Novel heterocyclic compounds

Abstract

The present invention provides novel heterocyclic compounds having the general formula (I) wherein A, B, U, V, X, Y, L1, R1 and R2 are as described herein; compositions comprising the compounds; methods of making the compounds; and methods of using the compounds. (I)

Description

Technical Field

[0001] This invention relates to organic compounds that can be used for the treatment or prevention of diseases and disorders associated with MAGL in mammals, and particularly to monoacylglycerol lipase (MAGL) inhibitors for the treatment or prevention of such diseases and disorders, such as neuroinflammation, neurodegenerative diseases, pain, cancer, mental 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, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or kidney disease. Background Technology

[0002] Endocannabinoids (ECs) are lipid signaling molecules that exert their biological effects through interactions with cannabinoid receptors (CBRs), CB1, and CB2. They regulate a variety of physiological processes, including neuroinflammation, neurodegenerative diseases, and tissue regeneration (Iannoti, FA). et al. , Progress in lipid research 2016, 62 , 107-28.). In the brain, the main endocannabinoid 2-arachidonicylglycerol (2-AG) is produced by diacylglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase (MAGL). MAGL hydrolyzes 85% of 2-AG; the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, DK). et al. , Science 2011, 334 MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglia (Chanda, PK). et al. , Molecular pharmacology 2010, 78 , 996; Viader, A. et al. , Cell reports 2015, 122-AG hydrolysis forms arachidonic acid (AA), a precursor to prostaglandins (PG) and leukotrienes (LT). AA oxidation metabolism is increased in inflamed tissues. The inflammatory process involves two major enzymatic pathways of arachidonic acid oxidation: cyclooxygenase, which produces PG, and 5-lipoxygenase, which produces LT. Among the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important. These products have been detected at sites of inflammation (e.g., in the cerebrospinal fluid of patients with neurodegenerative diseases) and are believed to contribute to the inflammatory response and disease progression. In mice lacking MAGL (Mgll- / -), 2-AG hydrolase activity in the nervous system is significantly reduced, while 2-AG levels are increased, while other arachidonic acid-containing phosphates and neutral lipids (including arachidonic acid ethanolamine (AEA) and other free fatty acids remain unchanged. Conversely, levels of AA-derived prostaglandins and other arachidic acids (including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2), and thromboxane B2 (TXB2)) were significantly reduced. Phospholipase A2 (PLA2) has been considered a major source of AA, but AA levels remained unchanged in the brains of cPLA2-deficient mice, thus enhancing the crucial role of MAGL in regulating AA production and brain inflammatory processes.

[0003] Neuroinflammation is a common pathological feature 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 mental disorders such as anxiety and migraine). In the brain, the production of arachidonic acid and prostaglandins controls the neuroinflammatory process. The pro-inflammatory agent lipopolysaccharide (LPS) leads to a stable, time-dependent increase in arachidonic acid production in the brain, a phenomenon significantly attenuated in Mg11- / - mice. LPS treatment also induces a general increase in pro-inflammatory cytokines, including interleukin-1-a (IL-1-a), IL-1b, and IL-6, and tumor necrosis factor-a (TNF-a) (which is suppressed in Mg11- / - mice).

[0004] Neuroinflammation is characterized by the activation of innate immune cells, microglia, and astrocytes in the central nervous system. Anti-inflammatory drugs have been reported to inhibit glial cell activation and disease progression (including Alzheimer's disease and multiple sclerosis) in preclinical models (Lleo A., Cell Mol Life Science. 2007, 64Importantly, genetic and / or pharmacological disruption of MAGL activity also blocks LPS-induced activation of microglia in the brain (Nomura, DK). et al. , Science 2011, 334 , 809.).

[0005] Furthermore, in animal models of various neurodegenerative diseases (including but not limited to Alzheimer's disease, Parkinson's disease, and multiple sclerosis), the genetic and / or pharmacological disruption of MAGL activity has been demonstrated to have a protective effect. For example, irreversible MAGL inhibitors have been widely used in preclinical models of neuroinflammation and neurodegenerative diseases (Long, JZ). wait people , Nature chemical biology 2009, 5 , 37.). Systemic injection of these inhibitors reproduced the Mgll- / - mouse phenotype in the brain, including elevated 2-AG levels, decreased AA levels, and associated arachidonic acid production, and prevented cytokine production and microglial activation following LPS-induced neuroinflammation (Nomura, DK). et al. , Science 2011, 334 (809.), fully confirming MAGL as a drug target.

[0006] As MAGL activity is genetically and / or pharmacologically disrupted, the endogenous levels of the natural MAGL substrate 2-AG in the brain increase. 2-AG has been reported to have beneficial effects on pain, such as analgesia in mice (Ignatowska-Jankowska B). et al. , J. Pharmacol. Exp. Ther. 2015, 353 , 424), and also has beneficial effects on mental disorders (such as depression in chronic stress models) (Zhong P). et al. , Neuropsychopharmacology 2014, 39 , 1763.).

[0007] Furthermore, oligodendrocytes (OLs), myelin cells of the central nervous system, and their precursors (OPCs) express cannabinoid receptor 2 (CB2) on their membranes. 2-AG is an endogenous ligand for both CB1 and CB2 receptors. It has been reported that the pharmacological inhibitory effects of cannabinoids and MAGLs weaken the excitatory toxicity of OLs and OPCs, and therefore may have neuroprotective effects (Bernal-Chico, A). et al. , Glia2015, 63 , 163.). Furthermore, pharmacological inhibition of MAGL increased the number of myelin OLs in the mouse brain, indicating that MAGL inhibition can promote… in vivo Differentiation of OPCs in the myelin OL (Alpar, A). et al. , Nature communications 2014, 5 , 4421.). In a mouse model of progressive multiple sclerosis, inhibition of MAGL also promotes myelin regeneration and functional recovery (Feliu A). et al. , Journal of Neuroscience 2017, 37 (35), 8385.).

[0008] In recent years, metabolism, especially lipid metabolism, has received considerable attention in cancer research. Researchers believe that de novo fatty acid synthesis plays a crucial role in tumor development. Numerous studies have demonstrated that endocannabinoids possess anti-tumor effects, including anti-proliferation, apoptosis induction, and anti-metastasis. MAGL, as an important degradative enzyme in lipid metabolism and the endocannabinoid system, and as a component of gene expression characteristics, influences various 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).

[0009] The endocannabinoid system is also involved in many gastrointestinal physiological and pathophysiological processes (Marquez, Suarez et al. 2009). All these effects are primarily driven by cannabinoid receptors (CBRs), CB1, and CB2. CB1 receptors are present throughout the GI tract in animals and healthy humans, particularly in the smooth muscle cells of the enteric nervous system (ENS) and epithelial lining, as well as blood vessels in the colonic wall (Wright, Rooney et al. 2005), (Duncan, Davison et al. 2005). Activation of CB1 produces antiemetic, antiperistaltic, and anti-inflammatory effects and helps modulate 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 primarily act on the human colonic tissue epithelium associated with inflammatory bowel disease (IBD). Activation of CB2 exerts its anti-inflammatory effect by reducing pro-inflammatory cytokines. MAGL expression is increased in the colonic tissue of patients with UC (Marquez, Suarez et al. 2009), and 2-AG levels are increased in the plasma of patients with IBD (Grill, Hogenauer et al. 2019). Several animal studies have confirmed the potential of MAGL inhibitors for symptomatic treatment of IBD. MAGL inhibition prevents TNBS-induced colitis in mice via CB1 / CB2 MoA and reduces local circulating inflammatory markers (Marquez, Suarez et al. 2009). Furthermore, MAGL inhibition improves intestinal wall integrity and intestinal permeability via CB1-driven MoA (Wang, Zhang et al. 2020).

[0010] In summary, inhibiting and / or activating MAGL is a promising novel therapeutic strategy for treating or preventing various diseases and disorders.

[0011] WO2020104494 discloses certain MAGL inhibitors. However, it has been found that while these MAGL inhibitors possess properties that make them particularly suitable for treating CNS indications such as multiple sclerosis, some properties (such as high permeability) mean that they are less suitable if varying exposure across tissues is required. This may make them less suitable for treating certain conditions where higher exposure levels in the target tissues compared to other parts of the body could be beneficial.

[0012] Therefore, there remains a high unmet medical need for novel MAGL inhibitors, particularly those with unique properties that allow for different exposures in different tissues. Summary of the Invention

[0013] In a first aspect, the present invention provides a compound of formula (I). (I) Among them A, B, U, V, X, Y, L 1 R 1 and R 2 As described in this article.

[0014] In another aspect, the present invention provides compositions comprising formula (I), processes for manufacturing formula (I), and methods for using formula (I). Detailed Implementation

[0015] definition

[0016] Features, integrals, properties, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. All features disclosed in this specification (including any appended claims, abstract, and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for at least some mutually exclusive combinations of such features and / or steps. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any appended claims, abstract, and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0017] The term "alkyl" refers to a monovalent or polyvalent (e.g., monovalent or divalent) straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms ("C1-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, such as 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.

[0018] The term "alkoxy group" refers to an alkyl group as defined above, attached to a parent molecule via an oxygen atom. Unless otherwise stated, an alkoxy group contains 1 to 6 carbon atoms ("C1-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.

[0019] The term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), or bromine (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halogenated" are fluorine (F) and chlorine (Cl).

[0020] The terms “heterocyclic alkyl” and “heterocyclic group” are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic or bicyclic system having 3 to 14 ring atoms, preferably 3 to 11 ring atoms, more preferably 3 to 9 ring atoms, and most preferably 4 to 7 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. “Bicyclic heterocyclic group” refers to a heterocyclic portion consisting of two rings having two common ring atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic portion (i.e., the two rings are connected via a common ring atom). Some non-limiting examples of heterocyclic groups include azirrobutane, pyrrolidine, 2-azirro[3.3]heptane, and 2-azirro[3.5]nonane.

[0021] The term "heteroaryl" refers to a monovalent or polyvalent monocyclic or bicyclic (preferably monocyclic) ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, and most preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic and contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing one, two, three, or four heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing one to two heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, and triazolyl.

[0022] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbon ring system ("C6-C") having a total of 6 to 10 ring members. 10 The aryl group is a ring system in which at least one ring is aromatic. Some non-limiting examples of aryl groups include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred but non-limiting example of an aryl group is the phenyl group.

[0023] As used herein, the term "cycloalkyl" refers to a ring of 3 to 10 carbon atoms ("C10"). 3-10 Cycloalkyl refers to a saturated monocyclic, bicyclic, tricyclic, tetracyclic, or pentacyclic hydrocarbon group. In some preferred embodiments, the cycloalkyl group is a monocyclic or bicyclic hydrocarbon group with 3 to 8 ring carbon atoms. In some particularly preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group with 3 to 8 ring carbon atoms or 3 to 6 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic moiety (i.e., the two rings are connected via a common ring atom). A preferred but non-limiting example of a pentacyclic cycloalkyl group is a cubic alkyl group (pentacyclic [4.2.0.0]). 2,5 .0 3,8 .0 4,7 [Octoane]. Preferably, the cycloalkyl group is a monocyclic or bicyclic hydrocarbon group with 3 to 6 cyclic carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cubic alkyl, 1-bicyclo[1.1.1]pentyl, norbornelalkyl, and 1-bicyclo[2.2.2]octyl. A particularly preferred but non-limiting example of a cycloalkyl group is cyclopropyl.

[0024] The term "cyano" refers to the –CN (nitrile) group.

[0025] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluorine. Particularly preferred but non-limiting examples of haloalkyl are trifluoromethyl (CF3) and 2,2,2-trifluoroethyl (CF3CH2-).

[0026] The term "haloalkylcycloalkyl" refers to a cycloalkyl group in which at least one hydrogen atom of the cycloalkyl group has been replaced by a haloalkyl group, preferably by CF3. Preferably, "haloalkylcycloalkyl" refers to a cycloalkyl group in which one, two, or three hydrogen atoms of the cycloalkyl group have been replaced by a haloalkyl group, most preferably by CF3. A particularly preferred but non-limiting example of a haloalkylcycloalkyl group is trifluoromethylcyclopropyl.

[0027] 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 one, two, or three hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluorine. A particularly preferred but non-limiting example of a haloalkoxy group is trifluoromethoxy (-OCF3).

[0028] The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effects and properties of a free base or free acid, and are not undesirable in biological or other respects. These salts are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. (especially 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, ethylsulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Furthermore, these salts can be prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of the following: 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, etc.). Specific pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride salts.

[0029] 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, diastereomers, or mixtures of diastereomers.

[0030] According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can be either "R" or "S" configuration.

[0031] The abbreviation "MAGL" refers to monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably in this document.

[0032] As used herein, the term "treatment" includes: (1) a state, ailment, or condition that suppresses at least one clinical or subclinical symptom of a disease (e.g.,, in the case of maintenance therapy, preventing, alleviating, or delaying the progression or recurrence of the disease); and / or (2) a symptom relief (i.e., the resolution of a state, symptom, or condition of the disease or at least one clinical or subclinical symptom). The benefit of treatment to a patient is statistically significant or at least perceptible to the patient or physician. However, it should be understood that when a patient is given medication to treat a disease, the outcome may not always be an effective treatment.

[0033] As used herein, the term “prevention” includes: prevention or delay of the development of clinical symptoms of a state, disease, or symptom in mammals, particularly in humans, that may have or be susceptible to the state, disease, or symptom but have not yet experienced or displayed clinical or subclinical symptoms of the state, disease, or symptom.

[0034] As used herein, the term "neuritis" refers to acute and chronic inflammation of the neural tissue that is the main tissue component of the two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS) and the peripheral nerves, branches 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 usually occurs immediately after injury to the central nervous system, for example, caused by traumatic brain injury (TBI).

[0035] As used in this article, the term “traumatic brain injury” (“TBI”, also known as “intracranial injury”) refers to brain damage caused by external mechanical forces such as rapid acceleration or deceleration, impact, shock wave, or projectile penetration.

[0036] As used herein, the term "neurodegenerative disease" refers to diseases associated with the 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 (ALS).

[0037] As used herein, the term "mental disorder" (also known as psychosis or mental illness) refers to a pattern of behavior or mental state that may cause distress or impair daily living. Such features may be persistent, recurrent, or intermittent, or may be an isolated event. Examples of mental disorders include, but are not limited to, anxiety disorders and depression.

[0038] As used herein, the term "pain" refers to an 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. A specific example of pain is neuropathic pain, which is caused by damage or disease affecting any part of the nervous system involved in bodily sensation (i.e., the somatosensory system). In one embodiment, "pain" is neuropathic pain resulting from amputation or open-chest surgery. In another embodiment, "pain" is chemotherapy-induced neuropathy.

[0039] As used herein, the term "neurotoxicity" refers to toxicity of the nervous system. This occurs when exposed to natural or man-made toxic substances (neurotoxins) that alter the normal activity of the nervous system, thereby causing damage to nerve tissue. Examples of neurotoxicity include, but are not limited to, neurotoxicity resulting from exposure to substances used in chemotherapy, radiation therapy, drug therapy, drug abuse, and organ transplantation, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some natural substances.

[0040] As used herein, the term "cancer" refers to a disease characterized by the presence of growths or tumors resulting from the abnormal, uncontrolled growth of cells (these cells are "cancer cells"). As used herein, the term cancer explicitly includes, but is not limited to, hepatocellular carcinoma, colon cancer, and ovarian cancer.

[0041] The compounds of the present invention

[0042] In a first aspect, the present invention provides a compound of formula (I). (I) Or its pharmaceutically acceptable salt, wherein: U is CH2 or (CH2)2; V is CH2 or (CH2)2; W 1 and W 2 Each is independently selected from O and NH; X is (CH2) n CH2OCH2; Y is selected from NH, CH2, and (CH2)2; n is selected from 1, 2, and 3; A and C are each independently selected from: (i) 5- to 14-membered heteroaryl groups, comprising 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 3- to 14-membered heterocyclic groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (iii) C3-C 10 -cycloalkyl; and (iv) C6-C 10 -Aryl; B is selected from: (i) 4- to 7-membered monocyclic heterocycles comprising 1, 2, or 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii) 7- to 11-membered spirocyclic heterocycles containing 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; L 1 and L 2 Each is independently selected from covalent bonds, O, NH, and CR. 6 R 7 CH2O, OCH2, CH2NH and NHCH2; R 1 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6 -alkyl)2PO-, group and groups ; R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group; R 3 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6 -alkyl)2PO-, halo-C 1-6 -alkyl-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl and groups ; R 4 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl, C 1-6-alkoxy, halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group; R 5a and R 5b Each was independently selected from C 1-6 -alkyl and halogenated-C 1-6 -alkyl; and R 6 and R 7 Each is independently selected from hydrogen and halogens.

[0043] 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: (i) 4- to 6-membered monocyclic heterocycles comprising 1 to 2 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii) 7- to 11-membered spirocyclic heterocycles containing 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon.

[0044] 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 selected from: ; ;and .

[0045] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is... .

[0046] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is... .

[0047] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is... .

[0048] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) U, V, X, and Y are all CH2; or (ii) Both U and V are CH2 and both X and Y are (CH2)2; or (iii) U and V are both CH2, X is (CH2)2, and Y is NH; or (iv) Both U and V are (CH2)2, and both X and Y are CH2; or (v) Both U and V are CH2, X is (CH2)3, and Y is NH; or (vi) U and V are both CH2, X is CH2OCH2, and Y is NH.

[0049] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein U and V are both CH2, X is (CH2)2, and Y is NH.

[0050] 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: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) C3-C 10 -cycloalkyl; and (iii) C6-C 10 -Aryl; and L 1 Selected from covalent bonds, O, CH2, CH2O and NHCH2.

[0051] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from halogen, cyano, and halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6 -alkyl)2PO-, group and groups ; R 2 Selected from hydrogen, halogen, cyano and C 1-6 -alkyl; R 3 Selected from halogen, cyano, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halogenated-C 1-6 -alkyl-C3-C 10 -Cycloalkyl and groups ; R 4 Selected from hydrogen, halogens and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Selected from C 1-6 -alkyl and halogenated-C 1-6 -alkyl; R 6 and R 7 Each is independently selected from hydrogen and halogens; W 1 Selected from O and NH; W 2 It is O; C is selected from: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 3- to 10-membered heterocyclic groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (iii) C3-C 10 -cycloalkyl; and (iv) C6-C 10 -Aryl; and L 2 Selected from covalent bonds, O, NH, CR 6 R 7 CH2O and CH2NH.

[0052] 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: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) C3-C 10 -cycloalkyl; and (iii) C6-C 10 -Aryl; L 1 Selected from covalent bonds, O, CH2, CH2O, and NHCH2; R 1 Selected from halogen, cyano, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6-alkyl)2PO-, group and groups ; R 2 Selected from hydrogen, halogen, cyano and C 1-6 -alkyl; R 3 Selected from halogen, cyano, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halogenated-C 1-6 -alkyl-C3-C 10 -Cycloalkyl and groups ; R 4 Selected from hydrogen, halogens and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Selected from C 1-6 -alkyl and halogenated-C 1-6 -alkyl; R 6 and R 7 Each is independently selected from hydrogen and halogens; W 1 Selected from O and NH; W 2 It is O; C is selected from: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 3- to 10-membered heterocyclic groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (iii) C3-C 10 -cycloalkyl; and (iv) C6-C 10 -Aryl; and L 2 Selected from covalent bonds, O, NH, CR 6 R 7 CH2O and CH2NH.

[0053] 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 bicyclo[1.1.1]pentane, cyclopropyl, phenyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, thiazolyl, and triazolyl; and L1 Selected from covalent bonds, O, CH2, CH2O and NHCH2.

[0054] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from fluorine, chlorine, cyano, CF3, CF3CH2, CF3O, (CH3)2PO-, and other groups. and groups ; R 2 Selected from hydrogen, fluorine, chlorine, cyano, and methyl; R 3 Selected from fluorine, cyano, CF3, CF3O, trifluoromethylcyclopropyl and other groups ; R 4 Selected from hydrogen, fluorine, chlorine, and methyl; R 5a For CF3; R 5b Selected from methyl and CF3; W 1 Selected from O and NH; W 2 It is O; C is selected from 1,3,4-thiadiazolyl, aziridine, cyclopropyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, and pyrrolidinyl; and L 2 Selected from covalent bonds, O, NH, CH2, CF2, CH2O, and CH2NH.

[0055] 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 bicyclo[1.1.1]pentane, cyclopropyl, phenyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, thiazolyl, and triazolyl; L 1 Selected from covalent bonds, O, CH2, CH2O, and NHCH2; R 1 Selected from fluorine, chlorine, cyano, CF3, CF3CH2, CF3O, (CH3)2PO-, and other groups. and groups ; R 2 Selected from hydrogen, fluorine, chlorine, cyano, and methyl; R 3 Selected from fluorine, cyano, CF3, CF3O, trifluoromethylcyclopropyl and other groups ; R 4 Selected from hydrogen, fluorine, chlorine, and methyl; R 5a For CF3; R 5b Selected from methyl and CF3; W 1 Selected from O and NH; W 2 It is O; C is selected from 1,3,4-thiadiazolyl, aziridine, cyclopropyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, and pyrrolidinyl; and L 2 Selected from covalent bonds, O, NH, CH2, CF2, CH2O, and CH2NH.

[0056] 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: (i) 5- to 6-membered heteroaryl groups, comprising 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) C3-C6-cycloalkyl; and (iii) C6-C 10 -Aryl; and L 1 Selected from covalent bonds and CH2.

[0057] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from halogens, halogenated -C 1-6 -alkyl, halo-C 1-6 -alkoxy group and groups ; R 2 Selected from hydrogen, halogens, and cyano groups; R 3 Selected from halogenated-C 1-6 -alkyl and groups ; R 4 Selected from hydrogen and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Halogenated-C1-6 -alkyl; W 1 For NH; W 2 It is O; C is selected from: (i) a 5- to 6-membered heteroaryl group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii) C6-C 10 -Aryl; and L 2 It is a covalent bond.

[0058] 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: (i) 5- to 6-membered heteroaryl groups, comprising 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) C3-C6-cycloalkyl; and (iii) C6-C 10 -Aryl; L 1 Selected from covalent bonds and CH2; R 1 Selected from halogens, halogenated -C 1-6 -alkyl, halo-C 1-6 -alkoxy group and groups ; R 2 Selected from hydrogen, halogens, and cyano groups; R 3 Selected from halogenated-C 1-6 -alkyl and groups ; R 4 Selected from hydrogen and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Halogenated-C 1-6 -alkyl; W 1 For NH; W 2 It is O; C is selected from: (i) a 5- to 6-membered heteroaryl group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii) C6-C 10 -Aryl; and L 2 It is a covalent bond.

[0059] 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 bicyclo[1.1.1]pentane, phenyl, and pyridyl; and L 1 Selected from covalent bonds and CH2.

[0060] 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 1 Selected from fluorine, CF3, CF3O, and other groups and groups ; R 2 Selected from hydrogen, fluorine, chlorine, and cyano groups; R 3 Selected from CF3 and groups ; R 4 Selected from hydrogen and methyl; R 5a For CF3; R 5b For CF3; W 1 For NH; W 2 It is O; C is selected from phenyl and pyrazolyl groups; and L 2 It is a covalent bond.

[0061] 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 bicyclo[1.1.1]pentane, phenyl, and pyridyl; L 1 Selected from covalent bonds and CH2; R 1 Selected from fluorine, CF3, CF3O, and other groups and groups ; R 2Selected from hydrogen, fluorine, chlorine, and cyano groups; R 3 Selected from CF3 and groups ; R 4 Selected from hydrogen and methyl; R 5a For CF3; R 5b For CF3; W 1 For NH; W 2 It is O; C is selected from phenyl and pyrazolyl groups; and L 2 It is a covalent bond.

[0062] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) U, V, X, and Y are all CH2; or (ii) Both U and V are CH2 and both X and Y are (CH2)2; or (iii) U and V are both CH2, X is (CH2)2, and Y is NH; or (iv) Both U and V are (CH2)2, and both X and Y are CH2; or (v) Both U and V are CH2, X is (CH2)3, and Y is NH; or (vi) U and V are both CH2, X is CH2OCH2, and Y is NH; A is selected from: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) C3-C 10 -cycloalkyl; and (iii) C6-C 10 -Aryl; B is selected from: (i) 4- to 6-membered monocyclic heterocycles containing 1 to 2 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 7- to 11-membered spirocyclic heterocycles containing 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; C is selected from: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 3- to 10-membered heterocyclic groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (iii) C3-C 10 -cycloalkyl; and (iv) C6-C 10 -Aryl; L 1 Selected from covalent bonds, O, CH2, CH2O, and NHCH2; R 1 Selected from halogen, cyano, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6 -alkyl)2PO-, group and groups ; R 2 Selected from hydrogen, halogen, cyano and C 1-6 -alkyl; R 3 Selected from halogen, cyano, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halogenated-C 1-6 -alkyl-C3-C 10 -Cycloalkyl and groups ; R 4 Selected from hydrogen, halogens and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Selected from C 1-6 -alkyl and halogenated-C 1-6 -alkyl; R 6 and R 7 Each is independently selected from hydrogen and halogens; W 1 Selected from O and NH; W 2 It is O; and L 2 Selected from covalent bonds, O, NH, CR 6 R 7 CH2O and CH2NH.

[0063] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: U and V are both CH2, X is (CH2)2, and Y is NH; A is selected from: (i) 5- to 6-membered heteroaryl groups, comprising 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) C3-C6-cycloalkyl; and (iii) C6-C 10 -Aryl; B is selected from: ; ;and ; C is selected from: (i) a 5- to 6-membered heteroaryl group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii) C6-C 10 -Aryl; L 1 Selected from covalent bonds and CH2; R 1 Selected from halogens, halogenated -C 1-6 -alkyl, halo-C 1-6 -alkoxy group and groups ; R 2 Selected from hydrogen, halogens, and cyano groups; R 3 Selected from halogenated-C 1-6 -alkyl and groups ; R 4 Selected from hydrogen and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Halogenated-C 1-6 -alkyl; W 1 For NH; W 2 It is O; and L 2 It is a covalent bond.

[0064] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: U and V are both CH2, X is (CH2)2, and Y is NH; A is selected from bicyclo[1.1.1]pentane, phenyl, and pyridyl; B is selected from: ; ;and ; C is selected from phenyl and pyrazolyl groups; L 1 Selected from covalent bonds and CH2; R 1 Selected from fluorine, CF3, CF3O, and other groups and groups ; R 2 Selected from hydrogen, fluorine, chlorine, and cyano groups; R 3 Selected from CF3 and groups ; R 4 Selected from hydrogen and methyl; R 5a For CF3; R 5b For CF3; W 1 For NH; W 2 It is O; L 2 It is a covalent bond.

[0065] 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: (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-(trifluoromethyliminesulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethyliminesulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [3-[3-[difluoro-[4-(trifluoromethyl)phenyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-thiadiazol-2-yl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; [6-[(4-dimethylphosphoryl-2-fluoro-phenyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[5-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazin-2-yl]azacyclobutane-1-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [6-[(3-chloro-5-fluoro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[(5-fluoro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[4-(trifluoromethyl)thiazolyl]oxy-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[4-(trifluoromethylsulfonyl)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; [6-[(5-chloro-2-pyridinyl)oxy]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; 2-[3-[1-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)azacyclobutane-3-yl]-1-bicyclo[1.1.1]pentyl]-5-fluorobenzonitrile; 4-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[3-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[4-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-(4-fluorophenyl)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azacyclobutane-1-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-yl]methyl ketone; 3-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]azacyclobutane-1-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[[6-(trifluoromethyl)-3-pyridyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[5-[[1-(trifluoromethyl)cyclopropyl]methylamino]pyrazin-2-yl]azacyclobutane-1-yl]methyl ketone; [3-[4-(4-chloro-2-methylsulfonyl-phenyl)phenyl]azacyclobutane-1-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethyl)thiazolyl-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carboxylonitrile; 2-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carboxylonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 4-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; [6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; 4-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-3-fluorobenzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [7-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; [7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; 3-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[3-[3-[[6-(trifluoromethyl)-3-pyridyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carboxylonitrile; [6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl) methyl ketone; 5-[[2-(6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; [6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl) methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[5-(trifluoromethoxy)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[4-(2,2,2-trifluoroethyl)phenyl]azacyclobutane-1-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-yl]methyl ketone; [6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl) methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[4-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [6-[(5-chloro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl) methyl ketone; [6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl) methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[(5-fluoro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; [3-[4-(2-chloro-4-methylsulfonyl-phenyl)phenyl]azacyclobutane-1-yl]-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl) methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[5-[[1-(trifluoromethyl)cyclopropyl]methylamino]pyrazin-2-yl]azacyclobutane-1-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[4-[4-(trifluoromethyl)pyrimidin-2-yl]oxyphenyl]azacyclobutane-1-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[6-[3-(trifluoromethyl)azacyclobutane-1-yl]-3-pyridyl]azacyclobutane-1-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[6-[(3S)-3-(trifluoromethyl)pyrrolidine-1-yl]-3-pyridyl]azacyclobutane-1-yl] methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[6-[(3R)-3-(trifluoromethyl)pyrrolidone-1-yl]-3-pyridyl]azacyclobutane-1-yl] methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azacyclobutane-1-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-yl]methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[3-[4-(2,2,2-trifluoroethyl)phenyl]azacyclobutane-1-yl] methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azacyclobutane-1-yl]methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[3-[4-(2,2,2-trifluoroethyl)phenyl]azacyclobutane-1-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; and (2,2-dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone.

[0066] 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: (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[4-(trifluoromethylsulfonyl)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]azacyclobutane-1-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; 2-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 4-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; [6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; and (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone.

[0067] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone.

[0068] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[4-(trifluoromethylsulfonyl)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone.

[0069] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone.

[0070] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]azacyclobutane-1-yl] methyl ketone.

[0071] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone.

[0072] 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 2-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile.

[0073] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone.

[0074] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone.

[0075] 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-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile.

[0076] 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 [6-[(5-chloro-3-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone.

[0077] 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 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile.

[0078] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone.

[0079] 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 (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone.

[0080] In one particular embodiment, the present invention provides a pharmaceutically acceptable salt, particularly a hydrochloride salt, of a compound of formula (I) as described herein. In another particular embodiment, the present invention provides a compound of formula (I) as described herein.

[0081] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more of their atoms with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radioactively labeled) compounds of formula (I) are considered to be within the scope of this 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, isotopes of these elements. 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Certain isotope-labeled compounds of formula (I) (e.g., those containing a radioactive isotope) can be used for drug and / or matrix tissue distribution studies. Radioactive isotope tritium (i.e....) 3 H) and carbon-14 (i.e. 14 C) This is particularly useful because they are easy to incorporate and detection methods are readily available. For example, compounds of formula (I) can be enriched with a given isotope of 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or 99%.

[0082] Using heavier isotopes (such as deuterium, i.e.) 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability, for example, in vivo An increase in half-life or a decrease in dosage requirements.

[0083] Using positron emission isotopes (such as 11 C 18 F, 15 O and 13N) substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the examples set forth below, using an appropriate isotopically labeled reagent instead of the previously used unlabeled reagent.

[0084] Preparation process

[0085] The preparation of compounds of formula (I) of the present invention can be carried out via sequential or concurrent synthetic routes. The synthesis of the present invention is illustrated in the following general scheme. The skills required to perform the reactions and purify the resulting products are known to those skilled in the art. Unless otherwise specified, the substituents and indices used in the following description of the methods have the meanings provided herein.

[0086] If any of the starting material, intermediate, or compound of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group may be introduced prior to the critical steps of the process, as is known in the art (as described, for example, in “Protective Groups in Organic Chemistry”, 5th edition, 2014, John Wiley & Sons, NY, by TW Greene and PGM Wutts, the contents of which are incorporated herein by reference in their entirety). Such protecting groups may be removed later in the synthesis using standard methods described in the literature.

[0087] If the starting material or intermediate contains a stereoisomeric center, the compound of formula (I) can be obtained in the form of diastereomers or mixtures of enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemic compounds can be separated into their corresponding counterparts, for example, by diastereomeric salts, which are separated by crystallization with optically pure acids, or by specific chromatographic methods using chiral adsorbents or chiral eluents. Similarly, starting materials and intermediates containing stereoisomeric centers can be separated to provide diastereomer / enantiomer-enriched starting materials and intermediates. The use of such diastereomer / enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally yield diastereomer / enantiomer-enriched compounds of the corresponding formula (I).

[0088] Those skilled in the art will recognize that, in the synthesis of compounds of formula (I), an "orthogonal protecting group strategy" will be applied (if undesirable), which allows for the 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 been reported in the literature (e.g., Barany and RBMerrifield, J. Am. Chem. Soc. 1977, 99 ,7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35 ,2056).

[0089] Those skilled in the art will recognize that the reaction sequence can vary depending on the reactivity and properties of the intermediate.

[0090] More specifically, the compound of formula (I) can be prepared by the methods given below, by the methods given in the examples, or by similar methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. Similarly, for information on reaction conditions reported in the literature affecting the reactions, see, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999. The reaction can be carried out conveniently with or without a solvent. There are no particular limitations on the properties of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and is at least partially capable of dissolving the reagents. The described reaction can occur over a wide temperature range, and precise reaction temperature is not critical to this invention. The above reaction can be conveniently carried out in the temperature range from -78°C to reflux. The reaction time required can also vary considerably, depending on many factors, particularly the reaction temperature and the properties of the reagents. However, it typically takes from 0.5 hours to several days to obtain the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme; however, the order of reaction steps can be freely changed depending on the starting materials and their corresponding reactivity.

[0091] If the starting materials or intermediates are not commercially available, or their synthesis is not described in the literature, they can be prepared in a manner similar to existing procedures for closely analogous products or as outlined in the experimental section.

[0092] 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 Service Registry Number, Cbz = benzyloxycarbonyl, CS2CO3 = 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; triethylenediamine, DAST = (diethylamino)sulfur trifluoride, DBU = 1,8-diazabicyclo[5,4,0]undec-7-ene, DEAD = diethyl azodicarbonate, DIAD = diisopropyl azodicarbonate, DIBAL-H = diisobutylaluminum hydride, DMAP = 4-Dimethylaminopyridine, DME = dimethoxyethane, DMEDA = 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 impact, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hours, FA = formic acid, FC = rapid chromatography, H2O = water, H2SO4 = sulfuric acid, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N',N'-tetramethyl-ureonium-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), K2CO3 = Potassium Carbonate, KHCO3 = Potassium Bicarbonate, KI = Potassium Iodide, KOH = Potassium Hydroxide, K3PO4 = Tripotassium Phosphate, LiAlH4 or LAH = Lithium Aluminum Hydride, LiHMDS = Lithium Bis(Trimethylsilyl)amino, LiOH = Lithium Hydroxide, MTBE = Methyl Tert-Butyl Ether, mCPBA = m-Clooperoxybenzoic Acid, MgSO4 = Magnesium Sulfate, min = minutes, mL = milliliters, MPLC = Medium Pressure Liquid Chromatography, MS = Mass Spectrometry, nBuLi = n-Butyl Lithium, NaBH3CN = Sodium Cyanoborohydride, NaH = Sodium Hydrate, NBS = N-Bromosuccinimide, NaHCO3 = Sodium bicarbonate, NaNO2 = sodium nitrite, NaBH(OAc)3 = sodium triacetoxyborohydride, NaOH = sodium hydroxide, Na2CO3 = sodium carbonate, Na2SO4 = sodium sulfate, Na2S2O3 = sodium thiosulfate, NEt3 = triethylamine (TEA), NH4Cl = ammonium chloride, NMP = N-methyl-2-pyrrolidone, OAc = acetoxy, T3P = propylphosphonic anhydride, PE = petroleum ether, PG = protecting group, Pd-C = palladium supported on activated carbon, PdCl2(dppf)-CH2Cl2 = 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex, Pd2(dba)3 = tris(dibenzylacetone)dipalladium(O), Pd(OAc)2 = palladium(II) acetate, Pd(OH)2 = palladium hydroxide, Pd(PPh3)4 = Tetra(triphenylphosphine)palladium(0), PMP = 1,2,2,6,6-pentamethylpiperidine, PTSA = p-toluenesulfonic acid, R = any group, RP = reversed 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,N',N'-tetramethylethylenediamine, TS-TPP = triphenylphosphine-polymer bonded, ZnCl2 = zinc chloride, Hal = halogen, preparative TLC = preparative thin-layer chromatography.

[0093] The compound of formula I of the present invention can be prepared by reacting the activated intermediate of formula 2 with a nucleophilic amine 1 by heating in a solvent (such as DMF or CH3CN) in the presence of a base (such as DIPEA). (Scheme 1) Alternatively, the activated intermediate can be formed on another coupling partner (1), which will prepare the urea of ​​formula I.

[0094]

[0095] Option 1

[0096] Activated intermediate 2 can be generated transiently in the reaction mixture or by reacting amine 3 with a coupling agent (such as di-(1H-1,2,4-triazol-1-yl)methyl ketone) in a solvent (such as CH2Cl2) in the presence of a base (such as DIPEA) (Scheme 2).

[0097]

[0098] Option 2

[0099] The structural units of Formula 3 can be obtained from commercial sources or can be generated via the synthetic strategy in Scheme 3 (where Y = NH, X = (CH2)2). Compound 8 can be obtained by reacting a suitable commercial amino-olefin 4 (e.g., CAS: 2416231-26-8 or 2840410-67-3 or 785783-65-5) with 2-chloroethanesulfonyl chloride in a solvent (such as CH2Cl2) in the presence of a suitable base (e.g., Et3N). Compound 6 can then be obtained by using a suitable catalyst (e.g., Grubbs Catalyst No. 2) in a suitable solvent (such as CH2Cl2). Compound 5 is produced by metathesis, followed by hydrogenation in the presence of 10% Pd / C to obtain compound 7, which can be deprotected under standard conditions (e.g., with TFA or PTSA when PG = Boc). (Scheme 3)

[0100] Option 3

[0101] The structural unit of Formula 3 (where Y = NH, X = (CH2)3) can be generated via the synthetic strategy in Scheme 4. Compound 13 can be obtained by reacting a suitable commercial amino-olefin 9 (e.g., CAS: 1440962-19-5 or 741687-08-1 or 1440960-50-8) with 2-chloroethanesulfonyl chloride in a solvent (such as CH2Cl2) in the presence of a suitable base (e.g., Et3N) to obtain compound 10. Compound 11 can then be obtained by reacting a suitable commercial amino-olefin 9 (e.g., CAS: 1440962-19-5 or 741687-08-1 or 1440960-50-8) in a suitable solvent (such as CH2Cl2) with a suitable catalyst (e.g., Grubbs Catalyst No. 2). Compound 10 is produced by metathesis, followed by hydrogenation in the presence of 10% Pd / C to obtain compound 12, which can be deprotected under standard conditions (e.g., with TFA or PTSA when PG = Boc). (Scheme 4)

[0102] Option 4

[0103] The structural unit of Formula 3 (where Y = NH, X = CH2OCH2) can be generated via the synthetic strategy in Scheme 5. Compound 20 can be obtained by reacting a suitable amino alcohol 14 (CAS: 1262411-27-7 or 889949-18-2 or 203186-96-3) with TBDPSCl in a solvent (such as CH2Cl2) in the presence of a suitable base (such as imidazole) to give compound 15, which can then be treated with chloromethanesulfonyl chloride (PMBCl) in CH2Cl2 in the presence of a suitable base (such as triethylamine) to give sulfonamide 16. The latter can be reacted with 1-(chloromethyl)-4-methoxy-benzene in a solvent (such as DMF) in the presence of a suitable base (such as K2CO3), followed by alcohol deprotection under standard conditions (such as TBAF in a solvent (such as THF) when PG = TBDPS) to give compound 18. Compound 18 can be cyclized in DMF with a suitable base (e.g., Cs₂CO₃) to generate compound 19, followed by simultaneous removal of the Boc and PMB protecting groups under standard conditions (e.g., by treatment with TFA) to produce compound 20, which is a trifluoromethanesulfonate. (Scheme 5)

[0104] Option 5

[0105] The structural unit of Formula 1 (where A = (hetero)aryl, L1 = CH2) can be generated by reacting (hetero)aryl 22 (X = Cl, Br, I) with borate ester 23 via a Suzuki reaction (e.g., (Pd(dppf)Cl2, K2CO3, dioxane / H2O)) to generate an olefin, followed by hydrogenation (e.g., Pd / C, H2). This can then be deprotected under standard conditions (e.g., with TFA or PTSA when PG = Boc). The desired borate ester intermediate 23 can be generated by reacting the corresponding ketone 21 with 4,4,5,5-tetramethyl-2-[(tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methyl]-1,3,2-dioxacyclopentaborane (LiTMP, THF, -78°C). (Scheme 6)

[0106]

[0107] Option 6

[0108] The structural unit of Formula 1 (where L1 = -O-) can be prepared by reacting a nucleophilic hydroxyl anion (generated by reacting alcohol compound 26 with a suitable base (e.g., NaH) with a suitable S N 2 / S N Ar is substituted at a position where a leaving group X (X = F, Cl, Br) is present in the (hetero)aryl halide or alkyl halide structural unit 25. This can then be deprotected under standard conditions (e.g., TFA or PTSA when PG = Boc). (Scheme 7) Alternatively, structural unit 1 can be generated by reacting phenolic compound 25 (X = OH) with alcohol 26 via a Mitsunobu reaction (using, for example, DIAD, PPh3), followed by deprotection under standard conditions (e.g., TFA or PTSA when PG = Boc). (Scheme 7)

[0109]

[0110] Option 7

[0111] Alternatively, the structural unit of Formula 31 (where L1 = covalent) can be generated by coupling an organoboronic acid derivative 28 (X = B(OR)2) with a suitably protected halide 29 (Y = I or Br) under nickel or palladium catalysis.

[0112] Alternatively, Ir[dF(CF3)ppy]2(dtbbpy)PF6, NiCl2.DME, dtbbpy, and (TMS)3SiH can be used to directly couple (hetero)aryl bromide 28 (X = Br) to aliphatic (hetero)cyclic halide 29 (Y = I or Br) in a photochemical reaction. Following coupling, a suitable deprotection step (e.g., TFA or PTSA, when PG = Boc) is performed. (Scheme 8)

[0113] Option 8

[0114] Alternatively, the structural unit of general formula 35 (where L1 = covalent, L2 = covalent) can be generated from a suitably protected carboxylic acid 32. Compound 34 can be obtained by reacting carboxylic acid 32 with hydrazide 33 in the presence of 4-methylmorpholine, isobutyl chloroformate, and diisopropylamine. The structural unit of general formula 35 can be obtained according to standard heterocyclic synthesis conditions and a suitable deprotection step. (Scheme 9)

[0115] Option 9

[0116] Alternatively, the structural unit of formula 39 (where L1 and L2 = covalent bonds) can be prepared by reacting a redox-active ester 37 with intermediate 38. Carboxylic acid 36 can be activated with a coupling agent such as DCC in the presence of DMAP and 2-hydroxyisoindoline-1,3-quinone to yield the corresponding phthalimide-oxycarbonyl 37. Intermediate 37 and bromide 38 undergo a photoreaction under an LED lamp in the presence of Ni(dtbbpy)Br2, a base (such as NaHCO3), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, yielding the structural unit of general formula 39 after appropriate deprotection. (Scheme 10)

[0117] Option 10

[0118] The structural unit of general formula 42 (where L1 and L2 = covalent bonds) can be prepared by using TMEDA and Fe(acac)3 in an iron-catalyzed Kumada-type cross-coupling in a polar aprotic solvent (such as THF) to react a suitably protected, commercially available intermediate iodide 41 with Grignard reagent 40 (commercially available or derived from the corresponding bromide or iodide). In situ (Generate) reacts, then deprotection is performed. (Scheme 11)

[0119] Option 11

[0120] The structural unit of general formula 47 (where L1 = covalent, L2 = CH2) can be prepared starting from the aldehyde structural unit 43, which, upon condensation with 4-methylbenzenesulfonylhydrazine 44, yields a toluenesulfonylhydrazone 45. This intermediate 45 can then be reacted with a commercially available, appropriately protected organoboronic acid 46 (commercially available, or prepared from the corresponding halide using standard chemical methods) in the presence of a base such as cesium carbonate to yield the corresponding intermediate of general formula 47 after a deprotection step. (Scheme 12)

[0121] Option 12

[0122] Structural unit (50) (where L1 = –CH2O–) can be generated from a suitably protected hydroxylated structural unit 49 and a (hetero)aryl structural unit 48 with a leaving group (X usually = Br) at the benzyl position via alkylation (e.g., using potassium tert-butoxide) and subsequent deprotection (e.g., using PTSA or TFA when PG = Boc). (Scheme 13) A similar method can also be used to mount small alkyl units with aliphatic rings (e.g., cyclopropyl).

[0123]

[0124] Option 13

[0125] The structural unit of Formula 54 (where L1 = covalent and L2 = -NH-CH2-) can be generated by: a appropriately protected acid structural unit 51 undergoing a Curtius rearrangement (e.g., using diphenyl azidophosphate, benzyl alcohol) and the resulting carbamate being deprotected (e.g., using Pd / C, H2) to give amine 52, which is then further reduced-amination with a suitable aldehyde 53, followed by deprotection. (Scheme 14)

[0126] Option 14

[0127] The structural unit of Formula 57 (where L1 = covalent and L2 = -NHCH2-) can be generated by reductive amination of aldehyde 55 with amine 56 in the presence of a reducing agent (such as sodium triacetoxyborohydride or sodium cyanoborohydride), followed by deprotection under standard conditions (e.g., PTSA when PG = Boc). (Scheme 15) In some cases, the reductive amination step can occur before the coupling of A and B (e.g., cross-coupling as described in Scheme 8).

[0128]

[0129] Option 15

[0130] In some cases, compounds of formula I can also be generated by combining the described steps in a new way, such as coupling of scheme 1 before refining the individual structural units using the same order as described above.

[0131] In some cases, Formula I compounds can be further functionalized to give other Formula I compounds. For example, Formula I compounds with (hetero)aryl bromides or iodides can be further functionalized with other groups (e.g., amino or alkyl groups) using metal-catalyzed cross-coupling conditions (such as the Buchwald or Suzuki reaction). Structural unit 1 can also undergo further functionalization reactions before or after the deprotection of a nucleophilic amine (e.g., forming amides under standard conditions, alkylating alcohols (e.g., using NaH in DMF and an alkylating agent), converting boron-containing groups to hydroxyl groups using basic peroxide conditions, oxidizing thioethers to sulfones, or using metal-catalyzed cross-coupling conditions (such as the Buchwald or Suzuki reaction) to install alkyl groups instead of Br or I groups) to produce other Formula I structural units. Formula I compounds with (hetero)aryl fluorides can be further functionalized via nucleophilic aromatic substitution to introduce, for example, amines, ethers, or thioethers.

[0132] In some cases, structural units can be generated from commercially available fragments using standard functional group interconversion techniques, such as mounting halides (e.g., using NIS or NBS); removing halides (e.g., under hydrogenation conditions); converting halides to other groups (such as amines or alkyl groups) using metal-catalyzed cross-coupling conditions (such as the Buchwald or Suzuki reaction); mounting and removing protecting groups; converting boron-containing groups to hydroxyl groups using basic peroxide conditions; cycloaddition of azidotrimethylsilane with nitrile to generate tetrazolium; Sandmeyer reaction of aniline to bromide; oxidation of thioethers to sulfones; oxidation of thioethers to sulfoxide imines using PhI(OAc)2 and NH2COONH4; alkylation of hydroxyl or amine groups via SN2 reaction or reductive amination; acylation using activated carbonyl derivatives; or mounting –SO2Me or –SO2CF3 groups from iodinated or brominated structural units using literature techniques; and in Chan-Lam... Under certain conditions, alkyl groups or carbocyclic rings (such as cyclopropyl groups) are attached to heteroaromatic nitrogen atoms using borate ester derivatives; or, in the presence of a base (such as Et3N), dimethylphosphoryl groups are attached to replace (hetero)aromatic halide (X = Br, I) groups via Pd-catalyzed cross-coupling with dimethylphosphine oxide. Such techniques can also be used to carefully prepare commercially available fragments before, after, or during the reactions described above in the synthetic sequence.

[0133] In one aspect, the present invention provides a method for manufacturing a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, the method comprising: (a) Make an amine of formula 1, wherein R 1 R2 A, B and L 1 As defined in this article,

[0134] Compounds of Formula 2, wherein U, V, X, and Y are as defined herein,

[0135] The reaction occurs in the presence of a base; or

[0136] (b) Make a compound of formula (2a), wherein U, V, X and Y are as defined herein,

[0137] With compound of formula 1a, where R 1 R 2 A, B and L 1 As described in this article,

[0138] The reaction occurs in the presence of a base. To form the compound of formula (I).

[0139] In one embodiment, the base is selected from trimethylamine and DIPEA.

[0140] In a preferred embodiment, the base is DIPEA.

[0141] In one embodiment, the method is carried out in a solvent, preferably in DMF or CH3CN.

[0142] In one aspect, the present invention provides a compound of formula (I) as described herein, which is manufactured according to any of the methods described herein.

[0143] MAGL inhibitory activity

[0144] The compounds of the present invention are MAGL inhibitors. Therefore, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for inhibiting MAGL.

[0145] In another aspect, the present invention provides a compound of formula (I) as described herein for use in a method for suppressing MAGL, the method comprising contacting MAGL with a compound of formula (I) as described herein.

[0146] In another aspect, the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for inhibiting MAGL.

[0147] In another aspect, the present invention provides a method for suppressing MAGL, the method comprising contacting MAGL with a compound of formula (I) described herein.

[0148] Enzymatic activity was determined by hydrolyzing the natural substrate 2-arachidonicylglycerol to obtain arachidonic acid, and the inhibitory activity of the compound of formula (I) according to the present invention against MAGL was analyzed, followed by mass spectrometry analysis. This determination is abbreviated below as "2-AG determination".

[0149] 2-AG assays were performed in 384-well plates (PP, Greiner catalog number 784201) with a total volume of 20 µL. Compound dilutions were prepared in 100% DMSO (VWR Chemicals 23500.297) using a 3-fold dilution step to achieve a final concentration range of 12.5 µM to 0.8 pM. 0.25 µL of the compound dilution (100% DMSO) was added to 9 µL of MAGL in the assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 ml), 0.01% (v / v) Tween). After shaking, the plate was incubated at RT for 15 min. 10 µL of 2-arachidonicylglycerol assay buffer was added to initiate the reaction. The final concentrations in this assay were 50 pM MAGL and 8 µM 2-arachidonicylglycerol. After shaking and incubation at RT for 30 min, the reaction was quenched by adding 40 µL of acetonitrile containing 4 µM d8-arachidonic acid. The arachidonic acid concentration was tracked using an online SPE system (Agilent Rapidfire) coupled with a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE column (G9205A) was used in the acetonitrile / water liquid phase. The mass spectrometer was operated in negative electrospray ionization mode, and the mass ion pair of arachidonic acid was 303.1. 259.1, the mass ion pair of d8-arachidonic acid is 311.1. 267.0. Calculate the activity of the compound based on the intensity ratio of [arachidonic acid / d8-arachidonic acid].

[0150] Table 1

[0151] In one aspect, the present invention provides compounds of formula (I) as described herein, and pharmaceutically acceptable salts or esters thereof, wherein the compounds of formula (I) and pharmaceutically acceptable salts or esters thereof have an MAGL inhibitory concentration of less than 25 µM, preferably less than 10 µM, more preferably less than 5 µM. 50 This value was measured as described in the MAGL determination described in this article.

[0152] In one embodiment, compounds of formula (I) as described herein, and their pharmaceutically acceptable salts or esters, have an IC50 between 0.000001 µM and 25 µM. 50 (MAGL inhibition) values, specific compounds have IC50 values ​​between 0.000005 µM and 10 µM. 50 Values, further specific compounds have IC50 values ​​between 0.00005 µM and 5 µM. 50 The value is as measured in the MAGL determination described herein.

[0153] Using the compounds of the present invention

[0154] In one aspect, the present invention provides a compound of formula (I) as described herein, which is used as a therapeutically active substance.

[0155] In another aspect, the present invention provides a compound of formula (I) as described herein for the treatment or prevention of diseases and ailments associated with MAGL.

[0156] In another aspect, the present invention provides a method for treating or preventing diseases and ailments associated with MAGL in human patients, the method comprising administering to the human patient an effective amount of a compound of formula (I) as described herein.

[0157] In another aspect, the present invention provides the use of compounds of formula (I) as described herein for the treatment or prevention of diseases and ailments associated with MAGL.

[0158] In another aspect, the present invention provides the use of compounds of formula (I) as described herein in the preparation of medicaments for the treatment or prevention of diseases and ailments associated with MAGL.

[0159] In one implementation, the diseases and disorders associated with MAGL are selected from neuroinflammatory diseases, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety disorders, migraines, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or kidney disease.

[0160] In one implementation, the diseases and disorders associated with MAGL are selected from neuroinflammatory diseases, neurodegenerative diseases, pain, cancer, and / or mental disorders.

[0161] In one implementation, the diseases and disorders 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, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or kidney disease.

[0162] In a preferred embodiment, the diseases and disorders associated with MAGL are selected from inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or kidney disease.

[0163] In a preferred embodiment, the diseases and disorders 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.

[0164] In a particularly preferred embodiment, the disease and ailment associated with MAGL is inflammatory bowel disease.

[0165] In a particularly preferred embodiment, the diseases and disorders associated with MAGL are symptoms associated with inflammatory bowel disease.

[0166] In a particularly preferred embodiment, the disease and ailment associated with MAGL is intestinal motility.

[0167] In a particularly preferred embodiment, the disease and ailment associated with MAGL is abdominal pain.

[0168] In a particularly preferred embodiment, the disease and ailment associated with MAGL is abdominal pain associated with irritable bowel syndrome.

[0169] Pharmaceutical composition and administration

[0170] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0171] Compounds of formula (I) and their pharmaceutically acceptable salts and esters may be used as pharmaceuticals (e.g., in the form of pharmaceutical formulations). Pharmaceutical formulations may be administered orally, such as orally (e.g., in the form of tablets, coated tablets, sugar lozenges, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, they may also be administered parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0172] Compounds of formula (I) and their pharmaceutically acceptable salts and esters may be processed with pharmaceutically inert, inorganic or organic excipients into tablets, coated tablets, sugar-coated pills and hard gelatin capsules. For example, lactose, corn starch or derivatives thereof (talc, stearic acid or its salts, etc.) may be used as such excipients for tablets, sugar-coated pills and hard gelatin capsules.

[0173] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0174] Suitable additives for preparing solutions and syrups include, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0175] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerin, and vegetable oil.

[0176] Suitable adjuvants for suppositories include, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols.

[0177] In addition, pharmaceutical preparations may contain preservatives, solubilizers, thickeners, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances with therapeutic value.

[0178] Dosage can vary within a wide range to suit the various requirements of each specific situation. Generally, a daily oral dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person), should be appropriate, preferably divided into 1-3 individual doses (which may consist of, for example, the same amount). However, it will be apparent that, when indicated, the upper limits given herein may be exceeded.

[0179] Tablet formulations (wet granulation)

[0180] Preparation procedure

[0181] 1. Mix items 1, 2, 3 and 4 together and granulate with purified water.

[0182] 2. Dry the granules at 50℃.

[0183] 3. Pass the particles through suitable grinding equipment.

[0184] 4. Add item 5 and mix for three minutes; press on a suitable press.

[0185] Capsule formulation

[0186] Preparation procedure

[0187] 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

[0188] 2. Add items 4 and 5 and mix for 3 minutes.

[0189] 3. Fill into the appropriate capsules.

[0190] Example

[0191] The invention will be more fully understood by referring to the following examples. However, the claims should not be construed as limiting the scope of the examples.

[0192] In the case of preparation examples obtained as mixtures of enantiomers, pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0193] Unless otherwise specified, all reaction examples and intermediates are prepared under an argon atmosphere.

[0194] Example 1

[0195] (6,6-dioxo-6) λ 6 -thia-2,5-diazaspiro[3,4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl) [[3,3]heptan-2-yl]methyl]-2-azaspiro[3,3]heptane-2-yl]methyl ketone

[0196] To the 6λ cooled to 0℃ 6 A solution of thiazo-2,5-diazaspiro[3.4]octane 6,6-dioxide; 4-methylbenzenesulfonic acid (A.1) (45 mg, 135 µmol) in N,N-dimethylformamide (706 µL) was added to DIPEA (122 mg, 164 µL, 942 µmol), followed by the addition of bis(1,2,4-triazol-1-yl) ketone (23.2 mg, 141 µmol), and the reaction mixture was stirred at 0 °C for 30 min. Then, 6-(3-fluoro-5-trifluoromethanesulfonyl-benzyl)-2-diazaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (B.1) (78.9 mg, 155 µmol) was added to the reaction mixture, and the reaction mixture was stirred at 50 °C for 18 h. The crude solution was directly purified by reversed-phase HPLC to give 20.4 mg of the title compound as a colorless gel. MS (ESI): m / z = 526.3 [M+H] +

[0197] Similar to Example 1, the examples in the table below are generated using their respective structural units AX and BX.

[0198]

[0199] Synthesis of structural units

[0200] Example A.1

[0201] 6λ 6 - thia-2,5-diazaspiro[3.4]octane 6,6-dioxide; 4-methylbenzenesulfonic acid

[0202] 1.0 g (3.43 mmol) of tert-butyl 6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carboxylate was dissolved in methanol (40 mL), p-toluenesulfonic acid (886 mg, 5.15 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. After that time, the mixture was evaporated under vacuum, ground with acetonitrile (15 mL), filtered, and dried to obtain 990 mg of the title compound (1160 mg, 3.47 mmol, 96% yield). MS (ESI): m / z = 163.0 [M-TsOH+H] +

[0203] Step a) 3-Vinyl-3-(vinylsulfonylamino)azacyclobutane-1-carboxylic acid tert-butyl ester

[0204] 3-Amino-3-vinyl-azacyclobutane-1-carboxylic acid tert-butyl ester (CAS: 2416231-26-8) (2.5 g, 12.6 mmol) was dissolved in anhydrous dichloromethane (100 mL), and triethylamine (5.27 mL, 37.83 mmol) was added to the reaction mixture. The resulting solution was cooled to 0 °C, and then 10 mL of anhydrous dichloromethane sulfonyl chloride (1.38 mL, 13.24 mmol, 1.05 eq) was slowly added. The resulting mixture was allowed to warm to room temperature and stirred at 30 °C for 16 h. The mixture was then washed with saturated NH4Cl solution (3 x 100 mL), dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to obtain the title compound (3.5 g, 12.14 mmol, 87% yield), which was used in the next step without further purification. MS (ESI): m / z = 233.0 [M-tBu+H] +

[0205] Step b) 6,6-Dioxo-6λ 6 -Thia-2,5-diazaspiro[3,4]octane-7-ene-2-carboxylic acid tert-butyl ester

[0206] 3-Vinyl-3-(vinylsulfonylamino)azacyclobutane-1-carboxylic acid tert-butyl ester (380.0 mg, 1.32 mmol) was dissolved in anhydrous dichloromethane (100 mL), and argon gas was bubbled through the resulting solution over a period of 20 min. Then, (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (0.06 g, 0.07 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 50 °C for 18 h under an inert argon atmosphere. The reaction mixture was evaporated under vacuum, and the resulting residue was dissolved in MTBE (30 mL) and filtered through a silica gel pad. The filter pad was washed with an additional amount of MTBE (100 mL), and the combined filtrates were evaporated under vacuum to obtain the title compound (400.0 mg, 1.54 mmol, 93% yield), which was used in the next step without further purification. MS (ESI): m / z = 259.0 [MH] -

[0207] Step c) 6,6-Dioxo-6λ 6 -Thia-2,5-diazaspiro[3,4]octane-2-carboxylic acid tert-butyl ester

[0208] A methanol suspension (30 mL) of tert-butyl 6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-7-ene-2-carboxylate (1.09 g, 3.43 mmol) and carbon-supported palladium (10%) (0.36 mL, 0.34 mmol) was stirred for 16 h under a hydrogen atmosphere (balloon). The reaction mixture was filtered to remove the palladium catalyst, and the filtrate was concentrated under vacuum to give the title compound (948.0 mg, 3.61 mmol, 95% yield) as a pale yellow solid. MS (ESI): m / z = 261.2 [MH] -

[0209] Example A.2

[0210] 6λ 6 - thia-2,5-diazaspiro[3.5]nonane 6,6-dioxide; 4-methylbenzenesulfonic acid

[0211] To a 50 mL ethyl acetate solution (2.2 g, 7.96 mmol) of 6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carboxylic acid monohydrate (1.97 g, 10.35 mmol) was added. The mixture was stirred at 20 °C for 36 h, and the precipitated solid was filtered, washed with EtOAc and Et2O, and dried under vacuum to provide the title compound (2504.0 mg, 7.19 mmol, 86% yield) as a white solid. MS (ESI): m / z = 177.2 [M-TsOH+H] +

[0212] Step a) 3-Allyl-3-(vinylsulfonylamino)azacyclobutane-1-carboxylic acid tert-butyl ester

[0213] A solution (50 mL) of tert-butyl 3-allyl-3-amino-azacyclobutane-1-carboxylate (CAS: 1440962-19-5) (1.5 g, 7.07 mmol) and triethylamine (4.92 mL, 35.33 mmol) in dichloromethane was cooled to 0 °C, and then 2-chloroethanesulfonyl chloride (1.11 mL, 10.6 mmol) was added dropwise at the same temperature. The resulting mixture was stirred at 30 °C for 16 h. The reaction mixture was washed with water, the organic phase was separated, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane / EtOAc, 10:1 to 1:1) to provide the title compound (1.03 g, 3.41 mmol, 47% yield) as a yellow gel. MS (ESI): m / z = 301.0 [MH] -

[0214] Step b) 6,6-Dioxo-6λ 6 -Thia-2,5-diazaspiro[3,5]nonane-7-ene-2-carboxylic acid tert-butyl ester

[0215] To a toluene suspension (100 mL) of tert-butyl 3-allyl-3-(vinylsulfonylamino)azacyclobutane-1-carboxylate (1.03 g, 3.41 mmol) degassed under argon, ruthenium (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (0.14 g, 0.17 mmol) was added. The resulting mixture was stirred at 80 °C for 24 h and concentrated under vacuum. The residue was then purified by column chromatography (EtOAc) to give the title compound (676.0 mg, 2.46 mmol, 69% yield) as a dark brown solid. MS (ESI): m / z = 273.0 [MH] -

[0216] Step c) 6,6-Dioxo-6λ 6 -Thia-2,5-diazaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester

[0217] A methanol suspension (50 mL) of 6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-7-ene-2-carboxylic acid tert-butyl ester (1.6 g, 5.83 mmol) and carbon-supported palladium (10%) (0.61 mL, 0.58 mmol) was stirred for 16 h under a hydrogen atmosphere (balloon). The reaction mixture was then filtered to remove the palladium catalyst and concentrated under vacuum to give 6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.6 g, 5.79 mmol, 94% yield) as a white solid. MS (ESI): m / z = 275.0 [MH] -

[0218] Example A.3

[0219] 8-oxa-6λ 6 - thia-2,5-diazaspiro[3.5]nonane 6,6-dioxide; 2,2,2-trifluoroacetic acid

[0220] A TFA solution (10.0 mL, 134.19 mmol) of 5-[(4-methoxyphenyl)methyl]-6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (840.0 mg, 2.11 mmol) was stirred at 30 °C for 12 h, followed by stirring at 40 °C for another 4 h. The reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was diluted with deionized water (50 mL) and washed with dichloromethane (20 mL x 2). The separated aqueous phase was lyophilized to provide the title compound (600.0 mg, 2.05 mmol, 92% yield) as a white solid. MS (ESI): m / z = 179.1 [M-TFA+H] + .

[0221] Step a) 3-Amino-3-[[tert-butyl(diphenyl)silyl]oxymethyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0222] To a 30 mL solution of tert-butyl 3-amino-3-(hydroxymethyl)azacyclobutane-1-carboxylate (CAS: 1262411-27-7) (2.1 g, 10.38 mmol) in dichloromethane, imidazole (2.12 g, 31.15 mmol) and tert-butylchlorodiphenylsilane (4.28 g, 15.57 mmol) were added. The reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the residue. The crude residue was purified by rapid silica gel chromatography (eluting with PE / EtOAc (1:1)) (TLC, PE:EtOAc=0:1, Rf=0.60) to provide the title compound (2.8 g, 6.35 mmol, 61% yield), which is a yellow gel, MS (ESI): m / z = 341.1 [M-C5H8O2+H] + .

[0223] Step b) 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(chloromethylsulfonylamino)aza tert-butyl cyclobutane-1-carboxylate

[0224] Triethylamine (4.57 mL, 32.79 mmol) was added to a dichloromethane solution (60 mL) of 3-amino-3-[[tert-butyl(diphenyl)silyl]oxymethyl]azacyclobutane-1-carboxylate (2.89 g, 6.56 mmol) at 0 °C. Then, a dichloromethane solution (30 mL) of chloromethylsulfonyl chloride (1.79 mL, 19.68 mmol) was added dropwise to the mixture at 0 °C, and the resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to provide the title compound (4.0 g, 7.23 mmol, 110% yield) as a yellow gel, which was used without further purification. MS (ESI):m / z = 453.2, [M-C5H8O2+H] +

[0225] Step c) 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-[chloromethylsulfonyl-[(4-methoxy] tert-butyl 1-carboxylate (phenyl)methyl]amino]azacyclobutane-1-carboxylate

[0226] To a solution of 40 mL of tert-butyl 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(chloromethylsulfonylamino)azacyclobutane-1-carboxylate (4.0 g, 7.23 mmol) in N,N-dimethylformamide, K₂CO₃ (3.0 g, 21.69 mmol) and 4-methoxybenzyl chloride (1.96 mL, 14.46 mmol) were added. The reaction mixture was stirred at 30 °C for 12 h. Then, K₂CO₃ (6.0 g, 43.38 mmol) and 4-methoxybenzyl chloride (2.45 mL, 18.08 mmol) were added again to the mixture, and the reaction mixture was stirred at 30 °C for another 18 h. The reaction mixture was filtered, and the filtrate was passed through a preparative HPLC column (Phenomenex luna C18 (250 μL)). [70 mm, 10 μm]; Mobile phase: [H₂O] and [acetonitrile] (conditions: [water (0.225% FA) - acetonitrile], B%: 55%-85%; Detector: UV 254 nm. RT: [25 min]) Purification. The purified solution was lyophilized to provide the title product (2.5 g, 3.71 mmol, yield 51%), which was a yellow gel. MS (ESI): m / z = 617.3 [M-tBu+H] + .

[0227] Step d) 3-[chloromethylsulfonyl-[(4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)azacyclobutane tert-butyl alkyl-1-carboxylate

[0228] To a THF solution (25 mL) of 3-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-[chloromethylsulfonyl-[(4-methoxyphenyl)methyl]amino]azacyclobutane-1-carboxylic acid tert-butyl ester (2.5 g, 3.71 mmol) in tetrabutylammonium fluoride (7.43 mL, 7.43 mmol) (1 M THF solution), the reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by silica gel rapid chromatography (eluting with PE / EtOAc (1:1)) (TLC, PE:EtOAc=1:1, Rf=0.30) to give the title product (1.4 g, 3.22 mmol, 87% yield), which is a yellow gel. MS (ESI): m / z = 335.0 [M-C5H8O2+H] + .

[0229] Step e) 5-[(4-methoxyphenyl)methyl]-6,6-dioxo-8-oxa-6λ6-thia-2,5-diaza Spiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0230] Cs₂CO₃ (3.15 g, 9.66 mmol) was added to a 15 mL solution of 3-[chloromethylsulfonyl-[(4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (1.4 g, 3.22 mmol) in N,N-dimethylformamide. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and the filtrate was passed through a preparative HPLC column (Phenomenex Luna C18 150). 40mm [15µm]; Mobile phase: [H2O] and [acetonitrile] (conditions: [water (0.225% FA) - acetonitrile], B%: 42% to 72%; Detector: UV 254 nm. RT: [10 min]). The purified solution was lyophilized to provide the product 5-[(4-methoxyphenyl)methyl]-6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (900.0 mg, 2.26 mmol, 70% yield), which was a white solid. MS (ESI): m / z = 421.3 [M+Na] + .

[0231] Example A.4

[0232] 2-Thia-6-azaspiro[3.3]heptane, 2,2-dioxide, hydrochloride (1:1)

[0233] The title compound can be purchased from a commercial source (CAS: 1427388-39-3) or prepared according to existing techniques described in the literature.

[0234] Example A.5

[0235] 7-Thia-2-azaspiro[3.5]nonane, 7,7-dioxide

[0236] The title compound can be purchased from a commercial source (CAS: 1363381-31-0) or prepared according to existing techniques described in the literature.

[0237] Example A.6

[0238] 2-Thia-7-azaspiro[3.5]nonane, 2,2-dioxide, hydrochloride (1:1)

[0239] The title compound can be purchased from commercial sources (CAS: 2172098-44-9) or prepared according to existing techniques described in the literature.

[0240] Example B.1

[0241] [3-(2-azaspiro[3.3]heptane-6-ylmethyl)phenyl]-imino-oxo-(trifluoromethyl)-λ 6 -Thioalkyl; 4-Methylbenzenesulfonic acid

[0242] A mixture (50 mL) of 6-[[3-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.1 g, 5.02 mmol) and p-toluenesulfonic acid (2160.37 mg, 12.55 mmol) in EtOAc was stirred at 50 °C for 24 h. The reaction mixture was then concentrated and the crude product was purified by rapid chromatography (SiO2, acetonitrile / methanol (0-20-100%), flow rate = 80 mL / min) to give [3-(2-azaspiro[3.3]heptane-6-ylmethyl)phenyl]-imino-oxo-(trifluoromethyl)-λ6-thione;4-methylbenzenesulfonic acid (1.81 g, 3.68 mmol, 70% yield) as a white solid. MS (ESI): m / z = 319.2 [M+H] + .

[0243] Step a) 6-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methylene]-2-azaspiro [3.3]Tertiary butyl heptane-2-carboxylate

[0244] Add 12.21 mL of 1.6 M BuLi in THF solution (19.54 mmol) to a 30 mL solution of 2,2,6,6-tetramethylpiperidine (2.76 g, 3.3 mL, 19.54 mmol). Stir the mixture and allow it to heat to 5 °C. Cool the reaction mixture to -74 °C. Add dropwise (15 mL) of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methyl]-1,3,2-dioxacyclopentaborane (4.8 g, 17.91 mmol, 1.1 eq) in THF solution below -70 °C. Stir the reaction mixture at -74 °C for 30 min. A THF solution (22 mL) of tert-butyl 6-keto-2-azaspiro[3.3]heptane-2-carboxylate (3.44 g, 16.28 mmol, 1 eq) was added dropwise over 45 minutes at -70°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 3 h. The reaction mixture was poured onto a saturated aqueous solution of NH4Cl (210 mL). A 2M aqueous solution of HCl was added to adjust the pH to 6. The mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under vacuum to give 7.2 g of crude title compound as a yellow solid. The crude material was purified by rapid chromatography (silica gel, 80 g, heptane containing 0% to 20% EtOAc) to give the title compound (4.37 g, 76%) as a white solid. MS (ESI): m / z = 279.9 [M+H-tBu] + .

[0245] Step b) 6-[[3-(trifluoromethyliminesulfonyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-methyl tert-butyl ester

[0246] 1.28 g (3.82 mmol) of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate and (3-bromophenyl)-imino-keto-(trifluoromethyl)-λ 6A solution of thionine (CAS: 2411289-54-6) (1 g, 3.47 mmol) and potassium carbonate (959.53 mg, 6.94 mmol) in 1,4-dioxane (18 mL) and water (3.6 mL) was degassed with argon for 10 min. A 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloromethane complex (283.48 mg, 0.347 mmol) was added to the reaction flask. The mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into a 2:1 EtOAc / THF mixture and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude material was purified by rapid chromatography (silica gel, 40 g, heptane containing 0% to 20% EtOAc) to provide the title compound (1.08 g, 74%) as a white solid. MS (ESI): m / z = 361.2 [M+H-tBu] + .

[0247] Step c) 6-[[3-(trifluoromethyliminesulfonyl)phenyl]methyl]-2-azaspiro[3,3]heptane-2-carboxylic acid tert-butyl ester

[0248] A solution of tert-butyl 6-[3-(trifluoromethyliminesulfonyl)benzyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.08 g, 2.58 mmol) in methanol (60 mL) and THF (20 mL) was degassed with argon for 10 min. 10% Pd / C (274.7 mg, 0.258 mmol) was added to the reaction mixture. The mixture was stirred at room temperature under a hydrogen atmosphere using a balloon for 1 h. The reaction mixture was filtered through a Sartorius filter and concentrated under vacuum to give the title compound (1.13 g, 99%) as a colorless oil. MS (ESI): m / z = 319.2 [M+H-BOC] + .

[0249] Example B.7

[0250] [4-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-fluoro-phenyl]-imino-oxo-(trifluoromethyl)-λ 6 - Thiocannes; 4-methylbenzenesulfonic acid

[0251] At 20 °C, p-toluenesulfonic acid (0.96 g, 5.58 mmol) was added to a mixture (20 mL) of 6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.03 g, 4.65 mmol) in EtOAc. The reaction mixture was then stirred at 80 °C for 12 h. The mixture was concentrated under vacuum to remove the solvent, then deionized water was added and the solution was lyophilized to give the title compound (2.05 g, 4.03 mmol, yield 83.2%) as a yellow gel. MS (ESI): m / z = 337.1 [M-TsOH+H] + .

[0252] Step a) 6-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methylene]-2-azaspiro [3.3]Tertiary butyl heptane-2-carboxylate

[0253] Add a 1.6 M BuLi THF solution (12.21 mL, 19.54 mmol) to a 30 mL THF solution of 2,2,6,6-tetramethylpiperidine (2.76 g, 3.3 mL, 19.54 mmol). Stir the mixture and allow it to heat to 5 °C. Cool the reaction mixture to -74 °C. Add a 15 mL THF solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methyl]-1,3,2-dioxacyclopentaborane (4.8 g, 17.91 mmol) dropwise to below -70 °C. Stir the reaction mixture at -74 °C for 30 minutes. A THF solution (22 mL) of tert-butyl 6-keto-2-azaspiro[3.3]heptane-2-carboxylate (3.44 g, 16.28 mmol) was added dropwise at -70 °C over 45 minutes. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 3 h. The reaction mixture was poured onto a saturated aqueous solution of NH4Cl (210 mL). A 2M aqueous solution of HCl was added to adjust the pH to 6. The mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under vacuum to give 7.2 g of crude title compound as a yellow solid. The crude material was purified by rapid chromatography (silica gel, 80 g, 0% to 20% AcOEt in heptane) to give the title compound (4.37 g, 76%) as a white solid. MS (ESI): m / z = 279.9 [M+H-tBu]+ .

[0254] Step b) 1-Bromo-2-fluoro-4-(trifluoromethylthio)benzene

[0255] To a 10 mL solution of 1-bromo-2-fluoro-4-iodobenzene (14.0 g, 46.53 mmol) in ACN, 2,2'-bipyridine (7.27 g, 46.53 mmol), trifluoromethylthiosilver (11.67 g, 55.83 mmol), and CuI (8.86 g, 46.53 mmol) were added. The mixture was stirred at 90 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered to give the crude product 1-bromo-2-fluoro-4-(trifluoromethylthio)-benzene (12.8 g, 46.53 mmol, 100.0% yield) in the filtrate. The crude product in the filtrate was used directly in the next step of the reaction without further purification.

[0256] Step c) 6-[[2-fluoro-4-(trifluoromethylthio)phenyl]methylene]-2-azaspiro[3.3]heptane-2-methyl tert-butyl ester

[0257] A solution of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (219.39 mg, 0.65 mmol) and 1-bromo-2-fluoro-4-(trifluoromethylthio)benzene (180.0 mg, 0.65 mmol), K2CO3 (180.88 mg, 1.31 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was added to a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (53.4 mg, 0.07 mmol). The mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. The mixture was purified by t-HPLC (PE:EtOAc = 3:1; UV) and concentrated under vacuum to give the title compound (140.0 mg, 0.35 mmol, 41% yield) as a brown oil. MS (ESI): m / z = 348.1 [M-tBu+H] + .

[0258] Step d) 6-[[2-fluoro-4-(trifluoromethylthio)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Uncle Butyl acetate

[0259] Under a nitrogen atmosphere at 25 °C, a wet Pd / C 10% solution (1.8 g, 1.31 mmol) of tert-butyl 6-[[2-fluoro-4-(trifluoromethylthio)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (5.3 g, 13.14 mmol) in EtOAc was added to 80 mL. The mixture was then stirred at 25 °C for 12 h under a hydrogen atmosphere using a balloon. The mixture was then filtered and the filtrate was concentrated to give the title compound (5.5 g, 13.57 mmol, 95% yield) as a colorless oil. MS (ESI): m / z = 350.0 [M-tBu+H] + .

[0260] Step e) 6-[[2-fluoro-4-(trifluoromethyliminesulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Uncle Butyl acetate

[0261] At 20 °C, 0.5 mL of a trifluoroethanol solution (50.0 mg, 0.12 mmol) of 6-[[2-fluoro-4-(trifluoromethylthio)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (PhI(OAc)2 (166.83 mg, 0.52 mmol) and NH2COONH4 (28.88 mg, 0.37 mmol) were added to PhI(OAc)2. The mixture was then stirred at 60 °C for 3 hours. The mixture was concentrated under vacuum to give a crude product. The crude material was purified by preparative TLC (PE:EtOAc = 3:1, UV) to give tert-butyl 6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (25.0 mg, 0.06 mmol, yield 46%), as a colorless oil. MS (ESI): m / z = 381.1 [M-tBu+H] + .

[0262] Example B.26

[0263] 6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3,3]heptane; 4-methylbenzenesulfonic acid

[0264] To a mixture (5 mL) of 6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (195.0 mg, 0.45 mmol) in EtOAc, p-toluenesulfonic acid (92.11 mg, 0.53 mmol) was added. The mixture was stirred at 80 °C for 12 h. The mixture was concentrated under vacuum to remove the solvent, and the resulting residue was mixed with deionized water and lyophilized to the title compound (214.1 mg, 0.42 mmol, 92% yield) as a grayish-white solid. MS (ESI): m / z = 338.0 [M-TsOH+H] + .

[0265] Step a) 6-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methylene]-2-azaspiro [3.3]Tertiary butyl heptane-2-carboxylate

[0266] Add a 1.6 M BuLi THF solution (12.21 mL, 19.54 mmol) to a 30 mL THF solution of 2,2,6,6-tetramethylpiperidine (2.76 g, 3.3 mL, 19.54 mmol). Stir the mixture and allow it to heat to 5 °C. Cool the reaction mixture to -74 °C. Add a 15 mL THF solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methyl]-1,3,2-dioxacyclopentaborane (4.8 g, 17.91 mmol) dropwise to below -70 °C. Stir the reaction mixture at -74 °C for 30 minutes. A THF solution (22 mL) of tert-butyl 6-keto-2-azaspiro[3.3]heptane-2-carboxylate (3.44 g, 16.28 mmol, 1 eq) was added dropwise over 45 minutes at -70°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 3 h. The reaction mixture was poured onto a saturated aqueous solution of NH4Cl (210 mL). A 2M aqueous solution of HCl was added to adjust the pH to 6. The mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under vacuum to give 7.2 g of crude title compound as a yellow solid. The crude material was purified by rapid chromatography (silica gel, 80 g, 0% to 20% AcOEt in heptane) to give the title compound (4.37 g, 76%) as a white solid. MS (ESI): m / z = 279.9 [M+H-tBu] + .

[0267] Step b) 1-Bromo-3-fluoro-5-(trifluoromethylthio)-benzene

[0268] To a mixture (10 mL) of 1-bromo-3-fluoro-5-iodobenzene (CAS: 845866-85-5) (1000.0 mg, 3.32 mmol) in ACN, 2,2'-bipyridine (519.06 mg, 3.32 mmol), CuI (632.96 mg, 3.32 mmol), and trifluoromethylsilver trisulfide (833.29 mg, 3.99 mmol) were added. The mixture was stirred at 90 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the crude title product (826.0 mg, 3.0 mmol, 90% yield) as a pale green solid, which was used without further purification.

[0269] Step c) 1-Bromo-3-fluoro-5-(trifluoromethylsulfonyl)-benzene

[0270] Sodium periodate (1049.78 mg, 4.91 mmol) and ruthenium(III) chloride hydrate (3.69 mg, 0.02 mmol) were added to a solution of 1-bromo-3-fluoro-5-(trifluoromethylthio)benzene (450.0 mg, 1.64 mmol) cooled to 0 °C in 1,2-dichloroethane (25 mL), ACN (25 mL), and water (50 mL). The reaction mixture was then stirred at 20 °C for 12 h. The mixture was added to 20 mL of water and extracted with EtOAc (30 mL x 3). The organic phase was concentrated under vacuum to give crude material. The crude material was purified by silica gel chromatography (PE:EtOAc = 5:1, UV) to give 1-bromo-3-fluoro-5-(trifluoromethylsulfonyl)benzene (300.0 mg, 0.98 mmol, 60% yield), which was a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 8.37 (td, J = 2.0, 8.2 Hz, 1H), 8.21 - 8.14 (m, 2H))

[0271] Step d) 6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2- tert-butyl formate

[0272] At 25 °C, tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.09 g, 3.26 mmol), 1-bromo-3-fluoro-5-(trifluoromethylsulfonyl)benzene (1.0 g, 3.26 mmol, 1.0 eq), and potassium carbonate (900.19 mg, 6.51 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added to a solution of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (265.75 mg, 0.33 mmol). The mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (PE:EtOAc = 5:1, UV) to give the title compound (1.2 g, 2.76 mmol, 85% yield) as a white solid. MS (ESI): m / z = 380.0 [M-tBu+H] + .

[0273] Step e) 6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-methyl tert-butyl ester

[0274] Under a nitrogen atmosphere at 20 °C, a solution (30 mL) of tert-butyl 6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methylene]-2-azaspiro[3,3]heptane-2-carboxylate (1.2 g, 2.76 mmol) in EtOAc was added to a wet Pd / C 10% solution (400.0 mg, 0.28 mmol). The mixture was stirred at 20 °C for 2 h under a hydrogen atmosphere using a balloon. The mixture was then filtered and the filtrate was concentrated to give the title compound (1.0 g, 2.29 mmol, 83% yield) as a white solid. MS (ESI): m / z = 382.1 [M+H] + .

[0275] Similar to Example B.1, the following structural units are generated in step b using (hetero)aryl bromide or iodide structural units for Suzuki coupling. In some cases, alternative salts (e.g., trifluoroacetate, xylenesulfonate, hydrochloride) are also used. Further structural unit substitutions can be made to introduce different spirocyclic systems; for example, Examples B.9, B.37, B.38, B.58, and B.59 use 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate tert-butyl ester (CAS: 1363381-22-9) instead of 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester in step a. In some cases, the synthesis is planned to include the removal of additional Br groups in a hydrogenation step.

[0276]

[0277] Example B.8

[0278] 3-[3-[difluoro-[4-(trifluoromethyl)phenyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane;4- Methylbenzenesulfonic acid

[0279] A solution (50 mL) of tert-butyl p-toluenesulfonic acid monohydrate (0.98 g, 5.17 mmol) of 3-[3-[difluoro-[4-(trifluoromethyl)phenyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylate (1.8 g, 4.31 mmol) in EtOAc was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated under vacuum. The residue was ground together with MTBE and filtered to provide the title compound (1.65 g, 3.37 mmol, 74% yield) as a white solid. MS (ESI): m / z = 318.0 [M-TsOH+H] + .

[0280] Step a) 3-(1-tert-butoxycarbonylazonylbutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0281] 3-(azacyclobutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid; 2,2,2-trifluoroacetic acid (5.5 g, 19.56 mmol) was dissolved in 1,4-dioxane (25 mL). An aqueous solution of sodium bicarbonate (1642.91 mg, 19.56 mmol) was added to the reaction mixture. Di-tert-butyl dicarbonate (4695.13 mg, 21.51 mmol) was dissolved in 1,4-dioxane (25 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 12 h and evaporated under vacuum. Water (100 mL) was added to the residue and the aqueous phase was treated with MTBE (2... Extraction was performed using 100 mL of sodium bisulfate solution. The aqueous phase was acidified to pH 2 with an aqueous solution of sodium bisulfate (1 M). MTBE (200 mL) was added to extract the aqueous phase, and the organic phase was collected, dried over Na₂SO₄, and evaporated under vacuum to provide the title compound (4.2 g, 15.71 mmol, 80% yield) as a white solid. MS (ESI): m / z = 266.2 [MH] - .

[0282] Step b) 3-[3-[methoxy(methyl)carbamoyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane- 1-Tert-butyl formate

[0283] N,N'-carbonyldiimidazole (1455.77 mg, 8.98 mmol) was added to a stirred THF solution (50 mL) of 3-(1-tert-butoxycarbonylazyrobutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (2000.0 mg, 7.48 mmol) at room temperature. The mixture was stirred at room temperature for 1 h, and then O,N-dimethylhydroxylamine HCl (875.71 mg, 8.98 mmol) and triethylamine (1.56 mL, 11.22 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (100 mL) and then thiamethoxam (50 mL) was added. 3) Extraction. The organic phase was washed with water (50 mL), aqueous HCl (1 N, 50 mL), and saturated NaHCO3 aqueous solution (50 mL), and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure to provide the title compound (2.4 g, 7.73 mmol, 98.18% yield) as a pale yellow solid. MS (ESI): m / z = 311.0 [M+H] + .

[0284] Step c): 3-[3-[4-(trifluoromethyl)benzoyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1- tert-butyl formate

[0285] To a THF solution (10 mL) of 3-[3-[methoxy(methyl)carbamoyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylate (3.4 g, 10.95 mmol) cooled to 0 °C, bromo[4-(trifluoromethyl)phenyl]magnesium (CAS: 402-51-7) (3.83 mL, 27.38 mmol) was added, and the reaction mixture was stirred at room temperature for 48 h, after which the reaction was quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over Na2SO4. After solvent removal, the residue was purified by FC to provide the title compound (250 mg, 0.630 mmol, 39% yield) as a pale yellow oil. MS (ESI): m / z = 296.0 [M-Boc+H] + .

[0286] Step d): 3-[3-[difluoro-[4-(trifluoromethyl)phenyl]methyl]-1-bicyclo[1.1.1]pentyl]aza-heterocyclic tert-butyl butane-1-carboxylate

[0287] At room temperature, toluene (15 mL) containing bis(2-methoxyethyl)aminosulfur trifluoride (5.04 g, 22.76 mmol) was added dropwise to a toluene solution (10 mL) of 3-[3-[4-(trifluoromethyl)benzoyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester (3.0 g, 7.59 mmol) (10 mL). The reaction was stirred for two days. The reaction mixture was then slowly added to 50 mL of saturated NaHCO3 aqueous solution cooled to 0 °C. The mixture was then extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by FC to the title compound (2.0 g, 4.79 mmol, yield 57.47%) as a pale yellow solid. MS (ESI): m / z = 318.2 [M-Boc+H] + .

[0288] Example B.10

[0289] 2-[3-(azacyclobutane-3-yl)-1-bicyclo[1.1.1]pentyl]-5-[1-(trifluoromethyl)cyclopropyl]-1, 3,4-Thiadiazole; 2,2,2-Trifluoroacetic acid

[0290] TFA (1.13 g, 766.29 µL, 9.95 mmol) was added to a 3 mL solution of tert-butyl 3-[3-[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-thiadiazol-2-yl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylate (435 mg, 994.66 µmol) in dichloromethane, and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under vacuum to give 559 mg of the crude title compound as a pale yellow gel, which was used without further purification with a purity of approximately 76%, the main contaminant being excess TFA. MS (ESI): m / z = 316.2 [M-TsOH+H] + .

[0291] Step a) 3-(1-tert-butoxycarbonylazonylbutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0292] 3-(azacyclobutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid; 2,2,2-trifluoroacetic acid (5.5 g, 19.56 mmol) was dissolved in 1,4-dioxane (25 mL). An aqueous solution of sodium bicarbonate (1 M, 1642.91 mg, 19.56 mmol) was added. Di-tert-butyl dicarbonate (4695.13 mg, 21.51 mmol) was dissolved in 1,4-dioxane (25 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 12 h and evaporated under vacuum. Water (100 mL) was added to the residue, and the aqueous phase was extracted with MTBE (2 x 100 mL). The aqueous phase was acidified to pH 2 with an aqueous solution of sodium bisulfate (1 M). MTBE (200 mL) was added, and the organic phase was dried over Na2SO4 and evaporated under vacuum to provide the title compound (4.2 g, 15.71 mmol, 80% yield) as a white solid. MS (ESI): m / z = 266.2 [MH]-.

[0293] Step b) 1-(trifluoromethyl)cyclopropaneformylhydrazine

[0294] N,N'-carbonyl-di-(1,2,3-triazole) (2.46 g, 14.99 mmol) was added to a THF solution (10 mL) of 1-(trifluoromethyl)cyclopropanecarboxylic acid (2.1 g, 13.63 mmol). The mixture was stirred at room temperature for 30 min, and hydrazine monohydrate (750.47 mg, 727.2 µL, 14.99 mmol, 1.100 eq) was added dropwise (gas escape was observed). The mixture was stirred at room temperature for 15 h to give a white suspension.

[0295] The reaction mixture was poured into a mixture of EtOAc and water. The insoluble matter was filtered off through a sintered glass filter. After extraction, the organic layer was collected, washed with brine, dried over Na₂SO₄, and concentrated under vacuum to provide the title compound (2.21 g, 91.63%) as a white solid. MS (ESI): m / z = 169.1 [M+H] + .

[0296] Step c) 3-[3-[[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]carbamoyl]-1-bicyclo[1.1.1] [Pentyl]-Azacyclobutane-1-carboxylic acid tert-butyl ester

[0297] CDI (477.68 mg, 2.95 mmol) was added to a 15 mL solution of 3-(1-tert-butoxycarbonylazyrobutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (750 mg, 2.81 mmol) in dichloromethane cooled to 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then at room temperature for 45 min. 1-(trifluoromethyl)cyclopropaneformylhydrazine (518.85 mg, 3.09 mmol) was then added, and the reaction mixture was stirred at room temperature for 18 h.

[0298] The reaction mixture was diluted with dichloromethane and poured into a separatory funnel containing 1M aqueous solution of Na₂CO₃ for extraction. The organic phase was collected, and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness to give 1230 mg of the crude title compound as a colorless gel, which was used without further purification. MS (ESI): m / z = 362.1 [M-tBu+H] + .

[0299] Step c) 3-[3-[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-thiadiazol-2-yl]-1-bicyclo[1.1.1] [Pentyl]-Azacyclobutane-1-carboxylic acid tert-butyl ester

[0300] Lawesson's reagent (525.48 mg, 1.3 mmol, 1.100 eq) was added to an anhydrous THF solution (27 mL) of 3-[3-[[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]carbamoyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester (580 mg, 1.18 mmol) under an inert atmosphere, and the reaction mixture was stirred at 70 °C for 18 h.

[0301] The reaction mixture was poured into a separatory funnel containing ethyl acetate and a 1M aqueous solution of Na₂CO₃ for extraction. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness to give 840 mg of the crude desired product. The crude material was purified by rapid chromatography (using a SiO₂ column, a mixture of heptane and ethyl acetate (5% to 80%) as eluent) to give 437 mg of the title compound as a white solid. MS (ESI): m / z = 416.3 [M+H] + .

[0302] Example B.20

[0303] 2,2,2-Trifluoroacetic acid; 3-[3-[4-(trifluoromethylsulfonyl)phenyl]-1-bicyclo[1.1.1]pentyl]aza Cyclobutane

[0304] TFA (1.09 g, 737.87 µL, 9.58 mmol) was added to a dichloromethane solution (4 mL) of 3-[3-(4-trifluoromethanesulfonylphenyl)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester (435 mg, 957.77 µmol), and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under vacuum to yield 593 mg of the crude title compound as a pale yellow, viscous oil, which was used without further purification (purity approximately 70%, major contaminant being excess TFA). MS (ESI): m / z = 332.0 [M-TFA+H] + .

[0305] Step a) 3-[3-(1,3-dioxoisoindoline-2-yl)oxycarbonyl-1-bicyclo[1.1.1]pentyl]nitrogen tert-butyl heterocyclobutane-1-carboxylate

[0306] To a solution (92 mL) of 3-(1-tert-butoxycarbonylazyrobutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (CAS: 2227205-20-9) (5 g, 18.7 mmol) in dichloromethane, 2-hydroxyisoindoline-1,3-quinone (3.36 g, 20.57 mmol), dicyclohexylcarbodiimide (4.25 g, 20.57 mmol), and DMAP (228.51 mg, 1.87 mmol) were added, followed by stirring of the reaction mixture at room temperature for 18 h. The volume of the reactants was reduced under vacuum and then adsorbed onto an H-MN Isolute. The crude material was then purified directly by rapid chromatography (using a SiO2 column, dichloromethane, and ethyl acetate (5% to 15%) as eluent) to give 7.28 g of the title compound as a white solid. MS (ESI): m / z = 357.1 [M-tBu+H]+.

[0307] Step b) 3-[3-[4-(trifluoromethylsulfonyl)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane- 1-Tert-butyl formate

[0308] Add tert-butyl 3-(3-phthaliminooxycarbonyl-1-bicyclo[1.1.1]pentyl)azacyclobutane-1-carboxylate (800 mg, 1.84 mmol), 1-bromo-4-trifluoromethanesulfonylbenzene (1.07 g, 3.69 mmol), Ni(dtbbpy)Br2 (179.44 mg, 368.54 µmol), NaHCO3 (619.14 mg, 7.37 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (933.47 mg, 3.69 mmol) to a microwave-safe vial. Then seal the vial and change the atmosphere to argon by evacuating / refilling with argon three times. Then add anhydrous N,N-dimethylacetamide (18 mL). The reaction mixture was then purged with argon for 5 min and stirred in a photoreactor under 395 nm LED irradiation (stirring 1000 rpm, fan speed 6800, LED intensity 50%) for 16 h. Volatiles were removed under vacuum, and the crude residue was partitioned between MTBE and a 1 M NaOH aqueous solution. The organic phase was collected, and the aqueous phase was back-extracted with MTBE. The combined organic phases were dried over sodium sulfate and evaporated to dryness to give 1.75 g of the crude desired product. The crude material was purified by rapid chromatography (using a SiO2 column, a mixture of heptane and MTBE (5% to 50%) as eluent) to give 436 mg of the title compound as a pale yellow, viscous oil. MS (ESI): m / z = 376.1 [M-tBu+H]+.

[0309] Example B.22

[0310] 2-[3-(azacyclobutane-3-yl)-1-bicyclo[1.1.1]pentyl]-5-fluorobenzonitrile; 2,2,2-trifluoroethyl acid

[0311] TFA (783.2 mg, 529.19 µL, 6.87 mmol) was added to a 3 mL solution of tert-butyl 3-[3-(2-cyano-4-fluoro-phenyl)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylate (240 mg, 686.9 µmol) in dichloromethane, and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under vacuum to yield 376 mg of crude title product as a pale yellow, viscous oil. This crude title product was used without further purification (purity approximately 65%, major contaminant being excess TFA). MS (ESI): m / z = 243.2 [M-TFA+H]+ .

[0312] Step a) 3-[3-(1,3-dioxoisoindoline-2-yl)oxycarbonyl-1-bicyclo[1.1.1]pentyl]nitrogen tert-butyl heterocyclobutane-1-carboxylate

[0313] To a solution of 3-(1-tert-butoxycarbonylazyrobutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (CAS: 2227205-20-9) (5 g, 18.7 mmol) in dichloromethane (92 mL), 2-hydroxyisoindoline-1,3-quinone (3.36 g, 20.57 mmol), dicyclohexylcarbodiimide (4.25 g, 20.57 mmol), and DMAP (228.51 mg, 1.87 mmol) were added, and the reaction mixture was stirred at room temperature for 18 h.

[0314] The reaction volume was reduced under vacuum and then adsorbed onto an H-MN Isolute. The crude material was then purified directly by rapid chromatography (using a 330 g SiO2 column, dichloromethane, and ethyl acetate (5% to 15%) as eluent) to give 7.28 g of the title compound as a white solid. MS (ESI): m / z = 357.1 [M-tBu+H] + .

[0315] Step b) 3-[3-(2-cyano-4-fluoro-phenyl)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0316] Add tert-butyl 3-(3-phthaliminooxycarbonyl-1-bicyclo[1.1.1]pentyl)azacyclobutane-1-carboxylate (488.39 mg, 1.12 mmol), 2-bromo-5-fluorobenzonitrile (150 mg, 0.750 mmol), Ni(dtbbpy)Br2 (73.03 mg, 0.150 mmol), NaHCO3 (251.99 mg, 3 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (379.92 mg, 1.5 mmol) to a microwave-safe vial. Then seal the vial and change the atmosphere to argon by evacuating / refilling with argon three times. Then add anhydrous N,N-dimethylacetamide (7.49 mL). The reaction mixture was then purged with argon for 5 minutes and stirred in a photoreactor under 395 nm LED irradiation (stirring 1000 rpm, fan speed 6800, LED intensity 50%) for 16 h. Volatiles were removed under vacuum, and the crude residue was partitioned between ethyl acetate and a 1 M aqueous solution of Na₂CO₃. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude material was purified by rapid chromatography (using a 40 g SiO₂ column, a mixture of heptane and MTBE (5% to 50%) as eluent) to give 183 mg of the desired product, a white solid, but impure due to contamination with phthalimide byproducts, with a purity of approximately 50%.

[0317] The fraction was partitioned between MTBE and a 1 M NaOH aqueous solution. The organic phase was collected, and the aqueous phase was back-extracted with MTBE. The combined organic phases were dried over sodium sulfate and evaporated to dryness to give 95 mg of the title product as a pale yellow solid. MS (ESI): m / z = 287.1 [M-tBu+H] + .

[0318] Example B.24

[0319] 2,2,2-Trifluoroacetic acid; 3-[3-[3-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane alkyl

[0320] TFA (996.26 mg, 673.15 µL, 8.74 mmol) was added to a dichloromethane solution (4 mL) of 3-[3-[3-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester (335 mg, 0.874 mmol), and the reaction mixture was stirred at room temperature for 18 h.

[0321] The volatiles were removed under vacuum to obtain 470 mg of crude title product (purity approximately 73%, major contaminant being excess TFA), which was used without further purification. MS (ESI): m / z = 284.1 [M-TFA+H] + .

[0322] Step a) 3-[3-[3-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-methyl tert-butyl ester

[0323] 3-(3-iodo-1-bicyclo[1.1.1]pentyl)azacyclobutane-1-carboxylic acid tert-butyl ester (CAS: 2375261-02-0) (500 mg, 1.43 mmol) and Fe(acac)3 (101.13 mg, 0.286 mmol) were added to the flask. The atmosphere was then switched to argon, followed by the addition of anhydrous THF (1.5 mL) and TMEDA (66.57 mg, 85.9 µL, 0.573 mmol, 0.400 eq). After 60 minutes, a 0.500 M THF solution of bromo-[3-(trifluoromethoxy)phenyl]magnesium (4.58 mL, 2.29 mmol) was slowly added to the stirred reaction solution using a syringe pump. The reaction was then stirred at room temperature for 1 h. The reaction was quenched by adding a few drops of saturated NH4Cl aqueous solution and stirred at room temperature for a few minutes. The crude reaction solution was extracted using a separatory funnel containing ethyl acetate and a saturated aqueous solution of NH4Cl. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness to give 805 mg of the crude desired product as a deep orange oil. The crude material was purified by rapid chromatography (using a mixture of SiO2 column, heptane, and MTBE (0% to 20%) as eluent) to give 445 mg of the title product as a pale yellow viscous oil, but not sufficiently pure. The fraction was purified by SFC to give 338 mg of the title compound as a colorless gel. MS (ESI): m / z = 328.1 [M-tBu+H] + .

[0324] Example B.25

[0325] 2,2,2-Trifluoroacetic acid; 3-[3-[4-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane alkyl

[0326] TFA (529.36 mg, 357.67 µL, 4.64 mmol) was added to a 2 mL solution of tert-butyl 3-[3-[4-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylate (178 mg, 0.464 mmol) in dichloromethane, and the reaction mixture was stirred at room temperature for 18 h.

[0327] The volatiles were removed under vacuum to give 268 mg of the crude title compound (approximately 68% purity, major contaminant being excess TFA), which was used without further purification. MS (ESI): m / z = 284.1 [M-TFA+H] + .

[0328] Step a) 3-[3-[4-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-methyl tert-butyl ester

[0329] 3-(3-iodo-1-bicyclo[1.1.1]pentyl)azacyclobutane-1-carboxylic acid tert-butyl ester (CAS: 2375261-02-0) (500 mg, 1.43 mmol) and Fe(acac)3 (101.13 mg, 0.286 mmol) were added to the flask. The atmosphere was then switched to argon, followed by the addition of anhydrous THF (1.5 mL) and TMEDA (66.57 mg, 85.9 µL, 0.573 mmol). After 60 minutes, a 0.500 M THF solution of bromo-[4-(trifluoromethoxy)phenyl]magnesium (4.58 mL, 2.29 mmol) was slowly added to the stirred reaction solution using a syringe pump. The reaction was then stirred at room temperature for 1 h. The reaction was quenched by adding a few drops of saturated NH4Cl aqueous solution and stirred at room temperature for a few minutes. The crude reaction solution was extracted using a separatory funnel containing ethyl acetate and a saturated aqueous solution of NH4Cl. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness to give 786 mg of the crude desired product as a deep orange oil. The crude material was purified by rapid chromatography (using a mixture of SiO2 column, heptane, and MTBE (0% to 30%) as eluent) to give 578 mg of the title compound as a light-colored, viscous oil, but not sufficiently pure. The fraction was presented for purification (reverse HPLC purification) to yield 178 mg of the title product as a colorless gel. MS (ESI): m / z = 328.1 [M-tBu+H] + .

[0330] Example B.27

[0331] 3-[3-(4-fluorophenyl)-1-bicyclo[1.1.1]pentyl]azacyclobutane; 2,2,2-trifluoroacetic acid

[0332] TFA (1.13 g, 765.43 µL, 9.94 mmol) was added to a 5 mL solution of 3-[3-(4-fluorophenyl)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester (371 mg, 0.994 mmol) in dichloromethane, and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under vacuum to give 587 mg of the crude title compound as a colorless, viscous oil (approximately 55% purity, with excess TFA as the main contaminant), which was used without further purification. MS (ESI): m / z = 218.1 [M-TFA+H] + .

[0333] Step a) 3-[3-(4-fluorophenyl)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0334] 3-(3-iodo-1-bicyclo[1.1.1]pentyl)azacyclobutane-1-carboxylic acid tert-butyl ester (500 mg, 1.43 mmol) and Fe(acac)3 (101.13 mg, 0.286 mmol) were added to the flask, followed by switching to an argon atmosphere. Then, ultradry THF (1.5 mL) and TMEDA (66.57 mg, 85.9 µL, 0.573 mmol) were added. After 45 minutes, a 0.500 M THF solution of 4-fluorophenyl magnesium bromide (4.58 mL, 2.29 mmol) was slowly added to the stirred reaction solution using a syringe pump. The reaction was then stirred at room temperature for 2 h. The reaction was quenched by adding a few drops of saturated NH4Cl aqueous solution and stirred at room temperature for a few minutes. The crude reaction solution was poured into a separatory funnel containing ethyl acetate and saturated NH4Cl aqueous solution for extraction. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness to give 754 mg of the crude desired product as a deep orange oil. The crude material was purified by rapid chromatography (using an 80 g SiO2 column with a mixture of heptane and MTBE (0% to 20%) as eluent) to give 371 mg of the title product as a white solid. MS (ESI): m / z = 262.2 [M-tBu+H] + .

[0335] Example B.28

[0336] N-[3-(azacyclobutane-3-yl)-1-bicyclo[1.1.1]pentyl]-5-(trifluoromethyl)pyrazine-2-amine;2, 2,2-Trifluoroacetic acid

[0337] TFA (712.18 mg, 481.2 µL, 6.25 mmol) was added to a 3 mL solution of tert-butyl 3-[3-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylate (245 mg, 0.625 mmol) in dichloromethane, and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed under vacuum to give 493 mg of crude title product, a colorless, viscous oil (approximately 50% purity, with excess TFA as the main contaminant). This crude title product was used without further purification. MS (ESI): m / z = 285.1 [M-TFA+H]+ .

[0338] Step a) 3-[3-(benzyloxycarbonylamino)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert- Butyl acetate

[0339] At ambient temperature, triethylamine (3.13 mL, 22.45 mmol) was added to a solution of 3-(1-tert-butoxycarbonylazyrobutane-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (2.0 g, 7.48 mmol) and benzyl alcohol (1618.14 mg, 14.96 mmol) in toluene (50 mL). The mixture was stirred for 5 min, and diphenylphosphonohydrazine (1.69 mL, 7.86 mmol) was added. The mixture was stirred at ambient temperature for another 15 min, and then stirred at 100 °C for 16 h. After cooling, it was poured into ice / water (50 mL) and extracted with MTBE. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by FC to provide the title compound (2.35 g, 6.31 mmol, 80% yield) as a colorless, viscous oil. MS (ESI): m / z = 273.0 [M-Boc+H]+.

[0340] Step b) 3-(3-amino-1-bicyclo[1.1.1]pentyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0341] A methanol solution (50 mL) of 3-[3-(benzyloxycarbonylamino)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester (4.15 g, 11.14 mmol, 1.0 eq) was mixed with 10% palladium supported on carbon (0.58 mL, 0.56 mmol, 0.05 eq). The reaction mixture was stirred at room temperature for 48 h under a hydrogen atmosphere. The solids were removed by filtration, and the filtrate was concentrated under vacuum to give the title compound (2.6 g, 10.91 mmol, 93% yield) as a colorless oil. MS (ESI): m / z = 239.2 [M+H] +

[0342] Step c) 3-[3-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-1-bicyclo[1.1.1]pentyl]aza-heterocyclic tert-butyl butane-1-carboxylate

[0343] To an anhydrous N,N-dimethylformamide solution (3 mL) of tert-butyl 3-(3-amino-1-bicyclo[1.1.1]pentyl)azacyclobutane-1-carboxylate (150 mg, 0.629 mmol) and DIPEA (162.54 mg, 219.64 µL, 1.26 mmol) cooled to 0 °C, 2-fluoro-5-(trifluoromethyl)pyrazine (146.34 mg, 0.881 mmol) was added, followed by stirring of the reaction mixture at 0 °C for 10 min. The reaction was allowed to rise to room temperature and stirred at room temperature for 3 h.

[0344] The volatiles were removed under vacuum to give a crude residue, which was then purified directly by rapid chromatography (using a mixture of 24 g SiO2 column, heptane, and ethyl acetate (10% to 60%)) to give 196 mg of the title product as a white solid. MS (ESI): m / z = 329.2 [M-tBu+H] + .

[0345] Example B.34

[0346] 5-[[3-(azacyclobutane-3-yl)-1-bicyclo[1.1.1]pentyl]methyl]-2-(trifluoromethyl)pyridine;4- Methylbenzenesulfonic acid

[0347] To a stirred EtOAc solution (25 mL) of tert-butyl 3-[3-[[6-(trifluoromethyl)-3-pyridyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylate (480.0 mg, 1.26 mmol), p-toluenesulfonic acid monohydrate (525.27 mg, 2.76 mmol, 2.2 eq) was added. The reaction mixture was stirred at 25 °C for 16 h. The resulting mixture was concentrated to provide the title compound (465.2 mg, 1.02 mmol, 77% yield) as a pale yellow solid. MS (ESI): m / z = 283.2 [M+H] +

[0348] Step a) 4-Methyl-N-[(E)-[6-(trifluoromethyl)-3-pyridyl]methyleneamino]benzenesulfonamide

[0349] A mixture (30 mL) of stirred 6-(trifluoromethyl)pyridine-3-carboxaldehyde (CAS: 386704-12-7) (2.7 g, 15.42 mmol) and 4-methylbenzenesulfonylhydrazine (3158.6 mg, 16.96 mmol) in methanol was refluxed for 16 h. The reaction was then cooled to room temperature and the solvent was evaporated. The solid was washed with Et₂O and hexane to provide the title compound (5.2 g, 15.15 mmol, 88.41% yield) as a yellow solid. MS (ESI): m / z = 344.0 [M+H] +

[0350] Step b) [3-(1-tert-butoxycarbonylazonylbutane-3-yl)-1-bicyclo[1.1.1]pentyl]boronic acid

[0351] At room temperature, 15 mL of an acetone solution (3.0 g, 8.59 mmol) of 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-carboxylic acid tert-butyl ester (CAS: 2826264-08-6) was added to water (7.5 mL) containing sodium periodate (6062.73 mg, 28.34 mmol) and ammonium acetate buffer (1986.26 mg, 25.77 mmol), and the mixture was stirred for 16 h. The reaction solution was then filtered, the filtrate was concentrated under reduced pressure, and ethyl acetate was added. The mixture was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (2.2 g, 8.24 mmol, 91% yield) as a white solid. MS (ESI): m / z = 168.2 [M-Boc+H] +

[0352] Step c) 3-[3-[[6-(trifluoromethyl)-3-pyridyl]methyl]-1-bicyclo[1.1.1]pentyl]aza-heterocyclic tert-butyl butane-1-carboxylate

[0353] A mixture (50 mL) of stirred [3-(1-tert-butoxycarbonylazyrobutane-3-yl)-1-bicyclo[1.1.1]pentyl]boronic acid (2.22 g, 8.3 mmol, 1.5 eq), 4-methyl-N-[(E)-[6-(trifluoromethyl)-3-pyridyl]methyleneamino]benzenesulfonamide (1.9 g, 5.53 mmol), and cesium carbonate (2.7 g, 8.3 mmol) in anhydrous 1,4-dioxane was refluxed under argon atmosphere for 48 h. The resulting precipitate was then filtered off, and the filtrate was evaporated to dryness. The resulting residue was partitioned between MTBE (200 mL) and water (50 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and evaporated under vacuum. The crude product was purified by column chromatography (petroleum ether / MTBE, where MTBE was 0% to 40%) to obtain the title compound (580.0 mg, 1.52 mmol, 27% yield), which was a pale yellow oil. MS (ESI): m / z = 283.2 [M-Boc+H] +

[0354] Example B.12

[0355] 2-(azacyclobutane-3-yl)-5-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazine; 4-methylbenzenesulfonic acid

[0356] A solution (20 mL) of p-toluenesulfonic acid (935.32 mg, 5.43 mmol) and tert-butyl 3-[5-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazin-2-yl]azacyclobutane-1-carboxylate (1.69 g, 4.53 mmol) in EtOAc was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtered solid was dried under vacuum to give the title compound (1.47 g, 3.3 mmol, 73% yield) as a white solid. MS (ESI): m / z = 274.2 [M-TsOH+H] + .

[0357] Step a) 3-[5-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazin-2-yl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0358] Over several minutes, under an argon atmosphere, a mixture (7:5, v / v) of trimethylsilyl chloride (0.29 mL, 2.32 mmol) and 1,2-dibromoethane (0.2 mL, 2.22 mmol) was carefully added via syringe to a stirred suspension of anhydrous N,N-dimethylacetamide containing 1.1 g (17.2 mmol) of zinc powder (3 mL). The temperature was raised to 60 °C, and stirring continued while the reaction mixture cooled back to room temperature. Then, over 3 minutes, a solution (7 mL) of N,N-dimethylacetamide containing 4.29 g (15.15 mmol) of 1-BOC-3-iodozacyclobutane was slowly added via syringe. The temperature was again raised to 65 °C, and stirring continued for 30 minutes while the mixture cooled back to room temperature. Under an argon atmosphere, a solution of the obtained organozinc iodide intermediate was slowly added via syringe to a suspension (15 mL) of Pd(dppf)Cl2·CH2Cl2 (453.58 mg, 0.56 mmol), cuprous iodide (I) (211.56 mg, 1.11 mmol), and 2-bromo-5-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazine (3.0 g, 10.1 mmol) in N,N-dimethylacetamide. The resulting reaction mixture was stirred at 80 °C for 18 h. After cooling to room temperature, a saturated aqueous solution of NH4Cl and MTBE were added to the reaction mixture. Insoluble matter was removed by filtration and the layers were separated. The aqueous layer was extracted again with MTBE. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated. The resulting residue was purified by silica gel rapid chromatography (120 g SiO2, hexane / MTBE, where MTBE was 0% to 65%) to give the title compound (1.9 g, 5.09 mmol, 48% yield) as a pale yellow solid. MS (ESI): m / z = 318.0 [M-tBu+H] +

[0359] Step b) 2-Bromo-5-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazine

[0360] Potassium tert-butoxide (519.68 mg, 4.64 mmol) was added in a single batch to a THF solution (10 mL) of [1-(trifluoromethyl)cyclopropyl]methanol (500.0 mg, 3.57 mmol) and 2-bromo-5-fluoropyrazine (694.74 mg, 3.93 mmol) cooled to 0 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the residue. The crude residue was partitioned between water (50 mL) and ethyl acetate (20 mL). The organic phase was collected, and the aqueous phase was back-extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title product (1.0 g, 3.37 mmol, 94% yield), which was a yellow gel and was used without further purification. MS (ESI): m / z = 297.0 [M+H] + .

[0361] Example B.15

[0362] 6-[(3-chloro-5-fluoro-2-pyridinyl)oxy]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[0363] A solution (33.33 mL) of ethyl acetate of 6-[(3-chloro-5-fluoro-2-pyridinyl)oxy]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (999.9 mg, 2.92 mmol) was mixed with p-toluenesulfonic acid monohydrate (1664.58 mg, 8.75 mmol) and stirred at room temperature for 18 h. The reaction mixture was then evaporated. The residue was treated with MTBE and the solid was filtered to give the title compound (1203.2 mg, 3.79 mmol, 94% yield) as a white solid. MS (ESI): m / z = 243.0 [M-TsOH+H] + .

[0364] Step a) 6-[(3-chloro-5-fluoro-2-pyridinyl)oxy]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0365] Potassium tert-butoxide (2154.58 mg, 19.2 mmol) was added in a single dose to a THF solution (273 mL) of 3-chloro-2,5-difluoropyridine (CAS: 851179-00-5) (2296.9 mg, 15.36 mmol) and 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (CAS: 1147557-97-8) (2730.0 mg, 12.8 mmol) and the reaction mixture was stirred for 18 h. The reaction mixture was then diluted with water and extracted in EtOAc (300 mL). The organic phase was washed with 2 x 400 mL of water and then with 1 x 300 mL of brine. The organic phase was then dried over Na2SO4 and concentrated to dryness. The crude material was purified by FC (120 g SiO2, petroleum ether / MTBE, where MTBE was 10% to 20%) to give the title compound (2.0 g, 5.83 mmol, 46% yield) as a pale yellow solid. MS (ESI): m / z = 343.0 [M+H] + .

[0366] Example B.19

[0367] 5-(2-azaspiro[3.3]heptane-6-yloxy)-2-(trifluoromethyl)benzonitrile; 4-methylbenzenesulfonic acid

[0368] To an ethyl acetate solution (10 mL) of 6-[3-cyano-4-(trifluoromethyl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (452.0 mg, 1.18 mmol), p-toluenesulfonic acid monohydrate (292.31 mg, 1.54 mmol) was added. The mixture was stirred at 20 °C for 16 h. The precipitated solid was filtered, washed with acetonitrile, and dried under vacuum to give the title compound (283.0 mg, 0.62 mmol, 53% yield) as a white solid. MS (ESI): m / z = 283.2 [M-TsOH+H] + .

[0369] Step a) 6-[3-cyano-4-(trifluoromethyl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0370] A toluene solution (10 mL) of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (500.0 mg, 2.34 mmol) and 5-hydroxy-2-(trifluoromethyl)benzonitrile (482.56 mg, 2.58 mmol) was cooled to 0 °C. Triphenylphosphine (799.39 mg, 3.05 mmol) and diisopropyl azodicarbonate (0.6 mL, 3.05 mmol) were added under an argon atmosphere. The mixture was heated to 20 °C and stirred for 16 h. The mixture was concentrated, and the residue was ground together with MTBE. The precipitated solid was filtered off, and the filtrate was concentrated under vacuum. The crude residue was purified by FC (silica, hexane containing 20% ​​EtOAc) to provide the title compound (430.0 mg, 1.12 mmol, 48% yield) as a white solid. MS (ESI): m / z = 327.2 [M-tBu+H] + .

[0371] Similar to Example B.15, the following structural units are generated using related (hetero)aryl halides or alkyl halides and hydroxyl spirocyclic structural units. In some cases, alternative solvents and bases are used for S. N Ar reaction, for example, using DMSO solvent or DMF containing NaH in step a).

[0372]

[0373] Example B.29

[0374] 3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azacyclobutane; 4-methylbenzenesulfonic acid

[0375] Add 4-toluenesulfonic acid monohydrate (4.61 g, 26.8 mmol) to a chilled EtOAc solution (130 mL) of tert-butyl 3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)azacyclobutane-1-carboxylate (7.8 g, 22.3 mmol) and heat the mixture under reflux for 3 h. Allow the rapidly forming suspension to cool to room temperature overnight. Filter the suspension, and wash the filter cake with EtOAc (20 mL) to give the title product as a white solid (7.28 g; 81.2%). MS (ESI): m / z = 250.2 [M-TsOH+H] + .

[0376] Step a) 3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azacyclobutane-1-carboxylic acid tert-butyl ester

[0377] A 25 mL solution of ice-cold tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (CAS: 141699-55-0) (2.02 g, 11.7 mmol) in DMF was added dropwise to mineral oil containing 55% sodium hydride (560 mg, 12.8 mmol), and the mixture was stirred in an ice bath for 30 min. A 5 mL solution of 1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (CAS: 239087-07-1) (3 g, 11.7 mmol) in DMF was added dropwise to the mixture. The slurry was stirred at room temperature for 3 h. The reaction mixture was poured onto saturated aqueous NH4Cl solution (70 mL) and ethyl acetate (70 mL), and the layers were separated after extraction. The aqueous layer was back-extracted once with ethyl acetate (50 mL). The organic layer was washed twice with water, dried with MgSO4, filtered, treated with silica gel, and then evaporated. The compound was purified by silica gel chromatography using an MPLC system on a 40 g column with n-heptane:ethyl acetate (100:0 to 60:40) to give the title compound as a pale yellow oil (3.66 g; 90%). MS (ESI): m / z = 294.1 [M-tBu+H] + .

[0378] Example B.30

[0379] 2-(azacyclobutane-3-yl)-5-[1-(trifluoromethyl)cyclopropyl]pyridine; 4-methylbenzenesulfonic acid

[0380] To a mixture of tert-butyl 3-[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]azacyclobutane-1-carboxylate (910 mg, 2.66 mmol) in EtOAc (5 mL), p-toluenesulfonic acid (1053 mg, 6.11 mmol) was added. The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound (1378 mg, 87% yield) as a white solid. MS (ESI): m / z = 243.1 [M-2TsOH+H] +

[0381] Step a) 3-(5-bromo-2-pyridyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0382] Add 1,2-dibromoethane (66.4 mg, 30.4 µL, 0.353 mmol) and TMSCl (44.9 µL, 0.353 mmol) to a suspension of zinc powder (346 mg, 5.3 mmol) in THF (8 mL), and stir the suspension at 60 °C for 15 min. Add a solution of tert-butyl 3-iodozacyclobutane-1-carboxylate (614 µL, 3.53 mmol) in DMA (8 mL). Stir the reaction mixture at 60 °C for another 15 min, then cool to 23 °C. 5-Bromo-2-iodopyridine (1.05 g, 3.71 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (144 mg, 0.177 mmol), and cuprous iodide (34.32 mg, 0.177 mmol) were added, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with ethyl acetate and water, and the mixture was filtered. The filtrates were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, dried over MgSO4, filtered, and evaporated. Purification by FC (SiO2; heptane / EtOAc) gave the title compound (0.713 g; 61%) as a light brown oil. MS (ESI): m / z = 257.0 [M-tBu+H] +

[0383] Step b) 3-[5-[1-(trifluoromethyl)vinyl]-2-pyridyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0384] To a solution of 1-(trifluoromethyl)vinylborate hexanediol ester (1418 mg, 6.39 mmol), 3-(5-bromo-2-pyridyl)azacyclobutane-1-carboxylic acid tert-butyl ester (2000 mg, 6.39 mmol), potassium carbonate (1765 mg, 12.8 mmol), and 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (521 mg, 0.640 mmol) in 1,4-dioxane (15 mL) and water (3 mL), the mixture was added and stirred at 100 °C for 12 h under a nitrogen atmosphere. The reaction mixture was filtered and evaporated. Purification by FC (SiO2; PE / EtOAc) yielded the title compound (1400 mg, 63% yield) as a yellow oil. MS (ESI): m / z = 273.1 [M-tBu+H] +

[0385] Step c) 3-[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0386] Sulfur diphenyl(methyl)tetrafluoroborate (2972 mg, 10.3 mmol) was added to a THF solution (20 mL) of tert-butyl 3-[5-[1-(trifluoromethyl)vinyl]-2-pyridyl]azacyclobutane-1-carboxylate (2160 mg, 7.93 mmol). The suspension was cooled to 0 °C, and a 1 M THF solution containing NaHMDS (12.7 mL, 12.7 mmol) was added dropwise. The reaction mixture was heated to 20 °C and stirred for 12 h. The mixture was a yellow suspension. Purification by FC (SiO2; PE / EtOAc) gave the title compound (910 mg, 2.66 mmol, 31% yield) as a yellow oil. MS (ESI): m / z = 287.0 [M-tBu+H] +

[0387] Example B.31

[0388] 3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)azacyclobutane 4-methylbenzenesulfonate

[0389] To a solution of tert-butyl 3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-carboxylate (7.00 g, 20.5 mmol) in ethyl acetate (70 mL), p-toluenesulfonic acid (4.24 g, 24.6 mmol) was added. The mixture was stirred at 80 °C for 3 h, cooled to room temperature, filtered, and the filter cake was collected to give 4-methylbenzenesulfonic acid; 3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane (7600 mg, yield 89.6%), a white solid. MS (ESI): m / z = 242.4 [M-TsOH+H] +

[0390] Step a) 3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0391] Add the following to a 500 mL vial equipped with a stir bar: 3-bromozacyclobutane-1-carboxylate tert-butyl ester (CAS: 3-bromozacyclobutane-1-carboxylate tert-butyl ester) (8017 mg, 34.0 mmol), 1-bromo-4-(1-trifluoromethyl-cyclopropyl)benzene (CAS: 1-bromo-4-(1-trifluoromethyl-cyclopropyl)benzene) (9000 mg, 34.0 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (381 mg, 0.340 mmol), NiCl2glyme (37.3 mg, 0.170 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (54.7 mg, 0.200 mmol), and bis(trimethylsilyl)silyl-trimethylsilane (8443 mg, 34.0 mmol) and Na2CO3 (7197 mg, 67.9 mmol) in DME (225 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), and the reaction temperature was maintained at 25 °C with a cooling fan for 20 h. LCMS showed that the reaction was complete. The reaction was filtered, and the filtrate was concentrated. The residue was purified by reversed-phase rapid chromatography (FA) and concentrated to give tert-butyl 3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-carboxylate (7700 mg, 66% yield), as a pale yellow solid. MS: MS(ESI): m / z = 286.0 [M-tBu+H] +

[0392] Similar to Example B.31, the following structural units are generated using relevant commercial structural units in step a).

[0393]

[0394] Example B.33

[0395] 1-[4-(azacyclobutane-3-yl)phenyl]-5-methyl-3-(trifluoromethyl)pyrazole; 4-methylbenzenesulfonic acid

[0396] To a solution (2.55 mL) of ethyl acetate of 3-[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]azacyclobutane-1-carboxylic acid tert-butyl ester (186 mg, 0.439 mmol), 4-methylbenzenesulfonic acid hydrate (171.15 mg, 0.900 mmol) was added, and the mixture was stirred under reflux for 2 h. The reaction was allowed to cool to room temperature, and then filtered to give the title compound as a white solid (0.218 g; 92%), MS (ESI): m / z = 282.2 [M-TsOH+H] + .

[0397] Step a) 3-[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0398] Add the following to a 20 mL vial equipped with a stir bar: photocatalyst (Ir[dF(CF3)PPY]2(DTBPY))PF6 (7.65 mg, 0.007 mmol), 1-(4-bromophenyl)-5-methyl-3-(trifluoromethyl)pyrazole (208 mg, 0.682 mmol), tert-butyl 3-bromoazacyclobutane-1-carboxylate (241.46 mg, 167.33 µL, 1.02 mmol), tris(trimethylsilyl)silane (169.53 mg, 210.33 µL, 0.682 mmol), and anhydrous sodium carbonate (144.52 mg, 1.36 mmol). Seal the vial and place it under argon atmosphere, then add DME (5.8 mL). Add nickel(II) ethylene glycol dimethyl ether complex (1.5 mg, 0.007 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (1.83 mg, 0.007 mmol) to separate vials. Seal the pre-catalyst vial, purge with argon, and then add DME (2.32 mL). Sonicate the pre-catalyst vial for 5 min, after which inject 1.16 mL (0.5 mol% catalyst, 0.005 eq) into the previously prepared reaction vessel. Degas the reaction mixture (a suspension) with argon. Stir the reaction for 16 h (75% intensity) under 420 nm light. Quench the reaction by exposure to air, filter, and wash with a small amount of EtOAc. Treat the filtrate with silica gel and evaporate it. The compound was purified by silica gel chromatography (on a 24 g column, using an MPLC (ISCO) system, eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50)) to give the title compound as an orange oil (0.186 g, 64%). MS (ESI): m / z = 326.2 [M-tBu+H] + .

[0399] Step b) 1-(4-bromophenyl)-5-methyl-3-(trifluoromethyl)pyrazole

[0400] In a dry flask equipped with a high-pressure air stream, copper(II) acetate (3.27 g, 17.99 mmol) was added to 132 mL of an acetonitrile solution of 5-methyl-3-(trifluoromethyl)-1H-pyrazole (2 g, 13.32 mmol), pyridine (2.11 g, 2.16 mL, 26.65 mmol), and 4-bromophenylboronic acid (4.01 g, 19.99 mmol), and the reaction was stirred overnight at room temperature. The reaction mixture was filtered, washed with acetonitrile, and evaporated to give the crude product. The compound was purified by silica gel chromatography (on a 40 g column, using an MPLC (ISCO) system, eluting with a gradient of n-heptane:ethyl acetate (100:0 to 65:35) to give the title compound as a pale yellow oil (3.82 g, 91%). MS (ESI): m / z = 304.9 [M+H] + .

[0401] Example B.43

[0402] 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3,3]heptane; 4-methylbenzenesulfonic acid

[0403] A solution of tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (675 mg, 1.95 mmol) and p-toluenesulfonic acid (404 mg, 2.35 mmol) in EtOAc (6 mL) was stirred at 80 °C for 12 h. The mixture was concentrated under vacuum to give a residue. Deionized water was added to the residue, and the mixture was lyophilized to give the title compound (794 mg, 96% yield) as a white solid. MS (ESI): m / z = 246.2 [M-TsOH+H] +

[0404] Step a) 6-[[4-(trifluoromethyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- Butyl acetate

[0405] Under an O2 atmosphere, copper diacetate (2380 mg, 11.9 mmol) was added to a solution of 4-(trifluoromethyl)-1H-pyrazole (2435 mg, 17.9 mmol), 6-[(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Example B.1, step a) (2000 mg, 5.97 mmol), and pyridine (1.45 mL, 17.9 mmol) in DMSO (80 mL), and the mixture was stirred at 100 °C for 12 h under O2 (balloon) conditions. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine (200 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (eluting with 0% to 30% ethyl acetate / petroleum ether) to give a crude product, which was then purified by reversed-phase HPLC (0.1% FA conditions) to give the title compound (640 mg, 31% yield) as a brown solid. MS (ESI): m / z = 288.1 [M-tBu+H] +

[0406] Step b) 6-[[4-(trifluoromethyl)pyridazin-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0407] To a solution of 6-[[4-(trifluoromethyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (690 mg, 2.01 mmol) in EtOAc (7 mL), wet Pd / C (230 mg, 0.200 mmol) was added, and the mixture was stirred at 25 °C for 2 h under a H2 atmosphere (balloon). The mixture was then filtered, and the filtrate was concentrated to give the title compound (690 mg, 99% yield) as a yellow solid. MS (ESI): m / z = 346.1 [M+H] +

[0408] Example B.54

[0409] 6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3,3]heptane; 4-methylbenzenesulfonic acid

[0410] A mixture (6 mL) of 6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1000.0 mg, 2.78 mmol) and p-toluenesulfonic acid (575.02 mg, 3.34 mmol) in ethyl acetate was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in deionized water and lyophilized to give the title compound (1.15 g, 2.67 mmol, 95% yield) as a white solid. MS (ESI): m / z = 260.0 [M-TsOH+H]+

[0411] Step a) 6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0412] Add 20 mL of DME to a vial containing 4-bromo-3-fluorotrifluorotoluene (CAS: 40161-54-4) (2.0 g, 8.23 ​​mmol), tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (5319.67 mg, 16.46 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (92.26 mg, 0.08 mmol), NiCl2.dtbbpy (16.38 mg, 0.04 mmol), bis(trimethylsilyl)silyl-trimethylsilane (2046.58 mg, 8.23 ​​mmol), and Na2CO3 (1744.69 mg, 16.46 mmol). Seal the vial and change the atmosphere to nitrogen. The reaction was stirred under a 34 W blue LED lamp (7 cm away) and the temperature was maintained at 25 °C for 14 h using a cooling fan. Volatile substances were removed under vacuum, and the crude residue was purified by rapid silica gel chromatography (fast silica gel column, 0% to 30% ethyl acetate / petroleum ether gradient eluent @ 40 mL / min) to give the crude product. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give the title compound (2000.0 mg, 5.57 mmol, 68% yield) as a white solid. MS (ESI): m / z = 304.2 [M-tBu+H] +

[0413] Step b) 6-Iodo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0414] Iodine (24.99 g, 98.47 mmol) was added to a mixture (800 mL) of stirred tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (14.0 g, 65.64 mmol), imidazole (13406.7 mg, 196.93 mmol), and triphenylphosphine (34435.13 mg, 131.29 mmol) in toluene. The resulting mixture was refluxed for 3 h. The mixture was cooled to room temperature, diluted with MTBE (500 mL), and washed with water (300 mL) and brine (200 mL). The separated organic layer was dried, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (330 g SiO2, petroleum ether / MTBE, where MTBE was 0% to 40%) to give the title compound (17.2 g, 53.22 mmol, 77% yield) as a white solid. MS (ESI): m / z = 224.0 [M-Boc+H] +

[0415] Example B.69

[0416] N-(2-azaspiro[3.3]heptane-6-ylmethyl)-1-(trifluoromethyl)cyclopropylamine; 4-methylbenzenesulfonic acid

[0417] p-Toluenesulfonic acid monohydrate (1024 mg, 5.38 mmol) was added to a stirred solution of 6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (600 mg, 1.79 mmol) in acetonitrile (20 mL). The reaction mixture was stirred for 16 h. The solvent was evaporated under reduced pressure, and the residue was ground together with MTBE to give the title compound (668 mg, 1.15 mmol, 64% yield) as a white solid. MS (ESI): m / z = 235.2 [M-TsOH+H] +

[0418] Step a) 6-[[1-(trifluoromethyl)cyclopropyl]carbamoyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- Butyl acetate

[0419] To a stirred solution of 2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid (CAS: 1211526-53-2) (2.0 g, 8.29 mmol) and 1-(trifluoromethyl)cyclopropylamine hydrochloride (CAS: 112738-67-7) (1340 mg, 8.29 mmol) in DMF (5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (3782 mg, 9.95 mmol) and N,N-diisopropylethylamine (5.05 mL, 29.0 mmol) were added. The mixture was stirred overnight at room temperature and then poured over water and extracted with EtOAc (2 x 50 mL). The combined organic fractions were washed three times with water, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The residue was ground together with 25 mL of MTBE to give the title compound (1.7 g, 4.88 mmol, 59% yield), a white solid. MS (ESI): m / z = 347.2 [MH] -

[0420] Step b) 6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- Butyl acetate

[0421] 1.1 g (3.16 mmol) of tert-butyl 6-[[1-(trifluoromethyl)cyclopropyl]carbamoyl]-2-azaspiro[3.3]heptane-2-carboxylate was dissolved in THF (30 mL). A borane-methyl sulfide complex (0.48 g, 6.32 mmol) was added at 0 °C. The reaction mixture was stirred under reflux for 6 h, then cooled to 0 °C and quenched dropwise with methanol (5 mL), and then concentrated under vacuum. The residue was diluted with brine and then extracted with EtOAc (3 times). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound as a colorless oil (600 mg, 1.79 mmol, 57% yield). MS (ESI): m / z = 279.0 [M-tBu+H] +

[0422] Example B.35

[0423] 5-(azacyclobutane-3-yl)-N-[[1-(trifluoromethyl)cyclopropyl]methyl]pyrazine-2-amine; di-4-methylbenzene sulfonic acid

[0424] A mixture of tert-butyl 3-[5-[[1-(trifluoromethyl)cyclopropyl]methylamino]pyrazin-2-yl]azacyclobutane-1-carboxylate (1.9 g, 5.1 mmol) and p-toluenesulfonic acid (1142 mg, 6.63 mmol) in EtOAc (20 mL) was stirred at 80 °C for 12 h. Further addition of p-toluenesulfonic acid (87.9 mg, 0.510 mmol) and stirring at 80 °C for another 12 h were then performed. The reaction was concentrated under vacuum to give a residue. 80 mL of water was added to this residue, and the mixture was lyophilized to give the title compound (2.38 g, 75% yield) as a yellow solid. MS (ESI): m / z = 273.2 [M-2TsOH+H] +

[0425] Step a) 3-(5-bromopyrazin-2-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0426] Add 1,2-dibromoethane (791 mg, 4.21 mmol) and trichloromethylsilane (458 mg, 4.21 mmol) to a mixture of zinc (4131 mg, 63.2 mmol) in THF (96 mL). Heat the mixture to 60 °C and stir for 15 min. Then add a mixture of 1-BOC-3-iodozacyclobutane (12.5 g, 44.2 mmol) in DMA (96 mL). Stir the mixture again for 15 min. Cool the mixture to 20 °C and add 2-bromo-5-iodopyrazine (12.0 g, 42.1 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (1720 mg, 2.11 mmol), and cuprous(I) iodide (0.07 mL, 2.11 mmol). The mixture was heated to 80 °C and stirred for 12 h. The mixture was then added to 200 mL of water and extracted with EtOAc (200 mL × 3). The combined organic phases were evaporated and purified by FC (SiO2; PE / EtOAc) to give the title compound (4.9 g, 37% yield) as a white solid. MS (ESI): m / z = 258.1 [M-tBu+H] +

[0427] Step b) 3-[5-[[1-(trifluoromethyl)cyclopropyl]methylamino]pyrazin-2-yl]azacyclobutane-1-methyl tert-butyl ester

[0428] Under a nitrogen atmosphere, a solution (55.5 mL) of tert-amyl alcohol containing [1-(trifluoromethyl)cyclopropyl]methylamine hydrochloride (1667 mg, 9.49 mmol), 3-(5-bromopyrazin-2-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (3000 mg, 9.55 mmol), and sPhos-Pd-G3 (836 mg, 0.950 mmol) was added to tBuONa 1 M THF solution (14.3 mL, 28.6 mmol). The mixture was degassed with nitrogen for 1 min and stirred at 100 °C under a nitrogen atmosphere for 12 h. The mixture was evaporated and purified by RP-HPLC to give the title compound (1.9 g, 53% yield) as a yellow solid. MS (ESI): m / z = 373.1 [M+H] +

[0429] Example B.36

[0430] 3-[4-(4-chloro-2-methylsulfonyl-phenyl)phenyl]azacyclobutane; 4-methylbenzenesulfonic acid

[0431] A solution of tert-butyl 3-[4-(4-chloro-2-methylsulfonyl-phenyl)phenyl]azacyclobutane-1-carboxylate (100.0 g, 237 mmol) and PTSA (44.89 g, 260.7 mmol) in EtOAc (1.7 L) was stirred at 80 °C for 12 h and then filtered. The filter cake was treated with EtOAc (1 L) and dried under vacuum to give the title compound (54 g, 71% yield) as a white solid. MS (ESI): m / z = 322.1 [M–TsOH+H] +

[0432] Step a): 3-(4-bromophenyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0433] To a mixture of 4-bromophenylboronic acid (CAS RN: 5467-74-3; 200.04 g, 996.08 mmol) and tert-butyl 3-iodozacyclobutane-1-carboxylate (CAS RN: 254454-54-1; 141.0 g, 498.04 mmol) in 2-propanol (500 mL), racemic-(1R,2R)-2-aminocyclohexane-1-ol (3.44 g, 29.88 mmol) and nickel(II) iodide (9.34 g, 29.88 mmol) were added. Under N2 and while maintaining a temperature below 30 °C, a mixture of sodium bis(trimethylsilyl)amide in THF (1 L, 1000 mmol) was slowly added to the reaction mixture. The resulting mixture was stirred at 25°C for 30 min, then heated to 80°C and stirred for 12 h. The reaction mixture was poured onto H₂O (3 L) and EtOAc (3 L), and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 2 L). The combined organic phases were evaporated and purified by FC (SiO₂; PE / EtOAc) to give the title compound (140 g, 90% yield) as a grayish-white solid. MS (ESI): m / z = 256.1 [M– t Bu+H] +

[0434] Step b): 3-[4-(4-chloro-2-fluoro-phenyl)phenyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0435] Pd(PPh3)2Cl2 (9.37 g, 12.81 mmol) was added to a solution of tert-butyl 3-(4-bromophenyl)azacyclobutane-1-carboxylate (80.0 g, 256.25 mmol), 4-chloro-2-fluorophenylboronic acid (89.36 g, 512.49 mmol), and Na2CO3 (54.32 g, 512.49 mmol) in 1,4-dioxane (1.6 L mL) and water (160 mL). The mixture was then stirred at 100 °C for 12 h under N2 and filtered. The filtrate was evaporated, and the residue was treated with water (2 L) and extracted with DCM (3 × 2 L). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. Grinding with PE (300 mL) at 25 °C yielded the title compound (50 g, 54% yield). MS (ESI): m / z = 306.1 [M– t Bu+H] +

[0436] Step c): 3-[4-(4-chloro-2-methylthio-phenyl)phenyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0437] NaSMe (63.14 g, 900.82 mmol) was added to a solution of tert-butyl 3-[4-(4-chloro-2-fluoro-phenyl)phenyl]azacyclobutane-1-carboxylate (150.0 g, 414.55 mmol) in DMSO (1.5 L) at 0 °C. The mixture was stirred at 25 °C for 12 h and then poured into water (5 L). The aqueous layer was extracted with EtOAc (83 x 3 L) and poured into a saturated aqueous solution of NaClO4. The combined organic layers were washed with brine, filtered through Na2SO4, and evaporated to give the title compound (130 g, 80% yield) as a yellow oil. MS (ESI): m / z = 334.1 [M– t Bu+H] +

[0438] Step d): 3-[4-(4-chloro-2-methylsulfonyl-phenyl)phenyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0439] 3-Chloroperoxybenzoic acid (172.6 g, 1000 mmol) was slowly added to a solution of tert-butyl 3-[4-(4-chloro-2-methylthio-phenyl)phenyl]azacyclobutane-1-carboxylate (130.0 g, 333.38 mmol) in DCM (1.3 L) at 25 °C. The mixture was stirred at this temperature for 4 h and then washed with a saturated aqueous solution of Na₂SO₃ (3 × 2 L). The aqueous layer was extracted with EtOAc (3 × 3 L). The combined organic layers were filtered through Na₂SO₄ and evaporated. Purification by FC (SiO₂; PE / EtOAc) gave the title compound (100 g, 71% yield) as a yellow oil. MS (ESI): m / z = 365.8 [M– t Bu+H] +

[0440] Example B.73

[0441] 3-[4-(2-chloro-4-methylsulfonyl-phenyl)phenyl]azacyclobutane; 4-methylbenzenesulfonic acid

[0442] To a solution of 3-[4-(2-chloro-4-methylsulfonyl-phenyl)phenyl]azacyclobutane-1-carboxylic acid tert-butyl ester (1.03 g, 2.32 mmol) in EtOAc (6 mL), p-toluenesulfonic acid monohydrate (551.41 mg, 2.9 mmol) was added, and the suspension was stirred and refluxed for 1 h. After cooling, the suspension was filtered. The filter cake was washed with a small amount of EtOAc and dried to give the title compound (0.940 g; 82.0%) as a yellow solid. MS (ESI): m / z = 322.1 [M+H] + .

[0443] Step a): 3-(4-bromophenyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0444] To a mixture of 4-bromophenylboronic acid (CAS RN: 5467-74-3; 200.04 g, 996.08 mmol) and tert-butyl 3-iodozacyclobutane-1-carboxylate (CAS RN: 254454-54-1; 141.0 g, 498.04 mmol) in 2-propanol (500 mL), racemic-(1R,2R)-2-aminocyclohexane-1-ol (3.44 g, 29.88 mmol) and nickel(II) iodide (9.34 g, 29.88 mmol) were added. Under N2 and while maintaining a temperature below 30 °C, a mixture of sodium bis(trimethylsilyl)amide in THF (1 L, 1000 mmol) was slowly added to the reaction mixture. The resulting mixture was stirred at 25°C for 30 min, then heated to 80°C and stirred for 12 h. The reaction mixture was poured onto H₂O (3 L) and EtOAc (3 L), and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 2 L). The combined organic phases were evaporated and purified by FC (SiO₂; PE / EtOAc) to give the title compound (140 g, 90% yield) as a grayish-white solid. MS (ESI): m / z = 256.1 [M– t Bu+H] +

[0445] Step b): 3-[4-(2-chloro-4-methanesulfonyl-phenyl)phenyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0446] A suspension of 2-(2-chloro-4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (829.55 mg, 2.62 mmol), tert-butyl 3-(4-bromophenyl)azacyclobutane-1-carboxylate (818 mg, 2.62 mmol), tetra(triphenylphosphine)palladium(0) (15.14 mg, 0.013 mmol), and K₂CO₃ (1.81 g, 13.1 mmol) in THF (10 mL) and water (1 mL) was heated at 110 °C in MW for 30 min under Ar conditions. The mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAC (2x). The combined organic layers were dried over MgSO₄, filtered, and evaporated. Purification by FC (SiO2; heptane / EtOAc) yielded the title compound (1.03 g; 88.5%) as a colorless oil. MS (ESI): m / z = 366.1 [M– t Bu+H] +

[0447] Example B.74

[0448] 2-[4-(azacyclobutane-3-yl)phenoxy]-4-(trifluoromethyl)pyrimidine; 4-methylbenzenesulfonic acid

[0449] To a 12 mL ethyl acetate solution (457 mg, 1.16 mmol) of 3-[4-[4-(trifluoromethyl)pyrimidin-2-yl]oxyphenyl]azacyclobutane-1-carboxylic acid tert-butyl ester (457 mg, 1.16 mmol), 4-methylbenzenesulfonic acid monohydrate (224.26 mg, 1.18 mmol) was added, and the mixture was heated under reflux overnight. The precipitate was filtered and washed with diethyl ether to give the title compound (476 mg, 71%) as a white solid. MS (ESI): m / z = 296.2 [M-TsOH+H]+

[0450] Step a) 3-[4-[4-(trifluoromethyl)pyrimidin-2-yl]oxyphenyl]azacyclobutane-1-carboxylic acid tert-butyl ester

[0451] To an ultradry N,N-dimethylformamide suspension (12 mL) of tert-butyl 3-(4-hydroxyphenyl)azacyclobutane-1-carboxylate (400 mg, 1.6 mmol), cesium carbonate (1.05 g, 3.22 mmol), and Cu (10.2 mg, 0.160 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (439.29 mg, 290.35 µL, 2.41 mmol) was added. The reaction mixture was stirred at 100 °C for 3.5 h. The reaction mixture was filtered, and the ultradry N,N-dimethylformamide (12 mL) was evaporated under high vacuum.

[0452] The crude residue was adsorbed onto dried Isolute HM-N and purified by rapid chromatography (solvent: heptane (A) / MTBE (B)) to give the title product (615 mg, 93%) as a pale yellow solid. MS (ESI): m / z = 340.2 [M-tBu +H]+

[0453] Step b) 3-(4-hydroxyphenyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0454] Add the following to a 250 mL vial equipped with a stir bar: tert-butyl 3-bromozacyclobutane-1-carboxylate (CAS: 1064194-10-0) (5000.0 mg, 21.18 mmol), 4-bromophenol (CAS: 106-41-2) (3663.76 mg, 21.18 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (237.39 mg, 0.21 mmol), NiCl2·ethylene glycol dimethyl ether (23.26 mg, 0.11 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (34.1 mg, 0.13 mmol), bis(trimethylsilyl)silyl-trimethylsilane (5265.77 mg, 21.18 mmol), and Na2CO3. DME (100 mL) of 4489.01 mg, 42.35 mmol was administered. The vial was sealed and the atmosphere was changed to nitrogen. The reaction was stirred under irradiation with a 34 W blue LED lamp (7 cm away) and the reaction temperature was maintained at 25 °C for 14 h using a cooling fan. The reaction was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by reversed-phase rapid chromatography and the product was lyophilized to the title compound (3200.0 mg, 12.84 mmol, yield 61%) as a grayish-white solid. MS (ESI): m / z = 194.0 [M-tBu+H] +

[0455] Example B.76

[0456] 5-(azacyclobutane-3-yl)-2-[(3S)-3-(trifluoromethyl)pyrrolidine-1-yl]pyridine; 4-methylbenzenesulfonic acid

[0457] A mixture (10 mL) of p-toluenesulfonic acid (1020.03 mg, 5.92 mmol) and 3-[6-[(3S)-3-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azacyclobutane-1-carboxylic acid tert-butyl ester (1000.0 mg, 2.69 mmol) in EtOAc was stirred at 80 °C for 12 h. The reaction was concentrated under vacuum to give the residue. The residue was dissolved in 35 mL of water and lyophilized to give the title compound (1450.0 mg, 2.36 mmol, 87% yield) as a pale yellow solid. MS (ESI): m / z = 272.2 [M-TsOH +H] +

[0458] Step a) 3-[6-[(3S)-3-(trifluoromethyl)pyrrolidine-1-yl]-3-pyridyl]azacyclobutane-1-methyl tert-butyl ester

[0459] Add tert-butyl 3-bromozacyclobutane-1-carboxylate (2392.3 mg, 10.13 mmol), 5-bromo-2-[3-(trifluoromethyl)pyrrolidone-1-yl]pyridine (2300.0 mg, 7.79 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (87.37 mg, 0.08 mmol), NiCl2·dtbbpy (15.51 mg, 0.04 mmol), Na2CO3 (1652.17 mg, 15.59 mmol), and bis(trimethylsilyl)silyl-trimethylsilane (1938.05 mg, 7.79 mmol) to an 8 mL vial equipped with a stir bar, followed by 25 mL of DME. Seal the vial and place it under nitrogen atmosphere. The reaction was stirred under irradiation with a 34 W blue LED lamp (7 cm away), and the reaction temperature was maintained at 25 °C for 14 h using a cooling fan. The mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (fast silica gel column, 0% to 30% ethyl acetate / petroleum ether gradient eluent @ 40 mL / min) to give the racemic product tert-butyl 3-[6-[racemic-3-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azacyclobutane-1-carboxylate, which is a yellow solid. The enantiomers were separated by a chiral SFC (mobile phase: supercritical CO2 containing 25% MeOH (0.1% NH3, H2O), flow rate: 240 g / min, circulation time: 4.3 min, total time: 65 min, single injection volume: 12.0 ml, back pressure: 100 bar to maintain CO2 in the supercritical flow) to give the title enantiomer (1050.0 mg, 2.83 mmol, yield 36%) (arbitrary partition stereochemistry) (optical rotation: +0.0325°). MS (ESI): m / z = 372.2 [M+H) +

[0460] The second enantiomer, 3-[6-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azacyclobutane-1-carboxylic acid tert-butyl ester (1050.0 mg, 2.83 mmol, yield 36%) (arbitrary partition stereochemistry) (optical rotation: -0.0333°), MS (ESI): m / z = 372.2 [M+H] +

[0461] Step b) 5-Bromo-2-[3-(trifluoromethyl)pyrrolidone-1-yl]pyridine

[0462] A DMSO solution (20 mL) of 5-bromo-2-fluoropyridine (2405.6 mg, 13.67 mmol), 3-(trifluoromethyl)pyrrolidine; hydrochloride (2000.0 mg, 11.39 mmol), and DIEA (3680.37 mg, 28.48 mmol) was stirred at 100 °C for 16 h. The reaction mixture was poured into water and extracted several times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography (elution with 0% to 30% ethyl acetate / petroleum ether gradient) to give the title compound (3.5 g, 11.86 mmol, 104% yield) as a pale yellow solid. MS (ESI): m / z = 249.9 [M+H] +

[0463] Example B.77

[0464] 5-(azacyclobutane-3-yl)-2-[(3R)-3-(trifluoromethyl)pyrrolidine-1-yl]pyridine; 4-methylbenzenesulfonic acid

[0465] A mixture (10 mL) of 3-[6-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azacyclobutane-1-carboxylic acid tert-butyl ester (1000.0 mg, 2.69 mmol) and p-toluenesulfonic acid (1020.03 mg, 5.92 mmol) in EtOAc was stirred at 80 °C for 12 h. The reaction was concentrated under vacuum to give the residue. The residue was dissolved in 35 mL of water and lyophilized to give the title compound (1414.0 mg, 2.3 mmol, 83% yield) as a pale yellow solid. MS (ESI): m / z = 272.1 (M-TsOH +H) +

[0466] Step a) 3-[6-[(3R)-3-(trifluoromethyl)pyrrolidine-1-yl]-3-pyridyl]azacyclobutane-1-methyl tert-butyl ester

[0467] Add tert-butyl 3-bromozacyclobutane-1-carboxylate (2392.3 mg, 10.13 mmol), 5-bromo-2-[3-(trifluoromethyl)pyrrolidone-1-yl]pyridine (2300.0 mg, 7.79 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (87.37 mg, 0.08 mmol), NiCl2·dtbbpy (15.51 mg, 0.04 mmol), Na2CO3 (1652.17 mg, 15.59 mmol), and bis(trimethylsilyl)silyl-trimethylsilane (1938.05 mg, 7.79 mmol) to an 8 mL vial equipped with a stir bar, followed by 25 mL of DME. Seal the vial and place it under nitrogen atmosphere. The reaction was stirred under irradiation with a 34 W blue LED lamp (7 cm away), and the reaction temperature was maintained at 25 °C for 14 h using a cooling fan. The mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (fast silica gel column, 0% to 30% ethyl acetate / petroleum ether gradient eluent @ 40 mL / min) to give the racemic product tert-butyl 3-[6-[racemic-3-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azacyclobutane-1-carboxylate, which is a yellow solid. The enantiomers were separated by a chiral SFC (mobile phase: supercritical CO2 containing 25% MeOH (0.1% NH3, H2O), flow rate: 240 g / min, circulation time: 4.3 min, total time: 65 min, single injection volume: 12.0 mL, back pressure: 100 bar to maintain CO2 in the supercritical flow) to give the title enantiomer (1050.0 mg, 2.83 mmol, yield 36%) (arbitrary partition stereochemistry) (optical rotation: -0.0333°). MS (ESI): m / z = 372.2 [M+H] +

[0468] The second enantiomer, 3-[6-[racemic-(3S)-3-(trifluoromethyl)pyrrolidin-1-yl]-3-pyridyl]azacyclobutane-1-carboxylic acid tert-butyl ester (1050.0 mg, 2.83 mmol, yield 36%) (arbitrary partition stereochemistry) (optical rotation: +0.0325°) MS (ESI): m / z = 372.2 [M+H] +

[0469] Step b) 5-Bromo-2-[3-(trifluoromethyl)pyrrolidone-1-yl]pyridine

[0470] A DMSO solution (20 mL) of 5-bromo-2-fluoropyridine (2405.6 mg, 13.67 mmol), 3-(trifluoromethyl)pyrrolidine; hydrochloride (2000.0 mg, 11.39 mmol), and DIPEA (3680.37 mg, 28.48 mmol) was stirred at 100 °C for 16 h. The reaction mixture was poured into water and extracted several times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the residue. The residue was purified by rapid silica gel chromatography (elution with 0% to 30% ethyl acetate / petroleum ether gradient) to give the title compound (3.5 g, 11.86 mmol, 104% yield) as a pale yellow solid. MS (ESI): m / z = 249.9 [M+H] + .

Claims

1. A compound of formula (I) (I) Or its pharmaceutically acceptable salt, wherein: U is CH2 or (CH2)2; V is CH2 or (CH2)2; W 1 and W 2 Each is independently selected from O and NH; X is (CH2) n CH2OCH2; Y is selected from NH, CH2, and (CH2)2; n is selected from 1, 2, and 3; A and C are each independently selected from: (i) 5- to 14-membered heteroaryl groups, comprising 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 3- to 14-membered heterocyclic groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon; (iii)C3-C 10 -cycloalkyl; and (iv)C6-C 10 -Aryl; B is selected from: (i) 4- to 7-membered monocyclic heterocycles containing 1, 2, or 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii) 7- to 11-membered spirocyclic heterocycles containing 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; L 1 and L 2 Each is independently selected from covalent bonds, O, NH, and CR. 6 R 7 CH2O, OCH2, CH2NH and NHCH2; R 1 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy group, halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6 -alkyl)2PO-, group and groups ; R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy group, halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group; R 3 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy group, halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6 -alkyl)2PO-, halo-C 1-6 -alkyl-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl and groups ; R 4 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy group, halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group; R 5a and R 5b Each is independently selected from C 1-6 -alkyl and halogenated-C 1-6 -alkyl; and R 6 and R 7 Each is independently selected from hydrogen and halogens.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected from: (i) 4- to 6-membered monocyclic heterocycles comprising 1 to 2 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii) 7- to 11-membered spirocyclic heterocycles containing 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein B is selected from: ; ;and .

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: (vii) U, V, X, and Y are all CH2; or (viii) Both U and V are CH2 and both X and Y are (CH2)2; or (ix)U and V are both CH2, X is (CH2)2, and Y is NH; or (x)U and V are both (CH2)2, and X and Y are both CH2; or (xi)U and V are both CH2, X is (CH2)3, and Y is NH; or (xii)U and V are both CH2, X is CH2OCH2, and Y is NH.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein U and V are both CH2, X is (CH2)2, and Y is NH.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: A is selected from: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii)C3-C 10 -cycloalkyl; and (iii)C6-C 10 -Aryl; L 1 Selected from covalent bonds, O, CH2, CH2O, and NHCH2; R 1 Selected from halogen, cyano, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6 -alkyl)2PO-, group and groups ; R 2 Selected from hydrogen, halogen, cyano and C 1-6 -alkyl; R 3 Selected from halogen, cyano, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, halogenated-C 1-6 -alkyl-C3-C 10 -Cycloalkyl and groups ; R 4 Selected from hydrogen, halogens and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Selected from C 1-6 -alkyl and halogenated-C 1-6 -alkyl; R 6 and R 7 Each is independently selected from hydrogen and halogens; W 1 Selected from O and NH; W 2 It is O; C is selected from: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 3- to 10-membered heterocyclic groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (iii)C3-C 10 -cycloalkyl; and (iv)C6-C 10 -Aryl; and L 2 Selected from covalent bonds, O, NH, CR 6 R 7 CH2O and CH2NH.

7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: A is selected from bicyclo[1.1.1]pentane, cyclopropyl, phenyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, thiazolyl, and triazolyl; L 1 Selected from covalent bonds, O, CH2, CH2O, and NHCH2; R 1 Selected from fluorine, chlorine, cyano, CF3, CF3CH2, CF3O, (CH3)2PO-, and other groups. and groups ; R 2 Selected from hydrogen, fluorine, chlorine, cyano, and methyl; R 3 Selected from fluorine, cyano, CF3, CF3O, trifluoromethylcyclopropyl and other groups ; R 4 Selected from hydrogen, fluorine, chlorine, and methyl; R 5a For CF3; R 5b Selected from methyl and CF3; W 1 Selected from O and NH; W 2 It is O; C is selected from 1,3,4-thiadiazolyl, aziridine, cyclopropyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, and pyrrolidinyl; and L 2 Selected from covalent bonds, O, NH, CH2, CF2, CH2O, and CH2NH.

8. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: A is selected from: (i) 5- to 6-membered heteroaryl groups, comprising 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) C3-C6-cycloalkyl; and (iii)C6-C 10 -Aryl; L 1 Selected from covalent bonds and CH2; R 1 Selected from halogens, halogenated -C 1-6 -alkyl, halo-C 1-6 -alkoxy group and groups ; R 2 Selected from hydrogen, halogens, and cyano groups; R 3 Selected from halogenated-C 1-6 -alkyl and groups ; R 4 Selected from hydrogen and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Halogenated-C 1-6 -alkyl; W 1 For NH; W 2 It is O; C is selected from: (i) a 5- to 6-membered heteroaryl group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii)C6-C 10 -Aryl; and L 2 It is a covalent bond.

9. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein: A is selected from bicyclo[1.1.1]pentane, phenyl, and pyridyl; L 1 Selected from covalent bonds and CH2; R 1 Selected from fluorine, CF3, CF3O, and functional groups and groups ; R 2 Selected from hydrogen, fluorine, chlorine, and cyano groups; R 3 Selected from CF3 and groups ; R 4 Selected from hydrogen and methyl; R 5a For CF3; R 5b For CF3; W 1 For NH; W 2 It is O; C is selected from phenyl and pyrazolyl groups; and L 2 It is a covalent bond.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (vii) U, V, X, and Y are all CH2; or (viii) Both U and V are CH2 and both X and Y are (CH2)2; or (ix)U and V are both CH2, X is (CH2)2, and Y is NH; or (x)U and V are both (CH2)2, and X and Y are both CH2; or (xi)U and V are both CH2, X is (CH2)3, and Y is NH; or (xii)U and V are both CH2, X is CH2OCH2, and Y is NH; A is selected from: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii)C3-C 10 -cycloalkyl; and (iii)C6-C 10 -Aryl; B is selected from: (i) 4- to 6-membered monocyclic heterocycles containing 1 to 2 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 7- to 11-membered spirocyclic heterocycles containing 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; C is selected from: (i) 5- to 10-membered heteroaryl groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) 3- to 10-membered heterocyclic groups, which contain 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (iii)C3-C 10 -cycloalkyl; and (iv)C6-C 10 -Aryl; L 1 Selected from covalent bonds, O, CH2, CH2O, and NHCH2; R 1 Selected from halogen, cyano, and halogenated-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, (C 1-6 -alkyl)2PO-, group and groups ; R 2 Selected from hydrogen, halogen, cyano and C 1-6 -alkyl; R 3 Selected from halogen, cyano, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy group, halogenated-C 1-6 -alkyl-C3-C 10 -Cycloalkyl and groups ; R 4 Selected from hydrogen, halogens and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Selected from C 1-6 -alkyl and halogenated-C 1-6 -alkyl; R 6 and R 7 Each is independently selected from hydrogen and halogens; W 1 Selected from O and NH; W 2 It is O; and L 2 Selected from covalent bonds, O, NH, CR 6 R 7 CH2O and CH2NH.

11. The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein: U and V are both CH2, X is (CH2)2, and Y is NH; A is selected from: (i) 5- to 6-membered heteroaryl groups, comprising 1, 2 or 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon; (ii) C3-C6-cycloalkyl; and (iii)C6-C 10 -Aryl; B is selected from: ; ;and ; C is selected from: (i) a 5- to 6-membered heteroaryl group comprising 1, 2, or 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; and (ii)C6-C 10 -Aryl; L 1 Selected from covalent bonds and CH2; R 1 Selected from halogens, halogenated -C 1-6 -alkyl, halo-C 1-6 -alkoxy group and groups ; R 2 Selected from hydrogen, halogens, and cyano groups; R 3 Selected from halogenated-C 1-6 -alkyl and groups ; R 4 Selected from hydrogen and C 1-6 -alkyl; R 5a Halogenated-C 1-6 -alkyl; R 5b Halogenated-C 1-6 -alkyl; W 1 For NH; W 2 It is O; and L 2 It is a covalent bond.

12. The compound of formula (I) according to claim 11, or a pharmaceutically acceptable salt thereof, wherein: U and V are both CH2, X is (CH2)2, and Y is NH; A is selected from bicyclo[1.1.1]pentane, phenyl, and pyridyl; B is selected from: ; ;and ; C is selected from phenyl and pyrazolyl groups; L 1 Selected from covalent bonds and CH2; R 1 Selected from fluorine, CF3, CF3O, and other groups and groups ; R 2 Selected from hydrogen, fluorine, chlorine, and cyano groups; R 3 Selected from CF3 and groups ; R 4 Selected from hydrogen and methyl; R 5a For CF3; R 5b For CF3; W 1 For NH; W 2 It is O; L 2 It is a covalent bond.

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of: (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-(trifluoromethyliminesulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethyliminesulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [3-[3-[difluoro-[4-(trifluoromethyl)phenyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-thiadiazol-2-yl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; [6-[(4-dimethylphosphoryl-2-fluoro-phenyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[5-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazin-2-yl]azacyclobutane-1-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [6-[(3-chloro-5-fluoro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[(5-fluoro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[4-(trifluoromethyl)thiazolyl]oxy-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[4-(trifluoromethylsulfonyl)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; [6-[(5-chloro-2-pyridinyl)oxy]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; 2-[3-[1-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)azacyclobutane-3-yl]-1-bicyclo[1.1.1]pentyl]-5-fluorobenzonitrile; 4-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[3-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[4-(trifluoromethoxy)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-(4-fluorophenyl)-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azacyclobutane-1-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-yl]methyl ketone; 3-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]azacyclobutane-1-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[[6-(trifluoromethyl)-3-pyridyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[5-[[1-(trifluoromethyl)cyclopropyl]methylamino]pyrazin-2-yl]azacyclobutane-1-yl]methyl ketone; [3-[4-(4-chloro-2-methylsulfonyl-phenyl)phenyl]azacyclobutane-1-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethyl)thiazolyl-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carboxylonitrile; 2-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carboxylonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 4-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; [6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; 4-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-3-fluorobenzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [7-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; [7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; 3-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[3-[3-[[6-(trifluoromethyl)-3-pyridyl]methyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carboxylonitrile; [6-[(5-chloro-3-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl) methyl ketone; 5-[[2-(6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl) methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[5-(trifluoromethoxy)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-8-oxa-6λ6-thia-2,5-diazaspiro[3.5]nonane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[4-(2,2,2-trifluoroethyl)phenyl]azacyclobutane-1-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-yl]methyl ketone; [6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl) methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[4-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [6-[(5-chloro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl) methyl ketone; [6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl) methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[(5-fluoro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; [3-[4-(2-chloro-4-methylsulfonyl-phenyl)phenyl]azacyclobutane-1-yl]-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl) methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[5-[[1-(trifluoromethyl)cyclopropyl]methylamino]pyrazin-2-yl]azacyclobutane-1-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[4-[4-(trifluoromethyl)pyrimidin-2-yl]oxyphenyl]azacyclobutane-1-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[6-[3-(trifluoromethyl)azacyclobutane-1-yl]-3-pyridyl]azacyclobutane-1-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[6-[(3S)-3-(trifluoromethyl)pyrrolidone-1-yl]-3-pyridyl]azacyclobutane-1-yl] methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[6-[(3R)-3-(trifluoromethyl)pyrrolidone-1-yl]-3-pyridyl]azacyclobutane-1-yl] methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azacyclobutane-1-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptane-6-yl)-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-yl]methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[3-[4-(2,2,2-trifluoroethyl)phenyl]azacyclobutane-1-yl] methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azacyclobutane-1-yl]methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (7,7-dioxo-7λ6-thia-2-azaspiro[3.5]nonane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[3-[4-(2,2,2-trifluoroethyl)phenyl]azacyclobutane-1-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azacyclobutane-1-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[6-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; (2,2-Dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone; and (2,2-dioxo-2λ6-thia-7-azaspiro[3.5]nonane-7-yl)-[6-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl]methyl ketone.

14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of: (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[3-[3-[4-(trifluoromethylsulfonyl)phenyl]-1-bicyclo[1.1.1]pentyl]azacyclobutane-1-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyliminosulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3,4]octane-2-yl)-[3-[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]azacyclobutane-1-yl]methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-yl] methyl ketone; 2-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; 4-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; [6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-yl]-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl) methyl ketone; 5-[[2-(6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptane-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone; and (6,6-dioxo-6λ6-thia-2,5-diazaspiro[3.4]octane-2-yl)-[6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-yl] methyl ketone.

15. A method for manufacturing a compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, said method comprising: (a) making an amine of formula 1, wherein R 1 R 2 A, B and L 1 As defined in claim 1, With the compound of formula 2, wherein U, V, X and Y are as defined in claim 1, The reaction occurs in the presence of a base; or (b) making a compound of formula (2a), wherein U, V, X and Y are as defined in claim 1, With compound of formula 1a, where R 1 R 2 A, B and L 1 As defined in claim 1, The reaction occurs in the presence of a base. To form the compound of formula (I).

16. The compound of formula (I) according to any one of claims 1 to 14, manufactured according to the method of claim 15.

17. The compound of formula (I) according to any one of claims 1 to 14, which is used as a therapeutically active substance.

18. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 14 and a therapeutically inert carrier.

19. Use of the compound of formula (I) according to any one of claims 1 to 14 for the treatment or prevention of diseases and ailments associated with MAGL.

20. The compound of formula (I) according to any one of claims 1 to 14, for the treatment or prevention of diseases and ailments associated with MAGL.

21. Use of the compound of formula (I) according to any one of claims 1 to 14 in the preparation of a medicament for the treatment or prevention of diseases and ailments associated with MAGL.

22. A method for treating or preventing diseases and disorders associated with MAGL in a human patient, the method comprising administering to the human patient an effective amount of the compound of formula (I) according to any one of claims 1 to 14.

23. The present invention as described above.

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