzenesulfonic acid (3.45 g, yield 98%) as a pale yellow solid. MS (ESI) m/z=242.1 [ M+H ] +.
Step 2 6- [ [5- (difluoromethyl) -3-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane; 4-methylbenzenesulfonic acid (P.59)
To a solution of tert-butyl 6- [ [5- (difluoromethyl) -3-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.88 g,11.3mmol,1 eq) in ethyl acetate (20 mL) was added p-toluenesulfonic acid (2.32 g,13.5mmol,1.2 eq). The mixture was stirred at 80 ℃ for 2h. The reaction mixture was concentrated in vacuo to give 6- [ [5- (difluoromethyl) -3-methyl-pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane; 4-methylbenzenesulfonic acid (4.31 g, yield 90%) as a pale yellow oil. MS (ESI) m/z=242.1 [ M+H ] +.
Structural unit P.62, 6- [ [3- (difluoromethyl) -1H-pyrazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane, 2-trifluoroacetate
Step 1 6- [ [5- (difluoromethyl) -2- (2-trimethylsilylethoxymethyl) pyrazol-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a mixture of 2- [ [ 5-bromo-3- (difluoromethyl) pyrazol-1-yl ] methoxy ] ethyl-trimethyl-silane (5.3 g,16.2mmol,1eq, cas 2416163-95-4), 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (5.97 g,17.8mmol,1.1eq, cas 2763647-64-7) and potassium carbonate (4.47 g,32.4mmol,2 eq) in 1, 4-dioxane (50 mL) and water (5 mL) was added under N 2, cyclopenta-2, 4-dien-1-yl (diphenyl) phosphine, dichloromethane, palladium dichloride, iron (2+) (1.32g,1.62mmol,0.1eq,CAS 95464-05-4). The mixture was stirred under an atmosphere of N 2 at 100 ℃ for 2h. The reaction mixture was poured into water (500 mL). The aqueous phase was extracted with EtOAc. The organic phase was washed with brine (600 mL), dried over anhydrous Na 2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=100/1 to 1/1) to give tert-butyl 6- [ [5- (difluoromethyl) -2- (2-trimethylsilylethoxymethyl) pyrazol-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (6.1 g,13.39mmol, yield 79%) as a pale yellow solid. MS (ESI) m/z=456.3 [ M+H ] +.
Step 2 6- [ [5- (difluoromethyl) -2- (2-trimethylsilylethoxymethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [5- (difluoromethyl) -2- (2-trimethylsilylethoxymethyl) pyrazol-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (7 g,15.36mmol,1 eq) in EtOAc (100 mL) under N 2 was added Pd/C10% (2 g,4.61mmol,0.3 eq). The mixture was stirred under an atmosphere of H 2 (15 PSI) at 25℃for 0.5H. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6- [ [5- (difluoromethyl) -2- (2-trimethylsilylethoxymethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (6 g, yield 85%) as a colorless oil.
Step 3 6- [ [3- (difluoromethyl) -1H-pyrazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane, 2-trifluoroacetate
To a solution of tert-butyl 6- [ [5- (difluoromethyl) -2- (2-trimethylsilylethoxymethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (6 g,13.1mmol,1 eq) in dichloromethane (40 mL) was added 2, 2-trifluoroacetic acid (20 mL) at 0 ℃. The mixture was stirred at 20 ℃ for 16h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18:250:80 mm x 10um; mobile phase: [ water (TFA) -ACN ]; B%:1% to 30%,20 min) to give 6- [ [3- (difluoromethyl) -1H-pyrazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane; 2, 2-trifluoroacetic acid (3.94 g, 87% yield) as a white solid. MS (ESI) m/z=228.2 [ m+h ] +.
Similar to structural unit p.62, the following structural units were generated in step 1 using the relevant heteroaryl bromide for the reaction.
Structural unit P.69 [4- (2-azaspiro [3.3] heptane-6-ylmethyl) -3-fluoro-phenyl ] -imino-oxo- (trifluoromethyl) -lambda 6 -sulfane, 4-methylbenzenesulfonic acid
Step 1-bromo-2-methylsulfinyl-4- (trifluoromethyl) benzene
1-Bromo-2-methylsulfanyl-4- (trifluoromethyl) benzene (3.7g,13.6mmol,1eq,CAS 142994-07-8) was dissolved in trifluoroacetic acid (37 mL,480mmol,35 eq). A solution of hydrogen peroxide (1.15 mL,13.6mmol,1 eq) in water (1.2 mL) was added at 0deg.C. The mixture was stirred at room temperature for 12h. The reaction mixture was concentrated in vacuo and diluted between DCM and aqueous NaHCO 3. The organic layer was dried over Na 2SO4 and concentrated in vacuo to give 1-bromo-2-methylsulfinyl-4- (trifluoromethyl) benzene (3.3 g,11.49mmol, 75% yield) as a pale yellow oil. MS (ESI) m/z=288.9 [ m+h ] +.
Step 2 [ 2-bromo-5- (trifluoromethyl) phenyl ] -imino-methyl-oxo-lambda 6 -sulfane
A30 mL sealed tube was charged with a solution of 1-bromo-2-methylsulfinyl-4- (trifluoromethyl) benzene (2.5 g,8.7mmol,1 eq), amino-4-nitrobenzoate, trifluoromethanesulfonic acid (7.23 g,21.7mmol,2.5eq, CAS 2055895-59-3), ferrous sulfate (264mg,1.74mmol,0.2eq,CAS 7720-78-7) and 1, 10-phenanthroline (627mg,3.48mmol,0.4eq,CAS 66-71-7) in ACN (20 mL). The reaction mixture was stirred at 30 ℃ for 48h. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO 3 solution (5 mL). The organic layer was separated, dried over anhydrous Na 2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 120g, acetonitrile in chloroform 0% to 50%) to give [ 2-bromo-5- (trifluoromethyl) phenyl ] -imino-methyl-oxo- λ6-sulfane (900 mg,3mmol, yield 30%) as a pale yellow solid. MS (ESI) m/z=302/304 [ M+H ] +.
Step 3 6- [ [2- (methyliminosulfonyl) -4- (trifluoromethyl) phenyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a stirred suspension of 6- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (998 mg,3mmol,1eq, cas 2763647-64-7), [ 2-bromo-5- (trifluoromethyl) phenyl ] -imino-methyl-oxo- λ6-sulfane (900 mg,3mmol,1 eq) and potassium carbonate (823 mg,6mmol,2 eq) in 1, 4-dioxane (30 mL) and water (6 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (364mg,0.45mmol,0.15eq,CAS 95408-45-0). The reaction mixture was stirred at 110 ℃ for 48h. The reaction mixture was concentrated in vacuo and diluted between EtOAc and brine. The organic layer was dried over Na 2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 80g, hexane/t-butyl methyl ether/methanol) to give t-butyl 6- [ [2- (methyliminosulfonyl) -4- (trifluoromethyl) phenyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (450 mg, yield 32%) as a white solid. MS (ESI) m/z=375.2 [ M-C 4H8+H]+.
Step 4 6- [ [2- (methyliminosulfonyl) -4- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Tert-butyl 6- [ [2- (methyliminosulfonyl) -4- (trifluoromethyl) phenyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (320 mg,0.74mmol,1 eq) was dissolved in EtOAc (30 mL) and hydrogenated over palladium on C (79 mg,0.07mmol,0.1 eq) at 22800mmHg for 10h. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6- [ [2- (methyliminosulfonyl) -4- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (300 mg, 86% yield) as a colorless oil. MS (ESI) m/z=333.2 [ M-C 4H8+H]+.
Step 5 [4- (2-azaspiro [3.3] heptan-6-ylmethyl) -3-fluoro-phenyl ] -imino-oxo- (trifluoromethyl) -lambda 6 -sulfane, 4-methylbenzenesulfonic acid
P-toluenesulfonic acid monohydrate (158 mg,0.83mmol,1.2 eq) was added to a stirred solution of tert-butyl 6- [ [2- (methyliminosulfonyl) -4- (trifluoromethyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (300 mg,0.69mmol,1 eq) in EtOAc (30 mL). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was concentrated in vacuo. The residue was purified by HPLC to give [2- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- (trifluoromethyl) phenyl ] -imino-methyl-oxo- λ6-sulfane, 4-methylbenzenesulfonic acid (137 mg, yield 37%) as a white solid. MS (ESI) m/z=333.0 [ M+H ] +.
Similar to structural unit P.69, the following structural units were generated in step 1 using the relevant bromo-methylthiobenzene compound for the reaction.
Structural unit P.113 2, 2-trifluoroacetic acid, 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane
To a solution of tert-butyl 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (180 mg, 452. Mu. Mol,1 eq) in dichloromethane (1.5 mL) was added TFA (516 mg,348uL,4.53mmol,10 eq). The reaction mixture was stirred at RT for 18h.
The reaction mixture was concentrated in vacuo to give 365mg of crude desired product as a near brown viscous oil with a purity of about 50%. MS (ESI) m/z=298.2 [ M+H ] +.
Step 1 6- [ (5-bromopyrimidin-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (5.88 g,17.55mmol,1eq, cas 2763647-64-7), 5-bromo-2-iodopyrimidine (5 g,17.55mmol,1 eq) in 1, 4-dioxane (75 mL) and water (15 mL) was added potassium carbonate (4.85 g,35.1mmol,2 eq) and 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.43g,1.76mmol,0.1eq,CAS 95464-05-4) at 20 ℃. The mixture was stirred at 80 ℃ under an atmosphere of N 2 for 12h. The residue was purified by flash chromatography on silica gel eluting with PE/EtOAc (5:1) to give tert-butyl 6- [ (5-bromopyrimidin-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (4.6 g,12.56mmol, 71% yield) as a white solid. MS (ESI) m/z=312.0 [ M-C 4H8+H]+.
Step 2 6- [ (5-bromopyrimidin-2-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (5-bromopyrimidin-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (4.8 g,13.11mmol,1 eq) in EtOAc (48 mL) at 25℃was added PtO 2 (1.63 g,7.19mmol,0.55 eq). The mixture was stirred at 25℃for 2.5H under an atmosphere of H 2 (15 PSI).
The reaction mixture was filtered and the residue was purified by flash chromatography on silica gel eluting with PE/EtOAc (3:1) to give tert-butyl 6- [ (5-bromopyrimidin-2-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.87 g,5.08mmol, 38% yield) as a white solid. MS (ESI) m/z=314.0 [ M-C 4H8+H]+.
Step 3 6- [ [5- [1- (trifluoromethyl) vinyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 4, 6-trimethyl-2- [1- (trifluoromethyl) vinyl ] -1,3, 2-dioxaborolan (1.52 g,6.84mmol,1.2eq, CAS 1011460-68-6) and 6- [ (5-bromopyrimidin-2-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (2.1 g,5.7mmol,1 eq), potassium carbonate (1.58 g,11.4mmol,2 eq) in 1, 4-dioxane (20 mL) and water (4 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (465mg,0.57mmol,0.1eq,CAS 95464-05-4). The mixture was stirred at 80 ℃ under an atmosphere of N 2 for 12h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with PE/EtOAc (3:1) to give tert-butyl 6- [ [5- [1- (trifluoromethyl) vinyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.05 g,5.35mmol, 93% yield) as a white solid. MS (ESI) m/z=328.0 [ M-C 4H8+H]+.
Step 4 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [5- [1- (trifluoromethyl) vinyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.05 g,5.35mmol,1 eq) in THF (35 mL) was added diphenyl (methyl) sulfonium tetrafluoroborate (2 g,6.95mmol,1.3eq, CAS 10504-60-6). NaHMDS/THF (8.55 mL,8.55mmol,1.6 eq) was added dropwise at 0deg.C. The reaction mixture was stirred at 25 ℃ for 1h. The reaction mixture was poured into saturated aqueous NH 4 Cl (80 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with PE/EtOAc (2:1) to give the crude product. The crude product was purified by preparative HPLC (column, [ Phenomenex luna C18.250.50 mm.10 um ]; mobile phase: [ ACN ] and [ H2O ] (conditions: [ water (0.225% FA) -ACN ], B%:65% to 90%; detector, UV 254nm. RT: [22min ]) to give tert-butyl 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.1 g,2.78mmol, yield 52%) as a white solid MS (ESI): m/z=342.1 [ M-C 4H8+H]+).
Similar to structural unit P.113, the following structural units are generated using the relevant heteroaryl bromides or heteroaryl chlorides.
Structural unit P.119:6- [ [4- (trifluoromethylsulfonyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane 4-methylbenzenesulfonic acid
A mixture of tert-butyl 6- [ [4- (trifluoromethylsulfonyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (630 mg,1.54 mmol) and p-toluenesulfonic acid (317 mg,1.85mmol,1.2 eq) in EtOAc (20 mL) was stirred under a N 2 balloon at 80℃for 12h. The reaction mixture was concentrated in vacuo and the residue was dissolved in H 2 O (30 mL). The solution was lyophilized to give 6- [ [4- (trifluoromethylsulfonyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane 4-methylbenzenesulfonic acid (732 mg,1.53mmol, 97% yield) as a pale yellow solid. MS (ESI) m/z=310.1 [ M+H ] +.
Step 1 6- [ (4-iodopyrazol-1-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Copper diacetate (49.4 g,247 mmol) was added to a solution of tert-butyl 6- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (45.6 g,136mmol, CAS 2763647-64-7), 4-iodopyrazole (24.0 g,123 mmol), boric acid (7.65 g,123 mmol) and pyridine (30 mL,371 mmol) in DCE (230 mL) under an O 2 atmosphere. The mixture was stirred at 70 ℃ for 12h under O 2 atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with PE/EtOAc (4:1) to give the crude product, which was purified by preparative HPLC (water (FA) -ACN 55% to 75%) to give the title compound as a white solid (17.7 g,44.1mmol, 35.6% yield). MS (ESI) m/z=346.0 [ M-C 4H8+H]+.
Step 2 6- [ [4- (trifluoromethylthio) pyrazol-1-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (4-iodopyrazol-1-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (30 mg,0.07 mmol) in ACN (3 mL) was added silver (I) triflate (46.9mg,0.22mmol,CAS 811-68-7), cuI (28.5 mg,0.15 mmol) and 2-pyridin-2-ylpyridine (23.4 mg,0.15 mmol) in a sealed tube. The reaction mixture was stirred at 90 ℃ for 12h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (water (FA) -ACN ]52% to 82%) to give the title compound (13.0 mg,0.03mmol, 46% yield) as yellow solid. MS (ESI) m/z=320.1 [ M-C 4H8+H]+.
Step 36- [ [4- (trifluoromethylthio) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [4- (trifluoromethylthio) pyrazol-1-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (2.8 g,7.46 mmol) in EtOAc (50 mL) was added Pd/C (1 g,0.75 mmol) at 25℃and stirred under a H 2 balloon (760 mm Hg) for 1H. The reaction mixture was filtered and concentrated in vacuo to give the title compound (2.8 g,7.42mmol, 99% yield) as a white solid. MS (ESI) m/z=322.2 [ M-C 4H8+H]+.
Step 4 6- [ [4- (trifluoromethylsulfonyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [4- (trifluoromethylthio) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1 g,2.65 mmol) in 1, 2-dichloroethane (4 mL), ACN (4 mL) and water (8 mL) at 0℃was added sodium periodate (1.13g,5.3mmol,CAS 811-68-7) and ruthenium (III) chloride hydrate (59.7 mg,0.26mmol, CAS 14898-67-0), and the mixture was stirred at 25℃for 12h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (water (FA) -ACN 50% to 80%) to give the title compound (630 mg,1.54mmol, 58% yield) as a grey solid. MS (ESI) m/z=354.3 [ M-C 4H8+H]+ ].
Structural unit P.123, 6- [ [ 1-cyclopropyl-3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid
To a mixture of tert-butyl 6- [ [ 1-cyclopropyl-3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (780 mg,2.05 mmol) in EtOAc (8 mL) at 25 ℃ was added p-toluene sulfonic acid (3838 mg,2.25 mmol), the reaction mixture was stirred at 80 ℃ for 12h and concentrated in vacuo. To the residue was added 20mL deionized water and 2mL ACN, and the residue was lyophilized to give the title compound (811 mg,1.77mmol, yield 85%) as a yellow oil. MS (ESI) m/z=286.1 [ M-TsOH+H ] +.
Step 1 6- [ [5- (trifluoromethyl) -1H-pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (5 g,14.9mmol, cas 2763647-64-7), 4-bromo-5- (trifluoromethyl) -1H-pyrazole (2.92 g,13.6 mmol) in 1, 4-dioxane (73 mL), water (14.6 mL) was added potassium carbonate (3.75 g,27.2 mmol), 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (554 mg,0.68 mmol) at 20 ℃. The reaction mixture was stirred at 100 ℃ for 12h under N 2. The reaction mixture was filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography (0% to 40% ethyl acetate/petroleum ether eluent) to give a crude product, which was further purified by flash chromatography (0% to 40% ethyl acetate/petroleum ether eluent) to give the title compound (79mg, 2.3mmol, 17% yield) as a yellow oil. MS (ESI) m/z=288.0 [ M-C 4H8+H]+.
Step 2 6- [ [ 1-cyclopropyl-3- (trifluoromethyl) pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a mixture of tert-butyl 6- [ [5- (trifluoromethyl) -1H-pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (600 mg,1.75 mmol), cyclopropylboronic acid (600 mg,6.99 mmol) in DCE (6 mL) was added pyridine (0.42 mL,5.24 mmol), boronic acid (108 mg,1.75 mmol), copper diacetate (698 mg,3.5 mmol) at 20 ℃. The reaction mixture was stirred at 100 ℃ for 16h under O 2 (balloon). The reaction mixture was filtered and diluted with 50mL of water and extracted with EtOAc 150mL (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na 2SO4, filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography (0% to 28% ethyl acetate/petroleum ether) to give the title compound (350 mg,0.91mmol, 52%) as a colorless oil. MS (ESI) m/z=328.0 [ M-C 4H8+H]+.
Step 3 6- [ [ 1-cyclopropyl-3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Pd/C (wet 216mg, 10%) was added to a mixture of tert-butyl 6- [ [ 1-cyclopropyl-3- (trifluoromethyl) pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (720 mg,1.88 mmol) in EtOAc (15 mL) at 25 ℃. The reaction mixture was stirred at 25℃for 0.5H under H 2 (15 Psi). The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (640 mg,1.66mmol, 88% yield) as a colorless oil. MS (ESI) m/z=330.0 [ M-C 4H8+H]+.
Structural unit P.126 [1- (2-azaspiro [3.3] heptan-6-ylmethyl) pyrazol-4-yl ] -imino-oxo- (trifluoromethyl) -lambda 6 -sulfane, 4-methylbenzenesulfonic acid
A mixture of tert-butyl 6- [ [4- (trifluoromethyiiminosulfonyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (650 mg,1.59 mmol) and p-toluenesulfonic acid (329 mg,1.91 mmol) in EtOAc (10 mL) was stirred under a N 2 balloon at 80℃for 12h. The reaction mixture was concentrated in vacuo and the residue was dissolved in H 2 O (30 mL). The solution was lyophilized to give the title compound (623 mg,1.3mmol, yield 77%) as a pale yellow oil. MS (ESI) m/z=309.1 [ M+H ] +.
Step 1 6- [ [4- (trifluoromethylsulfinyl) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A mixture of tert-butyl 6- [ [4- (trifluoromethylthio) pyrazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (P.119, step 3) (1.8 g,4.77 mmol), phI (OAc) 2 (6.14 g,19.1 mmol) and ammonium carbamate (1.49 g,19.1 mmol) in trifluoroethanol was stirred at 30℃for 12h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (water (FA) -ACN,60% to 80%) to give the title compound (650 mg,1.59mmol, 33% yield) as a grey solid. MS (ESI) m/z=353.1 [ M-C 4H8+H]+.
Structural units P.132 and P.156 4-methylbenzenesulfonic acid, 6- [ [2- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane and 4-methylbenzenesulfonic acid, 6- [ [1- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane
A solution of p-toluenesulfonic acid (247 mg,1.43 mmol) and tert-butyl 6- [ [2- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (510 mg,1.19 mmol) in EtOAc (5 mL) was stirred at 80℃for 12h. The mixture was concentrated in vacuo. Deionized water was added to the residue and lyophilized to give the title compound (550 mg,1.1mmol, 92% yield) as a colorless oil. MS (ESI) m/z=328.0 [ M+H ] +.
Step 1 6- [ [5- (trifluoromethyl) -1H-pyrazol-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 3-bromo-5- (trifluoromethyl) -1H-pyrazole (9g,41.87mmol,1eq,CAS 93608-11-8), 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (14g,41.8mmol,1eq CAS2763647-64-7), potassium carbonate (11.57 g,83.7mmol,2 eq) in 1, 4-dioxane (10 mL) and water (2 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (3.42g,4.19mmol,0.1eq,CAS 95464-05-4) at 25 ℃. The reaction mixture was stirred at 80 ℃ for 12h under N 2. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (SILICA FLASH Column, eluent of 0-46% ethyl acetate/petroleum ether gradient) (petroleum ether: ethyl acetate=1:1, rf=0.6) to give tert-butyl 6- [ [5- (trifluoromethyl) -1H-pyrazol-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (7.0 g,20.3mmol, yield 48%) as a white solid. MS (ESI) m/z=288.0 [ M-C 4H8+H]+.
Step 2 6- [ [5- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [5- (trifluoromethyl) -1H-pyrazol-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (1.26 g,3.67mmol,1 eq) in EtOAc (20 mL) was added Pd/C (505 mg,0.65mmol,0.18 eq) under N 2. The suspension was degassed under vacuum and purged with H 2. The reaction was stirred at 25℃for 0.5H under H 2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl 6- [ [5- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.26 g,3.65mmol, 99%) as a colorless oil. MS (ESI) m/z=290.0 [ M-C 4H8+H]+.
Step 3 6- [ [2- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester and 6- [ [1- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [5- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (13.7 g,39.67mmol,1 eq) in THF (278 mL) at 0deg.C was added NaH (2.38 g,59.5mmol,1.5 eq) for 0.5H. 2, 2-trifluoroethyl triflate (18.41g,79.3mmol,2eq,CAS 6226-25-1) was added at 20 ℃. The reaction mixture was stirred at room temperature for 12h. The reaction mixture was slowly quenched with ice and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Welch Ultimate XB-SiOH 250 x 50 x 10um, hexane-EtOH (0.1% nh 3.h2o)) and concentrated in vacuo to give tert-butyl 6- [ [1- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2 g,4.68mmol, 11% yield) as a colorless oil. MS (ESI) m/z=372.1 [ M-C 4H8+H]+ ] and 6- [ [2- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (8.74 g,20.45mmol, 51% yield) as a white solid. MS (ESI) m/z=372.1 [ M-C 4H8+H]+.
Step 4-4-Methylbenzenesulfonic acid 6- [ [2- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane (P.132) and 6- [ [1- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane (P.156).
In analogy to the structural unit p.1, step 3, 6- [ [2- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester and 6- [ [1- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester were treated with a solution of 4-methylbenzenesulfonic acid monohydrate at 80 ℃ for 12h to give 4-methylbenzenesulfonic acid, 6- [ [2- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane (586 mg,1.17mmol, 98% yield) as colorless oil. MS (ESI) m/z=328.0 [ M+H ] + (P.132), and 4-methylbenzenesulfonic acid, 6- [ [1- (2, 2-trifluoroethyl) -5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane (2.06 g,4.13mmol, 88% yield) as an off-white solid. MS (ESI) m/z=328.0 [ M+H ] +. (P.156).
Structural unit P.136 4-methylbenzenesulfonic acid 6- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane
To a mixture of tert-butyl 6- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.05 g,2.46mmol,1 eq) in EtOAc (10 mL) was added p-toluene sulfonic acid (460 mg,2.7mmol,1.1 eq) at 20 ℃. The reaction mixture was stirred at 80 ℃ for 12h. The reaction mixture was concentrated in vacuo. 20mL of deionized water and 2mL of acetonitrile were added, followed by lyophilization, to give 4-methylbenzenesulfonic acid, 6- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane (1.22 g,2.45mmol, yield 99%) as a pale yellow oil. MS (ESI) m/z=328.0 [ M+H ] +.
Step 1 6- [ [5- (trifluoromethyl) -1H-pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A solution of 4-bromo-5- (trifluoromethyl) -1H-pyrazole (8.35G, 38.84mmol,1eq, CAS 19968-17-3), 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (14.32g,42.73mmol,1.1eq,CAS 2763647-64-7), cs 2CO3 (77.69 mL,116.53mmol,3 eq) in 2-methylbutan-2-ol (90 mL, 823mmol, 21 eq) was added to Ad2nBuP-Pd-G3 (2.82G, 3.88mmol,0.1eq, CAS 1653-59-4) under an atmosphere of N 2. The reaction mixture was stirred at 90 ℃ for 16h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (400 mL). The organic phase was washed with brine (800 mL), dried over Na 2SO4 and purified by column chromatography (SiO 2, PE/acoet=1/0 to 1/1, PE/acoet=1/1, desired product rf=0.3) to give tert-butyl 6- [ [5- (trifluoromethyl) -1H-pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (9 g,26.2mmol, 67% yield) as yellow oil. MS (ESI) m/z=288.1 [ M-C 4H8+H]+.
Step 26- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a mixture of tert-butyl 6- [ [5- (trifluoromethyl) -1H-pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (2 g,5.83mmol,1 eq), cesium carbonate (5.69 g,17.48mmol,3 eq) in DMF (20 mL) was added a solution of 2, 2-trifluoroethyl triflate (2.7g,11.65mmol,2eq,CAS 6226-25-1) in DMF (2 mL) at 0 ℃. The mixture was stirred at 20 ℃ for 12h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with 50mL (50 mL) of saturated aqueous NaCl, dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (isco @;80g SepaFlash@Silica Flash Column,0~28% EtOAc/PE gradient of eluent at 60mL/min, rf=0.45) to give tert-butyl 6- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (1.1 g,2.59mmol, 44% yield) as a white solid. MS (ESI) m/z=370.0 [ M-C4H8+H ] +.
Step 3 6- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Pd/C (300 mg,10%, wet) was added to a mixture of tert-butyl 6- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (1 g,2.35mmol,1 eq) in EtOAc (10 mL) at 20 ℃. The reaction mixture was stirred at 20 ℃ for 1H under H 2. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6- [ [1- (2, 2-trifluoroethyl) -3- (trifluoromethyl) pyrazol-4-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.05 g,2.46mmol, yield 104%) as a colorless oil. MS (ESI) m/z=372.0 [ M-C 4H8+H]+.
Similar to structural unit P.136, the following structural units were generated in step 1 using the relevant heteroaryl halides for cross-coupling.
Structural unit P.137 2- [6- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- (trifluoromethyl) pyrrolo [2,3-b ] pyridin-1-yl ] ethanol; 4-methylbenzenesulfonic acid
In a sealed vial, a solution of tert-butyl 6- [ [1- [2- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -3- (trifluoromethyl) pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (80 mg,144.47 μmol,1 eq) and p-toluenesulfonic acid monohydrate (56 mg,296 μmol,2.05 eq) in ethyl acetate (0.5 mL) was stirred at reflux for 20 minutes. The suspension was allowed to cool to room temperature and then filtered. The filter cake was washed with ethyl acetate to give 2- [6- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- (trifluoromethyl) pyrrolo [2,3-b ] pyridin-1-yl ] ethanol, 4-methylbenzenesulfonic acid as a colorless solid (82 mg, 78% yield). MS (ESI) m/z=340.2 [ M+H ] +.
Step 16- [ [3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A mixture of 6-bromo-3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridine (560 mg,2.13mmol,1.1eq, CAS 1934574-07-8), 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (650mg,1.94mmol,1eq,CAS 2763647-64-7), chloro (crotyl) (tri-tert-butylphosphine) palladium (II) (38 mg, 96.94. Mu. Mol,0.05eq, CAS1334497-00-5 eq) and tripotassium phosphate (823 mg,3.88mmol,2 eq) in1, 4-dioxane (13 mL) and water (1.3 mL) was degassed with argon. The solution was stirred in a sealed vial at 70 ℃ overnight. The reaction mixture was poured over water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography, which was separated on a 25g column using MPLC (ISCO) system, eluting with a gradient of n-heptane to ethyl acetate (100:0 to 0:100) to give tert-butyl 6- [ [3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate as a pale yellow solid (0.323 g, 40% yield). MS (ESI) m/z=394.2 [ M+H ] +.
Step 2 6- [ [3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (500 mg,1.27mmol,1 eq) in EtOAc (8 mL) was added Pd/C (175 mg,0.22mmol,0.18 eq) under N 2. The suspension was degassed under vacuum and purged with H 2. The reaction mixture was stirred at 25℃for 0.5H under H 2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl 6- [ [3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (440 mg,1.11mmol, yield 85%) as a pale brown solid. MS (ESI) m/z=340.0 [ M-C 4H8+H]+.
Step 3 6- [ [1- [2- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -3- (trifluoromethyl) pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To an ice-cold solution of tert-butyl 6- [ [3- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (186 mg,470 μmol,1 eq) in DMF (1.5 mL) was added NaH (20 mg,517.42 μmol,1.1 eq) and the mixture was stirred at this temperature for 30 min. After addition of (2-bromoethoxy) -tert-butyldimethylsilane (123 mg,111.52ul, 517.42. Mu. Mol,1 eq) stirring was continued overnight at room temperature. The mixture was poured onto half-saturated aqueous NH 4 Cl and ethyl acetate, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed twice with water, dried over MgSO 4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography, which was separated on a 4g column using an MPLC (ISCO) system, eluting with a gradient of n-heptane: ethyl acetate (100:0 to 65:35) to give tert-butyl 6- [ [1- [2- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -3- (trifluoromethyl) pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate as a colorless oil (208 mg, 79% yield). MS (ESI) m/z=554.4 [ M+H ] +.
Structural unit P.143 6- [ difluoro- [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ difluoro- [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (77 mg, 196. Mu. Mol) in isopropyl acetate (3 mL) was added p-toluenesulfonic acid monohydrate (82 mg, 432. Mu. Mol). The mixture was stirred at 80 ℃ for 3h. The reaction mixture was concentrated in vacuo to give 6- [ difluoro- [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid (163 mg, 99% yield) as a colorless oil. MS (ESI) m/z=293.0 [ M+H ] +.
Step 1 6- [6- (trifluoromethyl) pyridine-3-carbonyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ methoxy (methyl) carbamoyl ] -2-azaspiro [3.3] heptane-2-carboxylate (4.3 g,15.1mmol, cas 2428601-18-5) and 5-bromo-2- (trifluoromethyl) pyridine (6.83g,30.2mmol,CAS 436799-32-5) in THF (100 mL) was added n-BuLi (18.2 mL,45.4 mmol) at-78 ℃ for 1h. The reaction mixture was stirred at 30 ℃ for 12h. The reaction mixture was poured into saturated aqueous NH 4 Cl (500 mL) and extracted with ethyl acetate. The organic layer was washed with brine. The residue was purified by flash chromatography on silica eluting with PE/EtOAc (2:1) to give the title compound (1400 mg,3.78mmol, 25% yield) as a brown solid. MS (ESI) m/z=315.1 [ M-C 4H8+H]+.1 H NMR (400 MHz, methanol) -d4)δ＝9.17(s,1H),8.49(dd,J＝1.5,8.3Hz,1H),7.95(d,J＝8.3Hz,1H),4.11-3.99(m,3H),3.84(s,2H),2.65-2.48(m,4H),1.43(s,9H).
Note that the regioisomer, tert-butyl 6- [2- (trifluoromethyl) pyridine-4-carbonyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1100 mg,2.97mmol, 20% yield) was formed simultaneously as a brown oil. 1 H NMR (400 MHz, methanol -d4)δ＝8.92(d,J＝5.0Hz,1H),8.15(s,1H),8.04(dd,J＝1.1,4.9Hz,1H),4.03(s,3H),3.83(s,2H),2.55(br dd,J＝8.3,12.1Hz,4H),1.43(s,9H).)
Step 2 6- [ difluoro- [6- (trifluoromethyl) -3-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
DAST (5 mL,37.8 mmol) was added dropwise to a solution of tert-butyl 6- [6- (trifluoromethyl) pyridine-3-carbonyl ] -2-azaspiro [3.3] heptane-2-carboxylate (750 mg,2.03 mmol) in DCM (5 mL) at 0℃under an atmosphere of N 2. The reaction mixture was stirred at 25 ℃ for 12h. The reaction mixture was added dropwise to saturated aqueous NaHCO 3 (200 mL) and extracted with DCM (50 mL x 2). The combined organic layers were dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (water (FA) -ACN 58% to 88%) to give the title compound (510 mg,1.3mmol, 64% yield) as a pale yellow solid .MS(ESI)：m/z＝337.0[M-C4H8+H]+;1H NMR(400MHz,METHANOL-d4)δ＝8.87(s,1H),8.26-8.13(m,1H),7.94(d,J＝8.3Hz,1H),4.03-3.83(m,4H),3.18-2.96(m,1H),2.47-2.27(m,4H),1.44(s,9H).
Similar to structural unit P.143, the following structural units were generated using the relevant heteroaryl bromides. In some cases, alternative salts (e.g., trifluoroacetate, xylene sulfonate, hydrochloride) are also used.
Structural units P.139 and P.140 6- [ (1R) -1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid and 6- [ (1S) -1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid
(Enantiomer is arbitrarily assigned)
A solution of 6- [ (1R) -1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (250 mg,0.65 mmol) and p-toluenesulfonic acid monohydrate (309 mg,1.63 mmol) in EtOAc (10 mL) was stirred at 60℃for 3h. After cooling to RT, the obtained precipitate was filtered, washed with EtOAc and dried in vacuo to give the title compound p.139 (237 mg,0.38mmol, 55% yield) as a white solid. MS (ESI) m/z=285.2 [ M+H ] +. Deprotection of the other enantiomer was performed in a similar manner to give the title compound p.140 (241 mg,0.38mmol, 58% yield) as a white solid. MS (ESI) m/z=285.2 [ M+H ] +.
Step 1 6- [1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) ethylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a stirred solution of 2, 6-tetramethylpiperidine (4.31 mL,25.6 mmol) in THF (75 mL) at-30℃under Ar was added n-BuLi (2.5M in hexane) (10.2 mL,25.6 mmol). The solution was stirred at-30 ℃ for 30min and cooled to-78 ℃. A solution of 4, 5-tetramethyl-2- [1- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) ethyl ] -1,3, 2-dioxapentaborane (6.61 g,23.4mmol, CAS 1227056-25-8) in 10mL anhydrous THF was added dropwise and the reaction mixture stirred at-78℃for 30min. A solution of tert-butyl 6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (4.5 g,21.3 mmol) in 15mL anhydrous THF was added dropwise at-78℃and the reaction mixture was allowed to warm and stirred at room temperature overnight. The reaction was quenched with water and the mixture was concentrated in vacuo. The residue was separated between water and DCM. The organic layer was washed with citric acid, water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (1:4 tbme/hexane) to give the title compound (3.1 g,8.88mmol, yield 41%) as a white solid. MS (ESI) m/z=294.2 [ M-C 4H8+H]+ ].
Step 2 6- [1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a stirred suspension of 2-chloro-4-methyl-5- (trifluoromethyl) pyridine (1.36g,6.93mmol,CAS 780802-36-0), 6- [1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) ethylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (2.2 g,6.3 mmol) and cesium carbonate (4.1 g,12.6 mmol) in anhydrous 1, 4-dioxane (110 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (771mg,0.94mmol,CAS 95464-05-4). The mixture was stirred under argon atmosphere at 80 ℃ for 48h. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The residue obtained was partitioned between EtOAc and water. The organic layer was dried over Na 2SO4 and concentrated to give the crude product, which was purified by column chromatography (hexane/MTBE 10% to 23%) to give the title compound (700 mg,1.83mmol, yield 28%) as a pale yellow solid. MS (ESI) m/z=327.2 [ M-C 4H8+H]+.
Step 3 6- [1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
In an autoclave, a stirred mixture of 6- [1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (700 mg,1.83 mmol) and Pd/C (5%) (200 mg) in EtOAc (50 mL) was hydrogenated at 15200mmHg (20 bar) at 25℃for 24h. The reaction mixture was filtered and concentrated in vacuo to give the title compound (680 mg,1.77mmol, 92% yield) as an orange gum; MS (ESI): m/z=329.0 [ m-C 4H8+H]+. A mixture of enantiomer 6- [1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (680 mg,1.77 mmol) was separated by chiral chromatography to give 6- [ (1S) -1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (270 mg,0.7mmol, 40% yield) (or enantiomer), retention time (min) 11.2, and 6- [ (1R) -1- [ 4-methyl-5- (trifluoromethyl) -2-pyridinyl ] ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (250 mg,0.65mmol, 37% yield) (or enantiomer), retention time (min) 13.9.
Structural unit P.146 2- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- (trifluoromethyl) -7H-pyrrolo [2,3-d ] pyrimidine, 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ [5- (trifluoromethyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (48 mg,1.1mmol,1 eq) in EtOAc (9.8 mL) was added p-toluenesulfonic acid monohydrate (749 mg,4mmol,3.5 eq). The mixture was stirred at 25 ℃ for 18h. The reaction mixture was concentrated in vacuo and the residue was treated with MTBE. The precipitate formed was filtered to give 2- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- (trifluoromethyl) -7H-pyrrolo [2,3-d ] pyrimidine, 4-methylbenzenesulfonic acid (729 mg,1.14mmol, 99% yield) as a pale yellow solid. MS (ESI) m/z=297.2 [ M+H ] +.
Step 16- (7H-pyrrolo [2,3-d ] pyrimidin-2-ylmethylene) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (2.2 g,6.6mmol,1.01eq, cas 2763647-64-7) and 2-chloro-7H-pyrrolo [2,3-d ] pyrimidine (1g,6.51mmol,1eq,CAS 335654-06-3), K 2CO3 (2.7 g,19.54mmol,3 eq) in 1, 4-dioxane (10 mL) and water (2 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (531mg,0.65mmol,0.1eq,CAS 95464-05-4). The mixture was stirred at 80℃for 12h under an N 2 balloon (760 mmHg). The reaction mixture was concentrated in vacuo and purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=2/1 to 1/1) to give tert-butyl 6- (7H-pyrrolo [2,3-d ] pyrimidin-2-ylmethylene) -2-azaspiro [3.3] heptane-2-carboxylate (650 mg,1.99mmol, yield 27%) as a pink solid. MS (ESI) m/z=327.2 [ M+H ] +.
Step 2 6- (7H-pyrrolo [2,3-d ] pyrimidin-2-ylmethyl) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- (7H-pyrrolo [2,3-d ] pyrimidin-2-ylmethylene) -2-azaspiro [3.3] heptane-2-carboxylate (650 mg,1.99mmol,1 eq) in EtOAc (10 mL) was added Pd/C (100 mg,0.6mmol,0.3 eq) under N 2. The suspension was degassed under vacuum and purged with H 2. The reaction was stirred at 25 ℃ for 1H under H 2 (15 psi) to give a black suspension. The precipitate was filtered off and the filtrate was dried in vacuo to give tert-butyl 6- (7H-pyrrolo [2,3-d ] pyrimidin-2-ylmethyl) -2-azaspiro [3.3] heptane-2-carboxylate (450 mg,1.37mmol, 68% yield) as a yellow solid. MS (ESI) m/z=329.3 [ M+H ] +.
Step 3 6- [ (5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- (7H-pyrrolo [2,3-d ] pyrimidin-2-ylmethyl) -2-azaspiro [3.3] heptane-2-carboxylate (650 mg,1.98mmol,1 eq) in ACN (20 mL) was added NIS (284 mg,2.38mmol,1.2 eq) and the reaction mixture was stirred at 25 ℃ for 2H to give a yellow suspension. The reaction mixture was added to water (20 ml) and the mixture was filtered. The filter cake was concentrated in vacuo to give tert-butyl 6- [ (5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (700 mg,1.54mmol, 75% yield) as a yellow solid. MS (ESI) m/z=455.1 [ M+H ] +.
Step 4 6- [ [ 5-iodo-7- (p-toluenesulfonyl) pyrrolo [2,3-d ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3, 3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (700 mg,1.54mmol,1 eq) in THF (5 mL) was added NaH (74 mg,1.85mmol,1.2 eq) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5h. 4-Methylbenzenesulfonyl chloride (587 mg,3.08mmol,2 eq) was added. The mixture was stirred at 25 ℃ for 12h to give a grey suspension. The reaction mixture was quenched by addition of 10mL of saturated aqueous NH 4 Cl at 0 ℃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with PE/EtOAc (PE/etoac=3:1) to give tert-butyl 6- [ [ 5-iodo-7- (p-toluenesulfonyl) pyrrolo [2,3-d ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (900 mg,1.48mmol, 96% yield) as a pale yellow solid. MS (ESI) m/z=455.1 [ M+H ] +.
Step 5 6- [ [5- (trifluoromethyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of benzyl tert-butyl 6- [ [ 5-iodo-7- (p-toluenesulfonyl) pyrrolo [2,3-d ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (900 mg,1.48mmol,1 eq) and copper (282 mg,4.44mmol,3 eq) in DMF (1 mL) was added diphenyl (trifluoromethyl) sulfonium, triflate (1.2 g,2.96mmol,2eq, CAS 147531-11-1). The reaction mixture was stirred at 80 ℃ for 12h and concentrated in vacuo. The residue was poured into water (10 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with PE/etoac=3:1 to give tert-butyl 6- [ [7- (p-toluenesulfonyl) -5- (trifluoromethyl) pyrrolo [2,3-d ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (300 mg,0.54mmol, 36% yield) as a pale red oil, and tert-butyl 6- [ [5- (trifluoromethyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (260 mg,0.66mmol, 44% yield) as a pale brown oil. MS (ESI) m/z=397.1 [ M+H ] +.
Structural unit P.161 6- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- (trifluoromethyl) -1, 2-benzoxazole; 4-methylbenzenesulfonic acid
A mixture of tert-butyl 6- [ [3- (trifluoromethyl) -1, 2-benzoxazol-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.4 g,3.53mmol,1 eq) and p-toluenesulfonic acid monohydrate (1 g,5.26mmol,1.49 eq) in EtOAc (100 mL) was stirred at 50deg.C for 3h. The reaction mixture was concentrated in vacuo and the resulting residue was stirred with TBME (100 mL) for 3h. The precipitate was filtered and dried to give 6- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- (trifluoromethyl) -1, 2-benzoxazole, 4-methylbenzenesulfonic acid (1.31 g,2.8mmol, yield 75.21%) as a white solid. MS (ESI) m/z=297.0 [ M+H ] +.
Step1 6- [ [ 3-fluoro-4- (2, 2-trifluoroacetyl) phenyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a stirred suspension of 6- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (3.72 g,11.1mmol,1eq, cas 2763647-64-7), 1- (4-bromo-2-fluoro-phenyl) -2, 2-trifluoro-ethanone (3.01g,11.1mmol,1eq,CAS 617706-18-0) and potassium carbonate (3.07 g,22.19mmol,2 eq) in 1, 4-dioxane (70 mL) and water (7 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.36g,1.66mmol,0.15eq,CAS 95464-05-4). The mixture was stirred at 80 ℃ for 18h. The reaction mixture was concentrated under vacuum. The residue was stirred with EtOAc (200 mL) and Na 2SO4. The mixture was filtered and concentrated in vacuo. The crude product was purified by FC to give tert-butyl 6- [ [ 3-fluoro-4- (2, 2-trifluoroacetyl) phenyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (2.8 g,7.01mmol, 58% yield) as a pale red solid. MS (ESI) m/z=300.0 [ M+H ] +.
FC conditions column Interchim, siO 2 (120 g), hexane/ethyl acetate (0% to 27%), flow = 80mL/min.
Step 2 6- [ [ 3-fluoro-4- (2, 2-trifluoroacetyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [ 3-fluoro-4- (2, 2-trifluoroacetyl) phenyl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (3 g,7.51mmol,1 eq) in EtOAc (150 mL) was added Pd/C (10%) (300 mg). The mixture was hydrogenated at 3800mmHg (in an autoclave) and then allowed to stir at room temperature for 36h. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give tert-butyl 6- [ [ 3-fluoro-4- (2, 2-trifluoroacetyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.0 g,7.47mmol, 90% yield) as a light brown oil. MS (ESI) m/z=346.0 [ M-C 4H8+H]+.
Step 3 6- [ [ 3-fluoro-4- [ N-hydroxy-C- (trifluoromethyl) carboimido ] phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [ 3-fluoro-4- (2, 2-trifluoroacetyl) phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3 g,7.47mmol,1 eq) in pyridine (40 mL) was added hydroxylamine, hydrochloride (0.93 g,13.45mmol,1.8 eq). The mixture was stirred at 50 ℃ for 18h. The mixture was concentrated in vacuo. The residue was stirred with water (50 mL) for 2h. The aqueous layer was decanted and the residue obtained was partitioned between TBME (100 mL) and water (15 mL). The organic layer was dried over Na 2SO4, filtered and concentrated in vacuo with toluene to give tert-butyl 6- [ [ 3-fluoro-4- [ N-hydroxy-C- (trifluoromethyl) carboimido ] phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.8 g,6.72mmol, 80% yield). MS (ESI) m/z=361.2 [ M-C 4H8+H]+.
Step 4 6- [ [3- (trifluoromethyl) -1, 2-benzooxazol-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A mixture of tert-butyl 6- [ [ 3-fluoro-4- [ N-hydroxy-C- (trifluoromethyl) carboimido ] phenyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.8 g,6.72mmol,1 eq) and potassium carbonate (1.39 g,10.09mmol,1.5 eq) in anhydrous DMF (60 mL) was stirred at 80℃for 18h. The reaction mixture was poured into water (300 mL) and extracted with EtOAc/TBME (100 mL/100 mL). The organic layer was washed with brine, dried over Na 2SO4 and concentrated in vacuo to give tert-butyl 6- [ [3- (trifluoromethyl) -1, 2-benzooxazol-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.5 g,3.78mmol, 53% yield). MS (ESI) m/z=341.0 [ M-C 4H8+H]+.
Structural unit P.162 1- (2-azaspiro [3.3] heptane-6-ylmethyl) -4- [1- (trifluoromethyl) cyclopropyl ] pyridin-2-one, 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ [ 2-oxo-4- [1- (trifluoromethyl) cyclopropyl ] -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (230 mg,0.56mmol,1 eq) in EtOAc (3 mL) was added p-toluenesulfonic acid (115 mg,0.67mmol,1.2 eq). The reaction was stirred at 80 ℃ for 12h. The reaction mixture was concentrated in vacuo. Deionized water (3 mL) was added to the residue, and the residue was then lyophilized to give 1- (2-azaspiro [3.3] heptane-6-ylmethyl) -4- [1- (trifluoromethyl) cyclopropyl ] pyridin-2-one, 4-methylbenzenesulfonic acid (236 mg,0.49mmol, 81% yield) as a yellow solid. MS (ESI) m/z=313.1 [ M+H ] +.
Step 16- [ (4-bromo-2-oxo-1-pyridinyl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 4-bromo-1H-pyridin-2-one (5 g,28.74mmol,1 eq) in DCE (100 mL) was added 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (11.56 g,34.48mmol,1.2eq, CAS 2763647-64-7), pyridine (4.55 g,57.47mmol,2 eq), boric acid (1.78 g,28.74mmol,1 eq) and Cu (OAc) 2 (7.75 g,38.79mmol,1.35 eq). The mixture was stirred at 70 ℃ under O 2 for 16h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/etoac=0:1, rf=0.4) and concentrated in vacuo to give tert-butyl 6- [ (4-bromo-2-oxo-1-pyridinyl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (2.74 g,7.19mmol, yield 25%) as a white solid. MS (ESI) m/z=325.0 [ M-C 4H8+H]+.
Step 2 6- [ (4-bromo-2-oxo-1-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (4-bromo-2-oxo-1-pyridinyl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (629 mg,1.65mmol,1 eq) in EtOAc (6 mL) was added PtO 2 (112 mg,0.49mmol,0.3 eq) under N 2. The suspension was degassed under vacuum and purged with H 2. The reaction was stirred at 25℃for 0.5H under H 2 (15 psi). The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/etoac=60%) (petroleum ether/etoac=1:1, rf=0.4) and concentrated in vacuo to give tert-butyl 6- [ (4-bromo-2-oxo-1-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (370 mg,0.97mmol, 58% yield) as a yellow oil. MS (ESI) m/z=327.0 [ M-C 4H8+H]+.
Step 3 6- [ [ 2-oxo-4- [1- (trifluoromethyl) vinyl ] -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ (4-bromo-2-oxo-1-pyridinyl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (300 mg,0.78mmol,1 eq) and 4, 6-trimethyl-2- [1- (trifluoromethyl) vinyl ] -1,3, 2-dioxaborolan (208 mg,0.94mmol,1.2eq, cas 1011460-68-6), K 2CO3 (324 mg,2.35mmol,3 eq) in 1, 4-dioxane (3 mL) and water (0.600 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (63.87mg,0.08mmol,0.1eq,CAS 95464-05-4). The mixture was degassed with N 2 and stirred under an atmosphere of N 2 at 80 ℃ for 12h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/etoac=60%) (petroleum ether/etoac=1:1, rf=0.4) and concentrated in vacuo to give tert-butyl 6- [ [ 2-oxo-4- [1- (trifluoromethyl) vinyl ] -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (360 mg,0.9mmol, 115% yield) as a yellow oil. MS (ESI) m/z=343.1 [ M-C 4H8+H]+.
Step 4 6- [ [ 2-oxo-4- [1- (trifluoromethyl) cyclopropyl ] -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [ 2-oxo-4- [1- (trifluoromethyl) vinyl ] -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (320 mg,0.8mmol,1 eq) in THF (3 mL) was added diphenyl (methyl) sulfonium tetrafluoroborate (323 mg,1.12mmol,1.4eq, CA 10504-60-6). NaHMDS/THF (1.36 mL,1.36mmol,1.69 eq) was added dropwise at 0deg.C. The reaction mixture was stirred under an atmosphere of N 2 at 25 ℃ for 1h. The reaction mixture was slowly added to 6mL of saturated aqueous NH 4 Cl. The mixture was added to 6mL of water and extracted with EtOAc (4 mL x 3). The organic phase was concentrated in vacuo. The crude product was purified by silica gel chromatography (PE: etoac=0:1) to give tert-butyl 6- [ [ 2-oxo-4- [1- (trifluoromethyl) cyclopropyl ] -1-pyridinyl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (250.0 mg,0.61mmol, 75% yield) as a yellow solid. MS (ESI) m/z=357.1 [ M-C 4H8+H]+.
Similar to structural unit p.162, the following structural units were generated in step 1 using the relevant heteroaryl compounds for Chan Lam type coupling.
Structural unit P.164 5- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazole, 2-trifluoroacetate acid
To a solution of tert-butyl 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (130 mg, 335. Mu. Mol,1 eq) in dichloromethane (1 mL) was added TFA (382 mg,258.53uL,3.36mmol,10 eq). The reaction mixture was stirred at room temperature for 18h. The reaction mixture was concentrated in vacuo to give 5- (2-azaspiro [3.3] heptane-6-ylmethyl) -3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazole, 2-trifluoro acetic acid (324 mg, 241% yield). MS (ESI) m/z=288.2 [ m+h ] +.
Step 1 6- [2- [ (Z) - [ amino- [1- (trifluoromethyl) cyclopropyl ] methylene ] amino ] oxy-2-oxo-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A solution of 2- (2-tert-butoxycarbonyl-2-azaspiro [3.3] heptan-6-yl) acetic acid (2.5 g,9.79mmol,1eq, CAS 1251002-39-7) and CDI (1905 mg,11.75mmol,1.2 eq) in DMF (30 mL) was stirred at room temperature for 3h. N' -hydroxy-1- (trifluoromethyl) cyclopropanecarboxamidine (1.64 g,9.79mmol,1eq, CAS 2174262-76-7) was added. The solution was stirred at 25 ℃ for 2h. The reaction mixture was purified by reverse phase HPLC (condition: water (0.02% FA), ACN) to give tert-butyl 6- [2- [ (Z) - [ amino- [1- (trifluoromethyl) cyclopropyl ] methylene ] amino ] oxy-2-oxo-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.5 g,3.7mmol, 37% yield) as a white solid. MS (ESI) m/z=350.1 [ M-C 4H8+H]+.
Step 2 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A mixture of 6- [2- [ (Z) - [ amino- [1- (trifluoromethyl) cyclopropyl ] methylene ] amino ] oxy-2-oxo-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.5 g,3.7mmol,1 eq) and tetrabutylammonium fluoride/THF (1.85 mL,1.85mmol,0.5 eq) in THF (20 mL) was stirred at 70℃for 1h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions: water (FA) -ACN, phenomenex luna C, 150 x 40mm x 15 um) and lyophilized to give tert-butyl 6- [ [3- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazol-5-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (803 mg,2.08mmol, 56.3% yield) as a pale yellow solid. MS (ESI) m/z=388.1 [ M+H ] +.
Structural unit P.165 3- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazole, 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (370 mg,0.96mmol,1 eq) in EtOAc (4 mL) was added p-toluenesulfonic acid (197mg, 1.15mmol,1.2 eq). The mixture was stirred at 80 ℃ for 12h. The reaction mixture was concentrated under vacuum. Deionized water (3 mL) was added to the residue and then lyophilized to give 3- (2-azaspiro [3.3] heptane-6-ylmethyl) -5- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazole, 4-methylbenzenesulfonic acid (406 mg,0.88mmol, 82% yield) as a white solid. MS (ESI) m/z=288.1 [ M+H ] +.
Step 1 6- (cyanomethyl) -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Pd/C (wet) (886 mg,1.14mmol,0.1 eq) was added to a solution of tert-butyl 6- (cyanomethylene) -2-azaspiro [3.3] heptane-2-carboxylate (2.66 g,11.35mmol,1eq, CAS 1428726-12-8) in methanol (26 mL) at 25 ℃. The reaction was stirred at 25 ℃ for 0.5H under an atmosphere of H 2 (H 2 balloon). The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl 6- (cyanomethyl) -2-azaspiro [3.3] heptane-2-carboxylate (2.6 g,11.0mmol, 96% yield) as a white solid. MS (ESI) m/z=181.0 [ M-C 4H8+H]+.
Step 2 6- [ (2Z) -2-amino-2-hydroxyimino-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Triethylamine (850 mg,8.46mmol,2 eq) was added to a mixture of hydroxylamine, hydrochloride (588 mg,8.46mmol,2 eq) in ethanol (10 mL) at 25 ℃. After 0.5h, tert-butyl 6- (cyanomethyl) -2-azaspiro [3.3] heptane-2-carboxylate (1 g,4.23mmol,1 eq) was added. The reaction was stirred at 50 ℃ for 2h. The reaction was concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined extracts were concentrated in vacuo to give tert-butyl 6- [ (2Z) -2-amino-2-hydroxyimino-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.03 g,3.82mmol, 90% yield) as a colorless oil. MS (ESI) m/z=270.2 [ M+H ] +.
Step 3 tert-butyl 6- [ (2Z) -2-amino-2- [1- (trifluoromethyl) cyclopropanecarbonyl ] oxyimino-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylate
A solution of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid (589 mg,3.82mmol,1eq, CAS 277756-46-4) and CDI (744 mg,4.59mmol,1.2 eq) in DMF (10 mL) was stirred at room temperature for 2h. 6- [ (2Z) -2-amino-2-hydroxyimino-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.03 g,3.82mmol,1 eq) was added to the solution and stirred at 25℃for 1h. The reaction mixture was purified by reverse phase HPLC (conditions: water (0.02% FA), ACN) to give tert-butyl 6- [ (2Z) -2-amino-2- [1- (trifluoromethyl) cyclopropanecarbonyl ] oxyimino-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylate (130 mg,0.32mmol, yield 8.4%) as a white solid. MS (ESI) m/z=350.1 [ M-C 4H8+H]+.
Step 4 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A solution of 6- [2- [ (Z) - [ amino- [1- (trifluoromethyl) cyclopropyl ] methylene ] amino ] oxy-2-oxo-ethyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (210 mg,0.52mmol,1 eq) and tetrabutylammonium fluoride/THF (0.13 mL,0.13mmol,0.25 eq) in THF (2 mL) was stirred at 70℃for 1h. The mixture was added to 2mL of water and extracted with EtOAc (15 mL x 3). The organic phase was concentrated in vacuo. The mixture was purified by preparative HPLC to give tert-butyl 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] -1,2, 4-oxadiazol-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (220 mg,0.57mmol, 109% yield) as a yellow solid. MS (ESI) m/z=332.1 [ M-C 4H8+H]+.
Structural unit P.167:4-methylbenzenesulfonic acid, 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane
To a solution of tert-butyl 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (300 mg,0.78mmol,1 eq) in EtOAc (6 mL) was added p-toluenesulfonic acid monohydrate (4474 mg,2.34mmol,3 eq). The mixture was stirred at 30 ℃ for 72h. The reaction mixture was concentrated under vacuum. The residue was purified by HPLC to give 4-methylbenzenesulfonic acid, 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane (81 mg,0.13mmol, 15% yield) as a yellow gum. MS (ESI) m/z=286.2 [ M+H ] +. HPLC conditions are apparatus (mobile phase, column) System 0-2-9min 0-70% H20/MEOH/0.1NH4OH flow 30ml/min ((Loading Pump 4ml MEOH) target Mass 337 column: XBridge BEH C18X 19mm,5m micro M.
Step 1 4- [1- (trifluoromethyl) cyclopropyl ] -1H-imidazole
2-Bromo-1- [1- (trifluoromethyl) cyclopropyl ] ethanone (0.5g,2.16mmol,1eq,CAS 1382999-80-5) was added to formamide (5 mL,125mmol,58 eq). The reaction mixture was stirred at 180 ℃ for 2h. After the reaction was completed, 50mL of water was added. The mixture was washed three times with dichloromethane and then the aqueous phase was adjusted to pH 8 with 1M aqueous NaOH. The aqueous phase was extracted twice with dichloromethane. The organic phase was dried, concentrated in vacuo and purified by HPLC to give 4- [1- (trifluoromethyl) cyclopropyl ] -1H-imidazole (110 mg,0.62mmol, 28% yield) as a brown solid. MS (ESI) m/z=177.2 [ m+h ] +. HPLC conditions are device (mobile phase, column) system 0-2-10min 0-75% H20/ACN, flow 30ml/min ((loading pump 4 mACN) target mass 177 column: chromatocrex C18 SMB100-5T 100*19mm,5micro.
Step 2 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a mixture of 4- [1- (trifluoromethyl) cyclopropyl ] -1H-imidazole (800 mg,3.41mmol,1 eq), cesium carbonate (2.21 g,6.81mmol,2 eq) in DMF (15 mL) was added tert-butyl 6- (methylsulfonylmethyl) -2-azaspiro [3.3] heptane-2-carboxylate (1.04 g,3.41mmol,1eq, CAS 2740574-92-7) at room temperature. The reaction mixture was stirred at 50 ℃ for 18h. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (2×200 ml), brine (100 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by FC to give tert-butyl 6- [ [4- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (800 mg,2.07mmol, 60% yield) and tert-butyl 6- [ [5- [1- (trifluoromethyl) cyclopropyl ] imidazol-1-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (300 mg,0.78mmol, 22% yield) as pale yellow solids. MS (ESI) m/z=286.2 [ M+H ] +.
Under the FC condition of Interhim, 40g of SiO 2, petroleum ether/MtBE, wherein MtBE is 15-100%, further MtBE/methanol, wherein methanol is 0-10%, and the flow rate=40 mL/min, and rv=21-23 CV.
Structural unit P.168 6- [ difluoro- [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane, 4-methylbenzenesulfonic acid
To a solution of tert-butyl 6- [ difluoro- [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3.38 g,8.59mmol,1 eq) in EtOAc (34 mL) was added p-toluenesulfonic acid (1.77 g,10.3mmol,1.2 eq). The reaction was stirred at 80 ℃ for 4h. The reaction mixture was concentrated in vacuo. Deionized water (30 mL) was added to the residue and lyophilized to give 6- [ difluoro- [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane; 4-methylbenzenesulfonic acid (3.96 g,8.51mmol, 97% yield) as a yellow solid. MS (ESI) m/z=294.3 [ M+H ] +.
Step 1 6- [ [6- (trifluoromethyl) pyridazin-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of 3-chloro-6- (trifluoromethyl) pyridazine (30 g,164mmol,1eq, CAS 258506-68-2) in 1, 4-dioxane (500 mL) and water (50 mL) was added tert-butyl 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (55.1 g,164mmol,1eq, CAS 2763647-64-7), potassium carbonate (45.43 g,328mmol,2 eq) and 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (13.41g,16.44mmol,0.1eq,CAS 95464-05-4). The reaction mixture was stirred at 100 ℃ under an atmosphere of N 2 for 12h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with PE/EtOAc (3:1) (TLC, PE: etoac=3:1, rf=0.40) to give the crude product. The crude product was washed with PE (300 mL). After filtration, the solid was collected and concentrated in vacuo to give tert-butyl 6- [ [6- (trifluoromethyl) pyridazin-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (46 g,121mmol, 73% yield) as a yellow solid. MS (ESI) m/z=300.3 [ M-C 4H8+H]+ ].
Step 2 6- [ [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 6- [ [6- (trifluoromethyl) pyridazin-3-yl ] methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (19 g,53.47mmol,1 eq) in EtOAc (600 mL) was added Pd/C (wet) (6.33 g,5.95mmol,0.11 eq) at 25 ℃. The reaction was stirred at 25 ℃ for 1H under an atmosphere of H 2 (H 2 balloon). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl 6- [ [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (19 g,53.17mmol, 99% yield) as a yellow solid. MS (ESI) m/z=358.2 [ M+H ] +.
Step 3 to a solution of tert-butyl 6- [6- (trifluoromethyl) pyridazin-3-carbonyl ] -2-azaspiro [3.3] heptane-2-carboxylate (tert-butyl 6- [ [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (15 g,41.9mmol,1 eq) in 1, 4-dioxane (300 mL) was added SeO 2 (27.94 g,251.8mmol,6 eq). The reaction mixture was stirred under an atmosphere of N 2 at 90 ℃ for 12h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent of 0-30% AcOEt/petroleum ether, petroleum ether/acoet=1/1, rf=0.5) and concentrated in vacuo to give 6- [6- (trifluoromethyl) pyridazine-3-carbonyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (4.3 g,11.58mmol, yield 27%) as a yellow solid. MS (ESI) m/z=316.0 [ M-C 4H8+H]+.
Step 4 6- [ difluoro- [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
DAST (30 mL,227mmol,28 eq) was added dropwise to a solution of tert-butyl 6- [6- (trifluoromethyl) pyridazine-3-carbonyl ] -2-azaspiro [3.3] heptane-2-carboxylate (3 g,8.08mmol,1 eq) in DCM (30 mL) under an atmosphere of N 2 at 0 ℃. The reaction mixture was stirred at 25 ℃ for 12h. The reaction mixture was added dropwise to saturated aqueous NaHCO 3 (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with PE/EtOAc (5:1) (TLC, PE: etoac=3:1, rf=0.40) to give tert-butyl 6- [ difluoro- [6- (trifluoromethyl) pyridazin-3-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (2.6 g,6.61mmol, yield 81.82%) as a yellow solid. MS (ESI) m/z=394.0 [ M+H ] +.
Similar to structural unit p.168, the following structural units were generated in step 1 using the relevant heteroaryl bromide or heteroaryl chloride for cross-coupling.
Structural unit P.178 6- (2-azaspiro [3.3] heptane-6-ylmethyl) -2- (trifluoromethyl) imidazo [1,2-a ] pyrimidine, 4-methylbenzenesulfonic acid
A mixture of p-toluenesulfonic acid (264 mg,2.12mmol,3 eq) and tert-butyl 6- [ [2- (trifluoromethyl) imidazo [1,2-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (280 mg,0.71mmol,1 eq) in EtOAc (30 mL) was stirred at 50deg.C for 24h. The mixture was concentrated in vacuo and purified by FC to give 6- (2-azaspiro [3.3] heptane-6-ylmethyl) -2- (trifluoromethyl) imidazo [1,2-a ] pyrimidine, 4-methylbenzenesulfonic acid (178 mg,0.38mmol, 53% yield) as a pale brown solid. MS (ESI) m/z=297.0 [ M+H ] +.
FC conditions are Interchem, 40g SiO2, MTBE/methanol (0% to 60%), flow = 40ml/min,16,1-18,3CV.
Step 1 6- [ (2-aminopyrimidin-5-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
1,1' -Bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.87g,2.3mmol,0.2eq,CAS 95408-45-0), potassium carbonate (3.17 g,22.99mmol,2.0 eq), 2-amino-5-bromopyrimidine (2 g,11.49mmol,1 eq) and 6- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (3.85 g,11.49mmol,1eq, CAS 2763647-64-7) were added to a mixture of 1, 4-dioxane (61 mL) and water (13 mL). The reaction mixture was stirred at 90 ℃ for 24h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by FC to give tert-butyl 6- [ (2-aminopyrimidin-5-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylate (1.5 g,4.96mmol, 43% yield) as a pale yellow solid. MS (ESI) m/z=303.2 [ m+h ] +.
FC conditions are Interchem, 120g SiO2, chloroform/acetonitrile (0% to 100%), flow rate = 80ml/min,22,6-28,3CV.
Step 2 6- [ (2-aminopyrimidin-5-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A mixture of 6- [ (2-aminopyrimidin-5-yl) methylene ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.5 g,4.96mmol,1 eq) and Pd/C,10% (158 mg,0.15mmol,0.03 eq) in EtOAc (80 mL) was hydrogenated at 19000mmHg and stirred at 25℃for 18h. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6- [ (2-aminopyrimidin-5-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (1.5 g,4.93mmol, 96% yield) as a white solid. MS (ESI) m/z=249.2 [ M-C 4H8+H]+.
Step 3 6- [ [2- (trifluoromethyl) imidazo [1,2-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
A solution of 6- [ (2-aminopyrimidin-5-yl) methyl ] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.5 g,4.93mmol,1 eq) and 3-bromo-1, 1-trifluoroacetone (940 mg,4.93mmol,1 eq) in ACN (9 mL) and toluene (1.5 mL) was stirred at 100℃for 24h. The reaction mixture was concentrated in vacuo and diluted between DCM and NaHCO 3 (10% aqueous). The organic layer was dried over Na 2SO4, filtered, and concentrated in vacuo. The crude product was purified by FC to give tert-butyl 6- [ [2- (trifluoromethyl) imidazo [1,2-a ] pyrimidin-6-yl ] methyl ] -2-azaspiro [3.3] heptane-2-carboxylate (340.0 mg,0.86mmol, 17% yield) as a yellow solid. MS (ESI) m/z=397.2 [ M+H ] +.
Under the FC condition of Interchem 40g SiO2, chloroform/ACN, wherein ACN is 0-40%, the flow rate=40 mL/min, and rv=10-12 CV.
Synthesis of non-commercial building blocks:
C.184
2- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methylene ] -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
2, 6-Tetramethylpiperidine (16mL,100mmol,1.2eq,CAS 768-66-1) was dissolved in THF (100 ml) and cooled to-30℃under Ar atmosphere. A solution of butyllithium (2.5M) (40.12 mL,100mmol,1.2 eq) was added dropwise and the reaction mixture stirred at the same temperature for 30min. The reaction mixture was cooled to-78 °. A solution of 4, 5-tetramethyl-2- [ (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) methyl ] -1,3, 2-dioxapentaborane (24.63g,91.93mmol,1.1eq,CAS 78782-17-9) in THF (20 ml) was added dropwise. After stirring for 30min, a solution of tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate (20 g,83.57mmol,1eq, cas 203661-69-2) in THF (30 ml) was added dropwise at-78 ℃. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The mixture was cooled to 0 ℃ and aqueous NH 4 Cl (30 mL) was added dropwise. After stirring for an additional 1h, the resulting mixture was filtered and the solvent was concentrated in vacuo. H2O (100 mL) was added to the residue, and the aqueous layer was extracted with EtOAc (250 mL). The organic phase was washed with brine (250 mL), dried over anhydrous Na 2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (intel, 330g sio2, hexane/MTBE (0% to 15% to 100%), flow rate = 100ml/min,5-9 CV) to give tert-butyl 2- [ (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene ] -7-azaspiro [3.5] nonane-7-carboxylate (20.4 g,56.15mmol, 63% yield) as a white solid. MS (ESI) m/z=308.2 [ M-C 4H8+H]+.
C.9
1-Bromo-3-dimethylphosphoryl-5- (trifluoromethyl) benzene
To a solution of dimethylphosphine oxide (methylphosphonoylmethane, 2.22g,28.5mmol,CAS 150765-29-0), 1-bromo-3-iodo-5- (trifluoromethyl) benzene (5g,14.3mmol,CAS 481075-59-6), 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (206mg,0.36mmol,CAS 161265-03-8) and triethylamine (2.98 mL,21.4 mmol) in 1, 4-dioxane (50 mL) was added tris (dibenzylideneacetone) dipalladium (0) (130.mg,0.14mmol,CAS 51364-51-3). The reaction mixture was stirred under argon at 25 ℃ for 48h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The extract was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give the title compound (1.9 g,6.31mmol, 42% yield) as an orange solid. MS (ESI) m/z=301.0 [ M+H ] +.
C.17
3-Bromo-5- [1- (trifluoromethyl) cyclopropyl ] -4H-1,2, 4-triazole
To a solution of 3- [1- (trifluoromethyl) cyclopropyl ] -1H-1,2, 4-triazole (5.07 g,27mmol,1 eq) in DMF (25 mL) was added NBS (10.65 g,59.82mmol,2.2 eq). The mixture was stirred at 60 ℃ for 15h. The reaction mixture was poured into EtOAc and washed with water, saturated NaCl. The organic layer was dried over Na 2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40g, etOAc in heptane 0% to 20%) to give 5-bromo-3- [1- (trifluoromethyl) cyclopropyl ] -1H-1,2, 4-triazole (3.08 g, 42% yield) as a white solid MS (ESI): m/z= 255.9[ {79br } m+h ] +,257.9[{81Br}M+H]+.
Step 1 (NE) -N- (dimethylaminomethylene) -1- (trifluoromethyl) cyclopropanecarboxamide
1- (Trifluoromethyl) cyclopropanecarboxamide (5 g,32mmol,1eq, CAS 1628184-67-7) was dissolved in N, N-dimethylformamide dimethyl acetal (27.24 g,228mmol,7 eq). The mixture was stirred at room temperature for 6h. The reaction mixture was poured into EtOAc and washed with water, saturated NaCl. The organic layer was dried over Na 2SO4 and concentrated in vacuo to give (NE) -N- (dimethylaminomethylene) -1- (trifluoromethyl) cyclopropanecarboxamide (6.5 g, 90% yield) as a yellow amorphous oil. MS (ESI) m/z=209.1 [ M+H ] +.
Step 2 3- [1- (trifluoromethyl) cyclopropyl ] -1H-1,2, 4-triazole
To an ice-cold solution of (NE) -N- (dimethylaminomethylene) -1- (trifluoromethyl) cyclopropanecarboxamide (6.5 g,28mmol,1 eq) in acetic acid (18 mL) was added hydrazine hydrate (1.55 g,30.9mmol,1.1 eq). The mixture was stirred at 50 ℃ for 2h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. NaOH 1N (pH 7 to 8) was added. The mixture was washed with water, saturated NaCl. The organic layer was dried over Na 2SO4 and concentrated in vacuo to give 3- [1- (trifluoromethyl) cyclopropyl ] -1H-1,2, 4-triazole (5.07 g, 96% yield) as a yellow solid. MS (ESI) m/z=178.1 [ M+H ] +.
C.72
1-Bromo-4-dimethylphosphoryl-2- (trifluoromethyl) benzene
To a solution of dimethylphosphine oxide (1.85g,23.7mmol,CAS 7211-39-4), 1-bromo-4-iodo-2- (trifluoromethyl) benzene (8.3g,23.7mmol,CAS 364-11-4), 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (137 mg,0.24mmol, CAS 161265-03-8) and triethylamine (3.86 mL,27.7 mmol) in 1, 4-dioxane (80 mL) was added tris (dibenzylideneacetone) dipalladium (0) (108mg,0.12mmol,CAS 51364-51-3). The mixture was stirred at room temperature under Ar for 24h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by FC (eluting with petroleum ether/MtBE, where MtBE is 0% to 100%, further eluting with MtBE/methanol, where methanol is 0% to 25%) to give 1-bromo-4-dimethylphosphoryl-2- (trifluoromethyl) benzene (50 mg,0.170mmol, 18.5% yield) as a white semi-solid. MS (ESI) m/z=301.0 [ {79Br } M+H ] +,303.0[{81Br}M+H]+.
C.115
2-Bromo-3-methoxy-5- (trifluoromethyl) pyrazine
To a mixture of 3-methoxy-5- (trifluoromethyl) pyrazin-2-amine (1.6 g,8.28mmol, cas 1823377-58-7) and CuBr (1.42 g,9.94 mmol) in ACN (15 mL) was added a solution of tert-butyl nitrite (1.28 g,12.4 mmol) in ACN (5 mL) at 25 ℃. The reaction mixture was stirred under an atmosphere of N 2 at 70 ℃ for 12h. The reaction mixture was filtered and the filtrate was concentrated in vacuo at room temperature. The residue was purified by column chromatography (ethyl acetate: petroleum ether 0% to 10%) and concentrated in vacuo at room temperature to give the title compound (800 mg,3.11mmol, yield 38%) as a colorless oil. MS (ESI) m/z=256.9 [ M+H ] +. Note that the product was volatile.
C.122
3-Bromo-5- [1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole
To a solution of 5- [1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-3-amine (2.3 g,12mmol, CAS 1001354-47-7) in ACN (40 mL) was added dropwise a solution of isoamyl nitrite (1.55 g,13.2 mmol) in ACN (5 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1h. CuBr 2 (1.61 g,7.22 mmol) was added to the mixture at 0 ℃ and the resulting mixture was stirred at 20 ℃ for 12h. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (water (0.1% fa) -ACN). The purified solution was lyophilized to give the title compound (740 mg,2.9mmol, 24.1% yield) as a pale green solid. MS (ESI) m/z=257.2 [ M+H ] +.
C.124
2-Chloro-5- [1- (trifluoromethyl) cyclopropyl ] pyrazine
To a solution of 2-chloro-5- [1- (trifluoromethyl) vinyl ] pyrazine (1.6 g,7.67 mmol) in THF (60 mL) was added diphenyl (methyl) sulfonium tetrafluoroborate (2.87g,9.97mmol,CAS 10504-60-6). The suspension was stirred at 0 ℃ for 0.5h. A solution of NaHMDS (12.3 mL,12.3mmol,1M in THF) was added dropwise. The reaction mixture was heated at 25 ℃ for 1h. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted twice with EtOAc (40 mL). The organic layers were combined, washed with brine, dried over Na 2SO4, and concentrated in vacuo. Purification by FC (SiO 2; PE/EtOAc) afforded the title compound (1.5 g, 63% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ=8.53 (s, 1H), 8.43 (d, j=1.2 hz, 1H), 1.48-1.42 (m, 2H), 1.36ppm (br s, 2H).
Step 1 2-chloro-5- [1- (trifluoromethyl) vinyl ] pyrazine
To a solution of 4, 6-trimethyl-2- [1- (trifluoromethyl) vinyl ] -1,3, 2-dioxaborolan (3.44 g,15.5mmol, CAS 1011460-68-6) and 2-bromo-5-chloropyrazine (3 g,15.5 mmol), potassium carbonate (4.29 g,31 mmol) in 1, 4-dioxane (60 mL) and water (6 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1266mg,1.55mmol,CAS 95464-05-4). The mixture was stirred at 80 ℃ under an atmosphere of N 2 for 12h, filtered and concentrated in vacuo. Purification by FC (SiO 2; PE) gave the title compound (1.6 g, 49% yield) as a yellow solid. MS (ESI) m/z=209.3 [ M+H ] +
C.125
3-Bromo-6- [1- (trifluoromethyl) cyclopropyl ] pyridazine
To a solution of 3-bromo-6- [1- (trifluoromethyl) vinyl ] pyridazine (340 mg,1.34 mmol) in THF (10 mL) was added diphenyl (methyl) sulfonium tetrafluoroborate (503mg,1.75mmol,CAS 10504-60-6). The suspension was stirred at 0 ℃ for 0.5h. A solution of NaHMDS (2.15 mL,2.15mmol,1M in THF) was added dropwise. The reaction mixture was stirred at 25 ℃ for 1h. The mixture was quenched with 6mL of methanol. The reaction mixture was partitioned between EtOAc (20 mL) and water (40 mL). The organic phase was concentrated in vacuo. Purification by preparative HPLC gave the title compound (280 mg, 78% yield) as a white solid. MS (ESI) m/z=267.3 [ m+h ] +.
Step 1 3-bromo-6- [1- (trifluoromethyl) vinyl ] pyridazine
To a solution of 4, 6-trimethyl-2- [1- (trifluoromethyl) vinyl ] -1,3, 2-dioxaborolan (560 mg,2.52mmol, CAS 1011460-68-6) and 3, 6-dibromopyridazine (500 mg,2.1 mmol), potassium carbonate (581 mg,4.2 mmol) in 1, 4-dioxane (10 mL) and water (2 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (172mg,0.210mmol,CAS 95464-05-4). The mixture was stirred at 80 ℃ for 3h under an atmosphere of N 2. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine, dried over Na 2SO4, and concentrated in vacuo. Purification by FC (SiO 2; PE) gave the title compound (300 mg, 56% yield) as a white crystalline solid. MS (ESI) m/z=253.3 [ M+H ] +.
C.128
4, 5-Dibromo-2- (2, 2-trifluoroethyl) triazole
To a solution of 4, 5-dibromo-2H-triazole (5 g,22mmol, CAS 22300-52-3) in ACN (50 mL) was added cesium carbonate (7.18 g,22 mmol). 2, 2-trifluoroethyl triflate (5.12g,22.0mmol,CAS 6226-25-1) was added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was poured into water. EtOAc was added, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na 2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, PE/EtOAc 0% to 7%). The fractions containing the pure product were combined and concentrated in vacuo to give 4, 5-dibromo-2- (2, 2-trifluoroethyl) triazole (5.3 g,17.2mmol, 77% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ=4.95 (q, j=7.9 hz, 2H).
C.145
2- [ [ 5-Bromo-3- (trifluoromethyl) pyrazolo [3,4-c ] pyridin-1-yl ] methoxy ] ethyl-trimethyl-silane
A mixture of 2- [ (5-bromo-3-iodo-pyrazolo [3,4-C ] pyridin-1-yl) methoxy ] ethyl-trimethyl-silane (5.6 g,12mmol,1eq, CA 209760-93-8), cuprous iodide (I) (11.74 g,61mmol,5 eq), potassium fluoride (3.58 g,61mmol,5 eq) and trifluoromethyl trimethylsilane (8.77 g,61mmol,5 eq) in NMP (113 mL) was stirred at 100℃for 18h. The reaction mixture was quenched by the addition of 1L of water and filtered off from the inorganic precipitate. The filtrate was extracted with ethyl acetate and the organic phase was washed with water, saturated NaCl solution, dried over Na 2 SO4 and concentrated in vacuo. The crude material was purified by FC to give 2- [ [ 5-bromo-3- (trifluoromethyl) pyrazolo [3,4-c ] pyridin-1-yl ] methoxy ] ethyl-trimethyl-silane (1.4 g,3.5mmol, 28% yield) as a pale yellow viscous oil. MS (ESI) m/z=396.0 [ M+H ] +. FC conditions, intel, 120SiO 2, hexane/ethyl acetate (0% to 22%), flow = 80ml/min.
C.149
1- (4-Bromophenyl) sulfonyl-3- (trifluoromethyl) azetidine
To a solution of 4-bromobenzenesulfonyl chloride (1.33 g,5.2mmol,1.3 eq) and 3- (trifluoromethyl) azetidine (500 mg,4mmol,1eq, cas 1221349-18-3) in DMF (5 mL) at 25 ℃ was added DIEA (3.46 mL,20mmol,5 eq). The mixture was shaken at 100℃for 2h. The crude material was purified by flash column (PE to PE: etoac=3:1; uv) and concentrated in vacuo to give 1- (4-bromophenyl) sulfonyl-3- (trifluoromethyl) azetidine (480 mg,2.85mmol, 71% yield) as a white solid. MS (ESI) m/z= 344.0[ {79br } m+h ] +,346.0[{81Br}M+H]+.
C.157
4-Chloro-2-methylsulfonyl-1- (trifluoromethyl) benzene
Sodium periodate (3.68 g,17.21mmol,2 eq) and ruthenium (III) chloride hydrate (19.4 mg,0.09mmol,0.01 eq) were added to a solution of 4-chloro-2-methylsulfanyl-1- (trifluoromethyl) benzene (1.95 g,8.6mmol,1eq, cas 1428234-60-9) in 1, 2-dichloroethane (20 mL) -ACN (20 mL) -water (40 mL) at 0 ℃. The mixture was stirred at 25 ℃ for 12h. The reaction mixture was diluted with water (40 mL) and extracted with 50mL DCM, 2×50mL EtOAc. The combined organic layers were washed with 75mL brine, dried over Na 2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO 2, petroleum ether: ethyl acetate=. 3:1) to give 4-chloro-2-methylsulfonyl-1- (trifluoromethyl) benzene (1.8 g,6.96mmol, 72% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) delta ppm 8.32 (d, J=1.96 Hz, 1H) 7.87 (d, J=8.44 Hz, 1H) 7.76 (dd, J=8.44, 1.22Hz, 1H) 3.22 (s, 3H).
C.158
7-Chloro-3- (trifluoromethyl) imidazo [1,2-a ] pyrimidine
In an autoclave, hydrogen fluoride (7.45 mL,368.53mmol,30 eq) was placed in precooled (liquid N 2) lithium; 7-chloroimidazo [1,2-a ] pyrimidine-3-carboxylate (2.5 g,12.28mmol,1eq, CA 2839138-71-3). Tetrafluoro- λ4-sulfane (2.65g,24.57mmol,2eq,CAS 7783-60-0) was then pressurized into the vessel. The reaction mixture was then stirred at 65 ℃ for 72h. The reaction mixture was carefully diluted with saturated K 2CO3 (150 ml). The aqueous layer was extracted with MTBE. The combined organic layers were washed with brine, dried over Na 2SO4, filtered and concentrated in vacuo, and purified by FC to give 7-chloro-3- (trifluoromethyl) imidazo [1,2-a ] pyrimidine (500 mg,2.25mmol, 16.3% yield) as a white solid. MS (ESI) m/z=222.0 [ M+H ] +.
FC conditions were 1) Interhim, 12g SiO 2, chloroform/acetonitrile (0% to 10%), flow rate=80 ml/min,6,2-9,6CV; 2) Interhim, 40g SiO 2, hexane/isopropanol (5% to 100%), flow rate=40 ml/min, RV=7, 8-31,1CV.
C.160
2-Bromo-5- [3- (trifluoromethyl) azetidin-1-yl ] pyrazine. To a solution of 3- (trifluoromethyl) azetidine, hydrochloride (500 mg,3.08mmol,1eq, CAS 1221272-90-7) and DIEA (1.55 g,15.3mmol,5 eq) in DMF (10 mL) was added 2, 5-dibromopyrazine (951 mg,4mmol,1.3 eq). The resulting solution was stirred at 100 ℃ for 2h. The reaction mixture was poured into saturated NaCl. The mixture was extracted with EtOAc. The organic phase was dried over anhydrous Na 2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO 2, petroleum ether/EtOAc) and concentrated in vacuo to give 2-bromo-5- [3- (trifluoromethyl) azetidin-1-yl ] pyrazine (500 mg,1.77mmol, 44% yield) as a yellow solid. MS (ESI) m/z=281.9 [ m+h ] +.
C.171
3-Bromo-1- (2, 2-trifluoroethyl) -1,2, 4-triazole
To a solution of 3-bromo-1H-1, 2, 4-triazole (8g,54mmol,1eq,CAS 7343-33-1) in THF (80 mL) at 0deg.C was added NaH (3.89 g,97mmol,1.8 eq). After 0.5h, 2-trifluoroethyl triflate (25.1g,108.14mmol,2eq,CAS 6226-25-1) was added. The mixture was stirred at 20 ℃ for 12h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Welch Ultimate XB-SiOH 250 x 70 x 10um, hexane-EtOH) and concentrated in vacuo to give 3-bromo-1- (2, 2-trifluoroethyl) -1,2, 4-triazole (6 g,26.09mmol, 48% yield) as a brown oil. MS (ESI) m/z=229.9 [ M+H ] +.
C.195
2-Chloro-4- [1- (trifluoromethyl) cyclopropyl ] pyrimidine
To a solution of 2-chloro-4- [1- (trifluoromethyl) vinyl ] pyrimidine (1 g,4.79mmol,1 eq) in THF (5 mL) was added diphenyl (methyl) sulfonium tetrafluoroborate (2.07 g,7.19mmol,1.5eq, CAS 10504-60-6) and NaHMDS (7.67 mL,7.67mmol,1.6 eq) at 20deg.C. The mixture was stirred at 20 ℃ for 12h under N 2. The reaction mixture was poured into H 2 O and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2SO4 and concentrated in vacuo to give 2-chloro-4- [1- (trifluoromethyl) cyclopropyl ] pyrimidine (1 g,4.49mmol, 93% yield) as a red oil. MS (ESI) m/z=233.0 [ M+H ] +.
Step 1 2-chloro-4- [1- (trifluoromethyl) vinyl ] pyrimidine
To a solution of 4-bromo-2-chloropyrimidine (2g,10.34mmol,1eq,CAS 885702-34-1), 4, 6-trimethyl-2- [1- (trifluoromethyl) vinyl ] -1,3, 2-dioxaborolan (2.29 g,10.34mmol,1eq, cas 1011460-68-6) and K 2CO3 (2.85 g,20.68mmol,2 eq) in 1, 4-dioxane (40 mL) and water (4 mL) was added 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (844mg,1.03mmol,0.1eq,CAS 95464-05-4). The mixture was stirred at 25 ℃ for 12h. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO 2, eluent of 0% to 3% ethyl acetate/petroleum ether, rf=0.6) and concentrated in vacuo to give 2-chloro-4- [1- (trifluoromethyl) vinyl ] pyrimidine (1.36 g,6.54mmol, 62% yield) as a yellow oil. MS (ESI) m/z=208.9 [ M+H ] +.

Claims (25)

1.一种式(I)化合物1. A compound of formula (I) 或其药用盐，其中：or a pharmaceutically acceptable salt thereof, wherein: (i)A选自1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、(i) A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-三唑基、三唑基、噻唑基、咪唑基、嘧啶基、吡嗪基、哒嗪基、吡唑基、噁唑基、1,2-二氢吡啶基、[1,2,4]三唑并[4,3-a]吡啶、[1,2,4]三唑并[1,5-a]吡啶、1H-吡咯并[2,3-b]吡啶、咪唑并[1,5-a]吡啶、咪唑并[1,2-a]吡啶、2H-吡唑并[3,4-b]吡啶、2H-吡唑并[4,3-b]吡啶、2H-吡唑并[4,3-c]吡啶、吡唑并[1,5-a]嘧啶、1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridinyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-吡唑并[3,4-d]嘧啶、[1,2,4]三唑并[1,5-a]嘧啶、咪唑并[1,2-a]吡嗪、1,2-苯并噁唑、1H-吲唑、1H-咪唑并[1,2-c]嘧啶-5-酮、2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-吡咯并[2,3-b]吡啶、咪唑并[1,2-a]嘧啶、2H-吡唑并[3,4-c]吡啶、7H-吡咯并[2,3-d]嘧啶、[1,2,4]三唑并[1,5-b]嘧啶、吡唑并[1,5-a]嘧啶、2H-吡唑并[4,3-b]吡啶、1H-咪唑并[4,5-b]吡啶、3H-咪唑并[4,5-b]吡啶、4,5,6,7-四氢吡唑并[1,5-a]嘧啶、1H-吡唑并[3,4-b]吡啶、1H-咪唑并[1,2-a]嘧啶-5-酮和2H-吲唑；1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one and 2H-indazole; R1选自卤素、C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、羟基-C1-6-烷基、C3-6-环烷基-、卤代-C1-6-烷基-C3-6-环烷基-、(卤代-C1-6-烷基)-(3元至6元杂环基)-、卤代-C1-6-烷氧基、(C1-6-烷基)2PO-和基团 R1 is selected from halogen, C1-6 -alkyl, C1-6 -alkoxy, halo- C1-6 -alkyl, hydroxy- C1-6 -alkyl, C3-6 -cycloalkyl-, halo- C1-6 -alkyl- C3-6 -cycloalkyl-, (halo -C1-6 -alkyl)-(3- to 6-membered heterocyclyl)-, halo- C1-6 -alkoxy, ( C1-6 -alkyl) 2PO- and the group R2选自氢、卤素、氰基、氧代、C1-6-烷基和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R3选自C1-6-烷基、卤代-C1-6-烷基和4元至6元杂环基，其中所述4元至6元杂环基任选地经卤代-C1-6-烷基取代基取代；R 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with a halo-C 1-6 -alkyl substituent; X选自O和NH；或者X is selected from O and NH; or (ii)A为吡啶基；(ii) A is pyridyl; R1选自卤素、C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、羟基-C1-6-烷基、C3-6-环烷基-、卤代-C1-6-烷基-C3-6-环烷基-、卤代-C1-6-烷氧基、(C1-6-烷基)2PO-和基团 R1 is selected from halogen, C1-6 -alkyl, C1-6 -alkoxy, halo- C1-6 -alkyl, hydroxy- C1-6 -alkyl, C3-6 -cycloalkyl-, halo- C1-6 -alkyl- C3-6 -cycloalkyl-, halo- C1-6 -alkoxy, ( C1-6 -alkyl) 2PO- and the group R2选自氢、卤素、氰基、C1-6-烷基和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl; R3选自C1-6-烷基、卤代-C1-6-烷基和4元至6元杂环基，其中所述4元至6元杂环基任选地经卤代-C1-6-烷基取代基取代；并且 R3 is selected from the group consisting of Ci -6 -alkyl, halo-Ci- 6 -alkyl and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with a halo-Ci -6 -alkyl substituent; and X选自O和NH；或者X is selected from O and NH; or (iii)A为苯基；(iii) A is phenyl; R1选自(C1-6-烷基)2PO-和基团 R 1 is selected from (C 1-6 -alkyl) 2 PO- and groups R2选自氢、卤素、氰基、C1-6-烷基和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl; R3选自C1-6-烷基、卤代-C1-6-烷基和4元至6元杂环基，其中所述4元至6元杂环基任选地经卤代-C1-6-烷基取代基取代；并且R 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with a halo-C 1-6 -alkyl substituent; and X选自O和NH；X is selected from O and NH; R4和R5各自独立地选自氢、卤素和C1-6-烷基；并且 R4 and R5 are each independently selected from hydrogen, halogen and C1-6 -alkyl; and B选自：B is selected from: 2.一种式(I)化合物2. A compound of formula (I) 或其药用盐，其中：or a pharmaceutically acceptable salt thereof, wherein: A为9元双环杂芳基，其包含1个至5个选自N、O和S的杂原子，其余环原子为碳；A is a 9-membered bicyclic heteroaryl group containing 1 to 5 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon; R1选自卤素、C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、羟基-C1-6-烷基、C3-6-环烷基-、卤代-C1-6-烷基-C3-6-环烷基-、卤代-C1-6-烷氧基、(C1-6-烷基)2PO-和基团 R1 is selected from halogen, C1-6 -alkyl, C1-6 -alkoxy, halo- C1-6 -alkyl, hydroxy- C1-6 -alkyl, C3-6 -cycloalkyl-, halo- C1-6 -alkyl- C3-6 -cycloalkyl-, halo- C1-6 -alkoxy, ( C1-6 -alkyl) 2PO- and the group R2选自氢、卤素、氰基、氧代、C1-6-烷基和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R3选自C1-6-烷基和卤代-C1-6-烷基；R 3 is selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; X选自O和NH；或者X is selected from O and NH; or R4和R5各自独立地选自氢、卤素和C1-6-烷基；并且 R4 and R5 are each independently selected from hydrogen, halogen and C1-6 -alkyl; and B选自：B is selected from: 3.根据权利要求1所述的式(I)化合物或其药用盐，其中：3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: (i)A为苯基；(i) A is phenyl; R1选自(C1-6-烷基)2PO-和基团 R 1 is selected from (C 1-6 -alkyl) 2 PO- and groups R2选自氢、卤素和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl; R3选自C1-6-烷基、卤代-C1-6-烷基和(卤代-C1-6-烷基)-(4元至6元杂环基)；并且R 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl and (halo-C 1-6 -alkyl)-(4- to 6-membered heterocyclyl); and X选自O和NH；或者X is selected from O and NH; or (ii)A为吡啶基；(ii) A is pyridyl; R1选自卤素、C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、卤代-C1-6-烷基-C3-6-环烷基-、卤代-C1-6-烷氧基、(C1-6-烷基)2PO-和基团 R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO- and the group R2选自氢、卤素、卤代-C1-6-烷基和氰基；R 2 is selected from hydrogen, halogen, halo-C 1-6 -alkyl and cyano; R3选自C1-6-烷基和卤代-C1-6-烷基；并且R 3 is selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and X选自O和NH；或者X is selected from O and NH; or (iii)A选自1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、(iii) A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-三唑基、三唑基、噻唑基、咪唑基、嘧啶基、吡嗪基、哒嗪基、吡唑基、噁唑基、1,2-二氢吡啶基、[1,2,4]三唑并[4,3-a]吡啶、[1,2,4]三唑并[1,5-a]吡啶、1H-吡咯并[2,3-b]吡啶、咪唑并[1,5-a]吡啶、咪唑并[1,2-a]吡啶、2H-吡唑并[3,4-b]吡啶、2H-吡唑并[4,3-b]吡啶、2H-吡唑并[4,3-c]吡啶、吡唑并[1,5-a]嘧啶、1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridinyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-吡唑并[3,4-d]嘧啶、[1,2,4]三唑并[1,5-a]嘧啶、咪唑并[1,2-a]吡嗪、1,2-苯并噁唑、1H-吲唑、1H-咪唑并[1,2-c]嘧啶-5-酮、2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-吡咯并[2,3-b]吡啶、咪唑并[1,2-a]嘧啶、2H-吡唑并[3,4-c]吡啶、7H-吡咯并[2,3-d]嘧啶、[1,2,4]三唑并[1,5-b]嘧啶、吡唑并[1,5-a]嘧啶、2H-吡唑并[4,3-b]吡啶、1H-咪唑并[4,5-b]吡啶、3H-咪唑并[4,5-b]吡啶、4,5,6,7-四氢吡唑并[1,5-a]嘧啶、1H-吡唑并[3,4-b]吡啶、1H-咪唑并[1,2-a]嘧啶-5-酮和2H-吲唑；1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one and 2H-indazole; R1选自C1-6-烷氧基、卤代-C1-6-烷基、羟基-C1-6-烷基、C3-6-环烷基-、卤代-C1-6-烷基-C3-6-环烷基-、(卤代-C1-6-烷基)-(3元至6元杂环基)-、卤代-C1-6-烷氧基和基团 R1 is selected from the group consisting of C1-6 -alkoxy, halo- C1-6 -alkyl, hydroxy- C1-6 -alkyl, C3-6 -cycloalkyl-, halo- C1-6 -alkyl- C3-6 -cycloalkyl-, (halo- C1-6 -alkyl)-(3- to 6-membered heterocyclyl)-, halo- C1-6 -alkoxy and the group R2选自氢、卤素、氰基、氧代、C1-6-烷基和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R3为卤代-C1-6-烷基；并且R 3 is halo-C 1-6 -alkyl; and X选自O和NH。X is selected from O and NH. 4.根据权利要求3所述的式(I)化合物或其药用盐，其中：4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein: (i)A为苯基；(i) A is phenyl; R1选自(C1-6-烷基)2PO-和基团 R 1 is selected from (C 1-6 -alkyl) 2 PO- and groups R2选自氢、卤素和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl; R3选自C1-6-烷基和卤代-C1-6-烷基；并且R 3 is selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and X为O；或者X is O; or (ii)A为吡啶基；(ii) A is pyridyl; R1选自卤素和卤代-C1-6-烷基；R 1 is selected from halogen and halo-C 1-6 -alkyl; R2选自氢和卤素；或者 R2 is selected from hydrogen and halogen; or (iii)A选自吡嗪基和吡唑基；(iii) A is selected from pyrazinyl and pyrazolyl; R1为卤代-C1-6-烷基；并且R 1 is halo-C 1-6 -alkyl; and R2为氢。 R2 is hydrogen. 5.根据权利要求4所述的式(I)化合物或其药用盐，其中：5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein: (i)A为苯基；(i) A is phenyl; R1选自(CH3)2PO-和基团 R 1 is selected from (CH 3 ) 2 PO- and a group R2选自氢、氟和CF3；R 2 is selected from hydrogen, fluorine and CF 3 ; R3选自甲基和CF3；并且R 3 is selected from methyl and CF 3 ; and X为O；或者X is O; or (ii)A为吡啶基；(ii) A is pyridyl; R1选自氟和CF3；R 1 is selected from fluorine and CF 3 ; R2选自氢和氟；或者 R2 is selected from hydrogen and fluorine; or (iii)A选自吡嗪基和吡唑基；(iii) A is selected from pyrazinyl and pyrazolyl; R1为CF3；并且R 1 is CF 3 ; and R2为氢。 R2 is hydrogen. 6.根据权利要求1所述的式(I)化合物或其药用盐，其中：6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: A选自1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、1,2,4-三唑基、三唑基、噻唑基、咪唑基、嘧啶基、吡嗪基、哒嗪基、吡唑基、噁唑基、1,2-二氢吡啶基、[1,2,4]三唑并[4,3-a]吡啶、A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridinyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]三唑并[1,5-a]吡啶、1H-吡咯并[2,3-b]吡啶、咪唑并[1,5-a]吡啶、咪唑并[1,2-a]吡啶、2H-吡唑并[3,4-b]吡啶、2H-吡唑并[4,3-b]吡啶、2H-吡唑并[4,3-c]吡啶、吡唑并[1,5-a]嘧啶、2H-吡唑并[3,4-d]嘧啶、[1,2,4]三唑并[1,5-a]嘧啶、咪唑并[1,2-a]吡嗪、1,2-苯并噁唑、1H-吲唑、1H-咪唑并[1,2-c]嘧啶-5-酮、1H-吡咯并[2,3-b]吡啶、咪唑并[1,2-a]嘧啶、2H-吡唑并[3,4-c]吡啶、[1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H- pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-吡咯并[2,3-d]嘧啶、[1,2,4]三唑并[1,5-b]嘧啶、吡唑并[1,5-a]嘧啶、2H-吡唑并[4,3-b]吡啶、1H-咪唑并[4,5-b]吡啶、3H-咪唑并[4,5-b]吡啶、4,5,6,7-四氢吡唑并[1,5-a]嘧啶、1H-吡唑并[3,4-b]吡啶、1H-咪唑并[1,2-a]嘧啶-5-酮和2H-吲唑；7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R1选自C1-6-烷氧基、卤代-C1-6-烷基、羟基-C1-6-烷基、C3-6-环烷基-、卤代-C1-6-烷基-C3-6-环烷基-、(卤代-C1-6-烷基)-(3元至6元杂环基)-、卤代-C1-6-烷氧基和基团 R1 is selected from the group consisting of C1-6 -alkoxy, halo- C1-6 -alkyl, hydroxy- C1-6 -alkyl, C3-6 -cycloalkyl-, halo- C1-6 -alkyl- C3-6 -cycloalkyl-, (halo- C1-6 -alkyl)-(3- to 6-membered heterocyclyl)-, halo- C1-6 -alkoxy and the group R2选自氢、卤素、氰基、氧代、C1-6-烷基和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R3为卤代-C1-6-烷基；并且R 3 is halo-C 1-6 -alkyl; and X选自O和NH。X is selected from O and NH. 7.根据权利要求1至6中任一项所述的式(I)化合物或其药用盐，其中B选自：7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein B is selected from: 8.根据权利要求1至6中任一项所述的式(I)化合物或其药用盐，其中B为 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein B is 9.根据权利要求1至6中任一项所述的式(I)化合物或其药用盐，其中B为 9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein B is 10.根据权利要求1至9中任一项所述的式(I)化合物或其药用盐，其中：10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: R4选自氢、卤素和C1-6-烷基；并且R 4 is selected from hydrogen, halogen and C 1-6 -alkyl; and R5选自氢和卤素。 R5 is selected from hydrogen and halogen. 11.根据权利要求1至9中任一项所述的式(I)化合物或其药用盐，其中：11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: R4和R5两者为氢；或者 R4 and R5 are both hydrogen; or R4和R5两者为卤素；或者 R4 and R5 are both halogen; or R4为C1-6-烷基并且R5为氢。R 4 is C 1-6 -alkyl and R 5 is hydrogen. 12.根据权利要求1至9中任一项所述的式(I)化合物或其药用盐，其中12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R4和R5两者为氢。 R4 and R5 are both hydrogen. 13.根据权利要求1所述的式(I)化合物或其药用盐，其中：13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: (i)A为苯基；(i) A is phenyl; R1选自(C1-6-烷基)2PO-和基团 R 1 is selected from (C 1-6 -alkyl) 2 PO- and groups R2选自氢、卤素和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl; R3选自C1-6-烷基、卤代-C1-6-烷基和(卤代-C1-6-烷基)-(4元至6元杂环基)；并且R 3 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl and (halo-C 1-6 -alkyl)-(4- to 6-membered heterocyclyl); and X选自O和NH；或者X is selected from O and NH; or (ii)A为吡啶基；(ii) A is pyridyl; R1选自卤素、C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、卤代-C1-6-烷基-C3-6-环烷基-、卤代-C1-6-烷氧基、(C1-6-烷基)2PO-和基团 R 1 is selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl) 2 PO- and the group R2选自氢、卤素、卤代-C1-6-烷基和氰基；R 2 is selected from hydrogen, halogen, halo-C 1-6 -alkyl and cyano; R3选自C1-6-烷基和卤代-C1-6-烷基；并且R 3 is selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and X选自O和NH；或者X is selected from O and NH; or (iii)A选自1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,4-噻二唑基、(iii) A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-三唑基、三唑基、噻唑基、咪唑基、嘧啶基、吡嗪基、哒嗪基、吡唑基、噁唑基、1,2-二氢吡啶基、[1,2,4]三唑并[4,3-a]吡啶、[1,2,4]三唑并[1,5-a]吡啶、1H-吡咯并[2,3-b]吡啶、咪唑并[1,5-a]吡啶、咪唑并[1,2-a]吡啶、2H-吡唑并[3,4-b]吡啶、2H-吡唑并[4,3-b]吡啶、2H-吡唑并[4,3-c]吡啶、吡唑并[1,5-a]嘧啶、1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridinyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-吡唑并[3,4-d]嘧啶、[1,2,4]三唑并[1,5-a]嘧啶、咪唑并[1,2-a]吡嗪、1,2-苯并噁唑、1H-吲唑、1H-咪唑并[1,2-c]嘧啶-5-酮、2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-吡咯并[2,3-b]吡啶、咪唑并[1,2-a]嘧啶、2H-吡唑并[3,4-c]吡啶、7H-吡咯并[2,3-d]嘧啶、[1,2,4]三唑并[1,5-b]嘧啶、吡唑并[1,5-a]嘧啶、2H-吡唑并[4,3-b]吡啶、1H-咪唑并[4,5-b]吡啶、3H-咪唑并[4,5-b]吡啶、4,5,6,7-四氢吡唑并[1,5-a]嘧啶、1H-吡唑并[3,4-b]吡啶、1H-咪唑并[1,2-a]嘧啶-5-酮和2H-吲唑；1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one and 2H-indazole; R1选自C1-6-烷氧基、卤代-C1-6-烷基、羟基-C1-6-烷基、C3-6-环烷基-、卤代-C1-6-烷基-C3-6-环烷基-、(卤代-C1-6-烷基)-(3元至6元杂环基)-、卤代-C1-6-烷氧基和基团 R1 is selected from the group consisting of C1-6 -alkoxy, halo- C1-6 -alkyl, hydroxy- C1-6 -alkyl, C3-6 -cycloalkyl-, halo- C1-6 -alkyl- C3-6 -cycloalkyl-, (halo- C1-6 -alkyl)-(3- to 6-membered heterocyclyl)-, halo- C1-6 -alkoxy and the group R2选自氢、卤素、氰基、氧代、C1-6-烷基和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R3为卤代-C1-6-烷基；R 3 is halo-C 1-6 -alkyl; X选自O和NH；X is selected from O and NH; R4和R5两者为氢；或者 R4 and R5 are both hydrogen; or R4和R5两者为卤素；或者 R4 and R5 are both halogen; or R4为C1-6-烷基并且R5为氢；并且R 4 is C 1-6 -alkyl and R 5 is hydrogen; and B选自：B is selected from: 14.根据权利要求13所述的式(I)化合物或其药用盐，其中：14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein: (i)A为苯基；(i) A is phenyl; R1选自(C1-6-烷基)2PO-和基团 R 1 is selected from (C 1-6 -alkyl) 2 PO- and groups R2选自氢、卤素和卤代-C1-6-烷基；R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl; R3选自C1-6-烷基和卤代-C1-6-烷基；并且R 3 is selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and X为O；或者X is O; or (ii)A为吡啶基；(ii) A is pyridyl; R1选自卤素和卤代-C1-6-烷基；R 1 is selected from halogen and halo-C 1-6 -alkyl; R2选自氢和卤素；或者 R2 is selected from hydrogen and halogen; or (iii)A选自吡嗪基和吡唑基；(iii) A is selected from pyrazinyl and pyrazolyl; R1为卤代-C1-6-烷基；并且R 1 is halo-C 1-6 -alkyl; and R2为氢； R2 is hydrogen; R4和R5两者为氢；并且 R4 and R5 are both hydrogen; and B选自：B is selected from: 15.根据权利要求14所述的式(I)化合物或其药用盐，其中：15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, wherein: (i)A为苯基；(i) A is phenyl; R1选自(CH3)2PO-和基团 R 1 is selected from (CH 3 ) 2 PO- and a group R2选自氢、氟和CF3；R 2 is selected from hydrogen, fluorine and CF 3 ; R3选自甲基和CF3；并且R 3 is selected from methyl and CF 3 ; and X为O；或者X is O; or (ii)A为吡啶基；(ii) A is pyridyl; R1选自氟和CF3；R 1 is selected from fluorine and CF 3 ; R2选自氢和氟；或者 R2 is selected from hydrogen and fluorine; or (iii)A选自吡嗪基和吡唑基；(iii) A is selected from pyrazinyl and pyrazolyl; R1为CF3；并且R 1 is CF 3 ; and R2为氢； R2 is hydrogen; R4和R5两者为氢；并且 R4 and R5 are both hydrogen; and B选自：B is selected from: 16.根据权利要求1至15中任一项所述的式(I)化合物或其药用盐，其中所述式(I)化合物选自由以下项组成的组：16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein the compound of formula (I) is selected from the group consisting of: (4aR,8aS)-6-[6-[[5-(三氟甲基)吡嗪-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基磺酰基)-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-甲基-5-(三氟甲基)吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)吡唑并[1,5-a]嘧啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(三氟甲基)环丙基]-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3,5-二氟-2-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(3,5-difluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(三氟甲基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-氟-3-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-fluoro-3-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(4-氟-2-甲基磺酰基-苯基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(4-fluoro-2-methylsulfonyl-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-甲基磺酰基苯基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(3-methylsulfonylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(2-氟-4-甲基磺酰基-苯基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(2-fluoro-4-methylsulfonyl-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-二甲基磷酰基-5-(三氟甲基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-dimethylphosphoryl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 5-[[2-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-2-氮杂螺[3.3]庚烷-6-基]甲基]-3-(三氟甲基)吡啶-2-甲腈；5-[[2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-3-(trifluoromethyl)pyridine-2-carbonitrile; 5-[[2-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-2-氮杂螺[3.3]庚烷-6-基]甲基]-2-(三氟甲基)吡啶-3-甲腈；5-[[2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carbonitrile; (4aR,8aS)-6-[6-[[5-(三氟甲基磺酰基)-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基磺酰基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[5-(三氟甲基亚氨磺酰基)-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonamidoyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]-1,3,4-噁二唑-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-[1-(三氟甲基)环丙基]-1,2,4-三唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]-1H-1,2,4-三唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(三氟甲基)环丙基]吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(三氟甲基)环丙基]咪唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-氟-5-(三氟甲基)-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(三氟甲氧基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲氧基)-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethoxy)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-氧代-4-(三氟甲基)-1-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-氧代-5-(三氟甲基)-1-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-oxo-5-(trifluoromethyl)-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-甲基磺酰基-3-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-methylsulfonyl-3-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-甲基磺酰基-2-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-methylsulfonyl-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-二甲基磷酰基-2-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-dimethylphosphoryl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1,2,4-噻二唑-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-甲基-5-(三氟甲基)三唑-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-methyl-5-(trifluoromethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-甲基-5-(三氟甲基)吡唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-甲基-5-(三氟甲基)吡唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-甲基-3-(三氟甲基)吡唑-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(2,2,2-三氟乙基)吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(2,2,2-trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-甲基-4-(三氟甲基)吡唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-甲基-5-(三氟甲基)吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-甲基-3-(三氟甲基)吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-三氟乙基)吡唑-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(三氟甲基)哒嗪-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基)嘧啶-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)嘧啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(三氟甲基)嘧啶-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)嘧啶-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)嘧啶-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基)-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1,2,4-噁二唑-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基)-1,2,4-噁二唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1,2,4-三唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)三唑-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基)-1,2,4-三唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-1,2,4-三唑-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)噁唑-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)oxazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)咪唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)咪唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(二氟甲基)-5-甲基-吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(二氟甲基)-3-甲基-吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-氯-3-氟-2-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-chloro-3-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-氯-5-氟-2-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(二氟甲基)-1H-吡唑-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(Difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-氯-3-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-chloro-3-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-氯-2-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-chloro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-氟-2-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-氟-5-(三氟甲基磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[3-氟-5-(三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[2-氟-4-(三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[2-fluoro-4-(trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[2-(甲基亚氨磺酰基)-4-(三氟甲基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[4-(甲基亚氨磺酰基)-3-(三氟甲基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[4-(methylsulfonimidoyl)-3-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[3-(甲基亚氨磺酰基)-5-(三氟甲基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[3-(methylsulfonimidoyl)-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-二甲基磷酰基-5-(三氟甲基)苄基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[3-dimethylphosphoryl-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-([S(R)]-三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(R)]-trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(S)]-三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-([S(S)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(S)]-三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-([S(S)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(R)]-三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-([S(R)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(R)]-三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-([S(R)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(S)]-三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-([S(S)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(S)]-三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-([S(S)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(R)]-三氟甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-([S(R)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[4-氟-2-(甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[4-fluoro-2-(methylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-二甲基磷酰基-5-氟-苯基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(3-dimethylphosphoryl-5-fluoro-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[4-(甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[4-(methylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[3-(甲基亚氨磺酰基)苯基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[3-(methylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-二甲基磷酰基苯基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(3-dimethylphosphorylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[5-(三氟甲基)吡嗪-2-基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[5-(三氟甲基)-2-吡啶基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[[5-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[(3,5-二氟-2-吡啶基)甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[(3,5-difluoro-2-pyridinyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[(5-氟-2-吡啶基)甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[(5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[6-(三氟甲基)-3-吡啶基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[6-(二氟甲氧基)-3-吡啶基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[[6-(difluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 5-[[(6S)-2-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-2-氮杂螺[3.4]辛烷-6-基]甲基]-2-(三氟甲基)吡啶-4-甲腈；5-[[(6S)-2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6R)-2-[(4aR,8aS)-3-氧代-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-6-羰基]-2-氮杂螺[3.4]辛烷-6-基]甲基]-2-(三氟甲基)吡啶-4-甲腈；5-[[(6R)-2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; (4aR,8aS)-6-[(6S)-6-[[5-(三氟甲基)吡嗪-2-基]甲基]-2-氮杂螺[3.4]辛烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[(6S)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[5-(三氟甲基)吡嗪-2-基]甲基]-2-氮杂螺[3.4]辛烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[(6R)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(三氟甲基)-3-吡啶基]甲基]-2-氮杂螺[3.4]辛烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[4-(三氟甲基磺酰基)苯基]甲基]-2-氮杂螺[3.4]辛烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[3-(三氟甲基磺酰基)苯基]甲基]-2-氮杂螺[3.4]辛烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(三氟甲基)吡嗪-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(三氟甲基)嘧啶-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[6-(三氟甲氧基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[2-氧代-4-(三氟甲基)-1-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(三氟甲基磺酰基)-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[4-(三氟甲基)噁唑-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[4-(trifluoromethyl)oxazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[4-(三氟甲基)咪唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[4-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[3-(三氟甲基)-1,2,4-三唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[3-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[(3-氯-5-氟-2-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[(5-氯-3-吡啶基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[(5-chloro-3-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[7-[(5-氟-2-吡啶基)甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[7-[(5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[7-[[5-(三氟甲基)-2-吡啶基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[7-[[5-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)咪唑并[1,2-a]吡嗪-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑并[4,3-b]吡啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)-[1,2,4]三唑并[1,5-a]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)吡唑并[1,5-a]嘧啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吲唑-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑并[3,4-d]嘧啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑并[4,3-c]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吲唑-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-indazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)咪唑并[1,5-a]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(三氟甲基)吲唑-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-(trifluoromethyl)indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)苯并[d]异噁唑-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)benzo[d]isoxazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)咪唑并[1,2-a]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]嘧啶-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(三氟甲基)环丙基]嘧啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-甲氧基-5-(三氟甲基)吡嗪-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-methoxy-5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-甲基-3-(三氟甲基)吡咯并[2,3-b]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基)-1H-吡唑-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(4-三氟甲磺酰基吡唑-1-基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(4-trifluoromethanesulfonylpyrazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡啶-7-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(三氟甲基)环丙基]-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]-1H-吡唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-环丙基-3-(三氟甲基)吡唑-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]吡嗪-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(三氟甲基)环丙基]哒嗪-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[6-[[4-(三氟甲基亚氨磺酰基)吡唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；rac-(4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonamidoyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)-[1,2,4]三唑并[1,5-a]嘧啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(2,2,2-三氟乙基)三唑-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(2,2,2-trifluoroethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-甲基-4-(三氟甲基)吡唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)噻唑-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(2,2,2-三氟乙基)-5-(三氟甲基)吡唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(三氟甲基)吡唑-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[3-甲磺酰基-5-(三氟甲基)苄基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-methylsulfonyl-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)三唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-三氟乙基)-3-(三氟甲基)吡唑-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2-羟基乙基)-3-(三氟甲基)吡咯并[2,3-b]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-(2-hydroxyethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-[1-(三氟甲基)环丙基]-1,3,4-噁二唑-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aS,8aR)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[二氟-[2-甲氧基-6-(三氟甲基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[difluoro-[2-methoxy-6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(1R)-1-[4-甲基-5-(三氟甲基)-2-吡啶基]乙基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(1S)-1-[4-甲基-5-(三氟甲基)-2-吡啶基]乙基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(1S)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[二氟-[2-(三氟甲基)-4-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)-4-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[二氟-[2-(三氟甲基)嘧啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[二氟-[6-(三氟甲基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)-[1,2,4]三唑并[1,5-a]吡啶-7-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡唑并[3,4-c]吡啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)咪唑并[1,2-a]吡啶-7-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[4-[3-(三氟甲基)氮杂环丁烷-1-基]磺酰基苄基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[4-[3-(trifluoromethyl)azetidin-1-yl]sulfonylbenzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(三氟甲基)环丙基]-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(三氟甲基)环丙基]嘧啶-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(三氟甲基)环丙基]-2-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(三氟甲基)环丙基]-4-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]-4-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[二氟-[6-(三氟甲氧基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-三氟乙基)-5-(三氟甲基)吡唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-甲磺酰基-4-(三氟甲基)苄基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[3-methylsulfonyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)咪唑并[1,2-a]嘧啶-7-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)imidazo[1,2-a]pyrimidin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[二氟-[2-甲氧基-5-(三氟甲基)-3-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[difluoro-[2-methoxy-5-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[3-(三氟甲基)氮杂环丁烷-1-基]吡嗪-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[3-(trifluoromethyl)azetidin-1-yl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(三氟甲基)苯并[d]异噁唑-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-(trifluoromethyl)benzo[d]isoxazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-酮基-4-[1-(三氟甲基)环丙基]-1-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-keto-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-[1-(三氟甲基)环丙基]-1,2,4-噁二唑-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]-1,2,4-噁二唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-酮基-1H-咪唑并[1,2-c]嘧啶-7-基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-keto-1H-imidazo[1,2-c]pyrimidin-7-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(三氟甲基)环丙基]咪唑-1-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[二氟-[6-(三氟甲基)哒嗪-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[二氟-[5-(三氟甲基)嘧啶-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-三氟乙基)-1,2,4-三唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(三氟甲基)-1H-吡唑-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[4-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(三氟甲基)环丙基]嘧啶-4-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[二氟-[5-(三氟甲基)吡嗪-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[difluoro-[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-氧代-5-[1-(三氟甲基)环丙基]-1-吡啶基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-oxo-5-[1-(trifluoromethyl)cyclopropyl]-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-氧代-1-(2,2,2-三氟乙基)咪唑并[1,2-a]嘧啶-7-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-oxo-1-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrimidin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)-[1,2,4]三唑并[1,5-b]哒嗪-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)咪唑并[1,2-a]嘧啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(三氟甲基)环丙基]吡嗪-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[2-(三氟甲基)吡唑并[1,5-a]嘧啶-6-基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[2-(三氟甲基)咪唑并[1,2-a]吡嗪-6-基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[3-(三氟甲基)-1H-吡唑并[4,3-c]吡啶-6-基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[3-(三氟甲基)-1H-吡唑并[3,4-d]嘧啶-6-基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[7-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(三氟甲基)-1H-吡唑并[4,3-b]吡啶-5-基]甲基]-7-氮杂螺[3.5]壬烷-7-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(三氟甲基)-1H-吡唑并[4,3-c]吡啶-6-基]甲基]-7-氮杂螺[3.5]壬烷-7-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(三氟甲基)-1H-吡唑并[3,4-d]嘧啶-6-基]甲基]-7-氮杂螺[3.5]壬烷-7-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[2-(三氟甲基)吡唑并[1,5-a]嘧啶-6-基]甲基]-7-氮杂螺[3.5]壬烷-7-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[2-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(三氟甲基)-1H-吡唑并[3,4-b]吡啶-3-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)-3H-咪唑并[4,5-b]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(三氟甲基)-1H-咪唑并[4,5-b]吡啶-5-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-(1H-吡唑并[4,3-b]吡啶-5-基甲基)-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-(1H-pyrazolo[4,3-b]pyridin-5-ylmethyl)-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-甲氧基吡咯并[2,3-c]吡啶-1-基)甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[(5-methoxypyrrolo[2,3-c]pyridin-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-甲基-3-(三氟甲基)吡唑并[3,4-b]吡啶-6-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；(4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 外消旋-(4aR,8aS)-6-[7-[[2-(三氟甲基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-6-基]甲基]-2-氮杂螺[3.5]壬烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮；以及rac-(4aR,8aS)-6-[7-[[2-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and (4aR,8aS)-6-[6-[[4-[1-(三氟甲基)环丙基]嘧啶-2-基]甲基]-2-氮杂螺[3.3]庚烷-2-羰基]-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮。(4aR,8aS)-6-[6-[[4-[1-(Trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one. 17.一种制造根据权利要求1至16中任一项所述的式(I)化合物或其药用盐的方法，所述方法包括：17. A method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, the method comprising: (a)使式1的胺，其中R1、R2、A和B如权利要求1至16中任一项中所定义，(a) making an amine of formula 1, wherein R 1 , R 2 , A and B are as defined in any one of claims 1 to 16, 与6-(1,2,4-三唑-1-羰基)-4,4a,5,7,8,8a-六氢吡啶并[4,3-b][1,4]噁嗪-3-酮(2)，With 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2), 在碱存在下反应；或者react in the presence of a base; or (b)使4a,5,6,7,8,8a-六氢-4H-吡啶并[4,3-b][1,4]噁嗪-3-酮(2a)(b) 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (2a) 与式1a化合物，其中R1、R2、A和B如权利要求1至16中任一项中所定义，A compound of formula 1a, wherein R 1 , R 2 , A and B are as defined in any one of claims 1 to 16, 在碱存在下反应，In the presence of a base, 以形成所述式(I)化合物。To form the compound of formula (I). 18.根据权利要求1至16中任一项所述的式(I)化合物，其根据权利要求17所述的方法进行制造。18. A compound of formula (I) according to any one of claims 1 to 16, which is manufactured according to the process of claim 17. 19.根据权利要求1至16中任一项所述的式(I)化合物，其用作治疗活性物质。19. Compounds of formula (I) according to any one of claims 1 to 16 for use as therapeutically active substances. 20.一种药物组合物，其包含根据权利要求1至16中任一项所述的式(I)化合物以及治疗惰性载体。20. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16 and a therapeutically inert carrier. 21.根据权利要求1至16中任一项所述的式(I)化合物用于治疗或预防哺乳动物的与MAGL相关联的疾病和疾患的用途。21. Use of a compound of formula (I) according to any one of claims 1 to 16 for treating or preventing diseases and disorders associated with MAGL in mammals. 22.根据权利要求1至16中任一项所述的式(I)化合物，其用于治疗或预防与MAGL相关联的疾病和疾患。22. A compound of formula (I) according to any one of claims 1 to 16 for use in the treatment or prevention of diseases and disorders associated with MAGL. 23.根据权利要求1至16中任一项所述的式(I)化合物在制备药物中的用途，所述药物用于治疗或预防与MAGL相关联的疾病和疾患。23. Use of a compound of formula (I) according to any one of claims 1 to 16 in the preparation of a medicament for the treatment or prevention of diseases and disorders associated with MAGL. 24.一种用于治疗或预防哺乳动物的与MAGL相关联的疾病和疾患的方法，所述方法包括向所述哺乳动物施用有效量的根据权利要求1至16中任一项所述的式(I)化合物。24. A method for treating or preventing diseases and disorders associated with MAGL in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) according to any one of claims 1 to 16. 25.如前所述的本发明。25. The invention as hereinbefore described.
CN202380058308.9A 2022-08-08 2023-08-07 Novel heterocyclic compounds Pending CN119654326A (en)

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