Cyclic cyanoenone derivatives as KEAP1 modulators

Abstract

The present invention relates to a cyclic cyanoketene derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R 2 、R 3 、R 4 and m are as defined herein. The present invention also relates to pharmaceutical compositions comprising cyclic cyanoenone derivatives of formula (I) and their use in therapy.

Description

[0001] The present invention relates to cyclic cyanoenone derivatives, pharmaceutical compositions comprising the cyclic cyanoenone derivatives, and cyclic cyanoenone derivatives for use in therapy.

[0002] Nuclear factor erythroid 2-related factor 2 (NRF2 (gene name: NFE2L2) is a basic leucine zipper (bZIP) transcription factor and a member of the Cap'n'Collar (CNC) transcription factor family. It acts as a master regulator of the cellular response to oxidative stress. Oxidative stress occurs when the cumulative damage caused by free radicals generated in response to physiological stress is no longer adequately neutralized by antioxidants, leading to lipid peroxidation and cellular damage. Oxidative stress is implicated in a variety of pathologies, including neurodegenerative diseases, cardiovascular disease, cancer, and diabetes, most of which are age-related.

[0003] Under normal physiological conditions, Kelch-like ECH-associated protein 1 (KEAP1), a repressor protein that binds to cytoplasmic actin, maintains low levels of NRE2 by promoting its CUL3-RBX1-mediated ubiquitination and subsequent proteasomal degradation. Under conditions of oxidative stress, oxidation of the sulfhydryl group on a specific cysteine ​​in KEAP1 or phosphorylation of KEAP1 and / or NRF2 induces KEAP1 to release NRE2. Freed from KEAP1, NRF2 is stabilized and translocated from the cytoplasm to the nucleus via a two-component nuclear localization signal, where it transactivates the expression of more than 200 cellular defense, repair, and detoxification enzymes, such as heme oxygenase 1, glutathione S-transferase, ferritin, and glutamate-cysteine ​​ligase. NRF2 binds to antioxidant response elements (AREs) located in the promoter regulatory regions of these genes. This coordinated and rapid upregulation of multiple genes ensures a robust response to multiple types of cellular stress.

[0004] In addition to its role in responding to oxidative and electrophilic stress, the KEAP-NRF2 system has been shown to regulate other key processes triggered in response to oxidative stress, including: autophagy; mitophagy; mitochondrial dysfunction; inflammation; and dysregulation of proteostasis leading to protein aggregation. Thus, the KEAP1 / NRF2 system appears to not only trigger mechanisms that reduce oxidative stress but also eliminate oxidatively damaged proteins.

[0005] There is substantial evidence that impaired NRF2 activation in neurodegenerative diseases / aging leads to redox homeostasis dysfunction, mitochondrial dysfunction, and autophagy. There is extensive pharmacological / genetic validation supporting the rescue of dysfunction of these mechanisms by NRF2 activation. Nrf2 nuclear trafficking has been shown to be impaired in a wide range of neurodegenerative diseases, as demonstrated in control and FRDA patient cells under basal conditions and during oxidative stress (Abeti et al., Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models. Front. Cell. Neurosci. 2018, 12: 188-198).

[0006] Overexpression of NRF2, inhibition of KEAP1, and small molecule pharmacological activators of NRF2 have shown protective effects in a wide range of animal models of neurodegenerative diseases. Nrf2-deficient cells and Nrf2 knockout mice are significantly more susceptible to the effects of malonate and 3NP and show increased transcription of astrocytes that regulate antioxidant response elements (AREs). Pre-activation of AREs by intrastriatal transplantation of astrocytes that overexpress Nrf2 before injury confers surprising protection against mitochondrial complex II inhibition (Calkins et al., Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc. Natl. Acad. Sci. USA 2005, 102(1): 244-249). Dopaminergic neurons from Nrf2- / -deficient mice are more susceptible to the neurotoxic effects of MPTP (Burton et al., In vivo modulation of the Parkinsonian phenotype by Nrf2. Neurotoxicology 2006, 27(6): 1094-1100; Chen et al., Nrf2-mediated Neuroprotection in the MPTP Mouse Model of Parkinson's Disease: Critical Role for the Astrocyte. Proc. Natl. Acad. Sci. USA, 2009, 106(8): 2933-2938) and 6-OHDA (Jakel et al., 2007) mouse models. Overexpression of Nrf2 in astrocytes protects against MPTP toxicity (Chen et al. Nrf2-mediated Neuroprotection in the MPTP Mouse Model of Parkinson's Disease: Critical Role for the Astrocyte. Proc. Natl. Acad. Sci. USA, 2009, 106(8): 2933-2938).Overexpression of Nrf2 reduces α-synuclein accumulation in the SN region (Gan et al., Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J Neurosci. 2012, 32(49): 17775-17778). In the rAAV-α-synuclein model, Nrf2 deficiency leads to increased α-synuclein aggregation, increased inflammation and neuronal death (Lastres-Becker et al. Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease. Antioxid Redox Signal. 2016, 25(2): 61-77). Overexpression of Nrf2 or its DNA-binding dimerization partner Maf-S and RNAi knockdown of Keap1 restore motor activity in flies expressing α-synuclein. α-Synuclein-induced dopaminergic neuron loss is inhibited by Maf-S overexpression or keap1 heterozygotes (Barone et al. Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease. Dis Model Mech. 2011, 4(5): 701-707). An AT-Nrf2 model (a model of amyloidosis and tauopathies) exhibits increased oxidative stress / neuroinflammatory markers, LTP, and spatial memory deficits in the brain (Rojo et al. NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology. Redox Biol. 2017, 13: 444-451).Intrahippocampal injection of alentiviral vector expressing Nrf2 improves spatial learning and alleviates astrocytosis in the APPxPS-1 Tg model of AD (Kanninen et al. Intrahippocampal injection of alentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 2009, 106(38): 16505-16510).

[0007] (Dimethyl fumarate - the active ingredient is monomethyl fumarate) is a weak activator of Nrf2 that has been approved for the treatment of relapsing-remitting multiple sclerosis. In a Phase II trial for the treatment of Friedreich's ataxia, the Nrf2 activator omaveloxolone (RTA) achieved the primary endpoint of change in the modified Friedreich Ataxia Rating Scale (mFARS) after 48 weeks of treatment compared to placebo.

[0008] Small molecules that promote NRF2 activation by blocking the NRF2-KEAP1 interaction (protein-protein inhibitors) or mimicking sulfhydryl oxidation on specific cysteines of KEAP1 (electrophiles) are expected to target multiple pathways that contribute to neuronal dysfunction and loss in a wide range of neurodegenerative disorders, including: Alzheimer's disease; amyotrophic lateral sclerosis; Down syndrome; Friedreich's ataxia; frontotemporal dementia; Huntington's disease; Parkinson's disease (reviewed in Johnson and Johnson, Nrf2--a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med. 2015, 88(Pt B): 253-267; Li et al., Reasonably activating Nrf2: A long-term, effective and controllable strategy for neurodegenerative diseases. Eur. J. Med. Chem. 2020, 185: 111862-111880). The use of Nrf2 activators is expected to delay onset, modify disease progression, and / or alleviate symptoms associated with these diseases.

[0009] Small molecules that promote NRF2 activation are known in the art. See, for example, WO 2019 / 104030 and WO 2019 / 122265. Although these compounds can be used, there is still a need for other safe and effective NRF2 activators.

[0010] In one aspect, the present invention provides a compound according to formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt or solvate thereof,

[0013] in:

[0014] R 1 and R 2 are independently H, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, -NR 5 -C 1-6 Alkyl, C 3-6 Cycloalkyl or a 3-6 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl, -OC 1-6 Alkyl and C 3-6 Each cycloalkyl group is independently optionally substituted with one or more halogens, and wherein the heterocycle is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-6 Alkyl and -OC 1-6 alkyl;

[0015] or R 1 and R 2 Together with the carbon to which they are bonded, they form C 3-6 Cycloalkyl or a 3-6 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, and wherein the C 3-6 Cycloalkyl and 3-6 membered saturated heterocyclic rings are optionally substituted by one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl and -OC 1-6 alkyl;

[0016] R 3 It is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10Aryl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 6 replace;

[0017] R 4 It is NR 7 R 8 NR 7 C(O)R 8 NR 7 S(O) n R 8 、CONR 9 R 10 、S(O) n NR 9 R 10 、C 6-10 Aryl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 11 replace;

[0018] or R 3 and R 4 Together with the carbon to which they are bonded, they form C 3-8 Cycloalkyl or a 3-11 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein said S is optionally oxidized to SO or SO2, and wherein said C 3-8 The cycloalkyl group and the 3-11 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 12 replace;

[0019] R 5 is H or C optionally substituted by one or more halogens 1-6 alkyl;

[0020] R 6 Halogen, hydroxyl, -C 1-6 Alkyl, -OC 1-6 Alkyl, -S(O) n C 1-6 Alkyl, -NR 5 -C 1-6 Alkyl, -C 6-10 Aryl or -OC6-10 Aryl, wherein the -C 1-6 The alkyl group is optionally substituted with one or more halogens, and wherein the -C 6-10 Aryl and -OC 6-10 The aryl group is optionally substituted by 1 to 4 substituents R 13 replace;

[0021] R 7 It is H, -C 1-6 Alkyl, -C 6-10 Aryl or 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the -C 1-6 Alkyl and the -C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said -C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-4 substituents R 13 replace;

[0022] R 8 It is H, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, -C 6-10 Aryl or 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the -C 1-6 Alkyl, -C 3-8 Cycloalkyl, -C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-4 substituents R 13 replace;

[0023] R 9 It is H, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, -C 6-10 Aryl or 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the -C 1-6 Alkyl, the -C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said -C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-4 substituents R 13 replace;

[0024] R 10 It is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10Aryl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl, the C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 13 replace;

[0025] Each R 11 and R 12 Independently selected from:

[0026] (1)-C 1-6 alkyl,

[0027] (2) halogens,

[0028] (3) Oxo,

[0029] (4)-(CH2) p C 3-6 Cycloalkyl,

[0030] (5)-(CH2) p C 6-10 Aryl,

[0031] (6)-(CH2) p het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N

[0032] (7)-(CH2) p -OR 14 ,

[0033] (8)-(CH2) p -NR 15 R 16 ,

[0034] (9)-(CH2) p -C(O)NR 17 R 18 ,

[0035] (10)-(CH2) p -S(O) n NR 17 R 18

[0036] (11)-(CH2) p -NR 17 C(O)R 18 ,

[0037] (12)-(CH2) p -NR 17 SO2R 伟 ,

[0038] (13)-(CH2) p -C(O)R 19 ,

[0039] (14)-(CH2) p -S(O) n R 19

[0040] (15)-(CH2) p -C(O)OR 20 and

[0041] (16)-(CH2) p -CN;

[0042] wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 The aryl group and the 3-9 membered heterocyclic ring are each independently substituted by one or more substituents selected from halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 Alkyl, and wherein the -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl and -SC 1-6 The alkyl group is optionally substituted with one or more halogens or one or more hydroxy groups;

[0043] or in C 3-8 Two R on adjacent atoms of a cycloalkyl group or a 3-11 membered saturated or unsaturated heterocyclic ring 12 The substituents, together with the ring atoms to which they are bound, form a fused bicyclic ring system which is optionally substituted by one or more substituents R 21 replace;

[0044] or in C 3-8 Two R on the same atom of a cycloalkyl group or a 3-11 membered saturated or unsaturated heterocyclic ring 12 The substituents, together with the ring atoms to which they are bound, form a spirobicyclic ring system which is optionally substituted by one or more substituents R 22 replace;

[0045] or in C 3-8 Two R on different atoms of a cycloalkyl group or a 3-11 membered saturated or unsaturated heterocyclic ring 12The substituents, together with the ring atoms to which they are bound, form a bridged bicyclic ring system which is optionally substituted with one or more substituents R 23 replace;

[0046] R 13 Is halogen, hydroxyl, nitrile, -C 1-6 Alkyl, -OC 1-6 Alkyl, -S(O) n R 24 、-NR 25 R 26 、-S(O) n NR 25 R 26 、C(O)NR 25 R 26 、-OC 3-8 Cycloalkyl, -C 3-8 Cycloalkyl, -C 6-10 Aryl or -OC 6-10 Aryl, wherein the -C 1-6 Alkyl and the -C 3-8 Each occurrence of cycloalkyl is independently optionally substituted with one or more halogens, and wherein said -C 6-10 Aryl and -OC 6-10 Aryl is optionally substituted with 1 to 4 substituents selected from halogen, hydroxy, -C 1-6 Alkyl and -OC 1-6 alkyl;

[0047] R 14 It is H, -C 1-6 Alkyl or -C 3-8 Cycloalkyl, the -C 1-6 Alkyl and -C 3-8 Cycloalkyl is optionally substituted with one or more halogens;

[0048] R 15 is H or -C optionally substituted by one or more halogens 1-6 alkyl;

[0049] R 16 It is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl or 5-8 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms independently selected from O, S and N, wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and 5-8 membered heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl and -OC 1-6alkyl;

[0050] R 17 is H or C optionally substituted by one or more halogens 1-6 alkyl;

[0051] R 18 、R 19 and R 20 are independently H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 6-12 Aryl or 5-10 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms independently selected from O, S and N, wherein said -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 6-12 Aryl and 5-10 membered heteroaryl are each optionally independently substituted by one or more substituents R 27 replace;

[0052] Each R 21 、R 22 and R 23 are independently selected from H, halogen, hydroxy, -C 1-6 Alkyl and -OC 1-6 Alkyl, wherein the -C 1-6 Alkyl and -OC 1-6 Each alkyl group is optionally substituted independently with one or more substituents selected from halogen, hydroxyl and -OC 1-6 alkyl;

[0053] R 24 Yes-C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 6-10 Aryl or 5-8 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms independently selected from O, S and N, wherein said -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 6-10 Aryl and 5-8 membered heteroaryl are each independently substituted by one or more substituents selected from halogen, hydroxyl, -C 1-6 Alkyl and -OC 1-6 alkyl;

[0054] R 25 is H or -C optionally substituted by one or more halogens 1-6 alkyl;

[0055] R26 It is H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 6-10 Aryl or 5-8 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms independently selected from O, S and N, wherein said -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 6-10 Aryl and 5-8 membered heteroaryl are each independently substituted by one or more substituents selected from halogen, hydroxyl, -C 1-6 Alkyl and -OC 1-6 alkyl;

[0056] R 27 Is halogen, hydroxyl, nitrile, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C(O)NHC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 6-10 Aryl, -OC 6-10 Aryl, -OC 1-2 Alkyl C 6-10 Aryl or 5-8 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms independently selected from O, S and N, wherein said -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 6-10 Each occurrence of aryl and 5-8 membered heteroaryl is independently substituted with one or more substituents selected from halogen, hydroxy, nitrile, -C 1-6 Alkyl, -OC 1-6 Alkyl and -N(C 1-6 alkyl)2, wherein the -C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently substituted with one or more halogens;

[0057] m is 0, 1, or 2;

[0058] Each n is independently 0, 1 or 2 and

[0059] Each p is independently 0, 1, or 2;

[0060] The premise is that compounds are not included

[0061] In another aspect, the present invention provides a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

[0062] The compound of formula (I) or its pharmaceutically acceptable salt or solvate can be used for treatment. In particular, the compound of formula (I) or its pharmaceutically acceptable salt or solvate can be used to treat or prevent diseases mediated by Nrf2 activation in patients. Therefore, the compound of formula (I) or its pharmaceutically acceptable salt or solvate can be used, for example, to treat or prevent neurodegenerative diseases, inflammatory diseases, autoimmune diseases or cancer in patients.

[0063] Therefore, in another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for treating or preventing a disease mediated by Nrf2 activation in a patient. The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for treating or preventing a neurological disease, inflammatory disease, autoimmune disease or cancer in a patient. The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for treating or preventing a neurological disease in a patient. The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for treating a neurodegenerative disease in a patient, wherein the neurodegenerative disease is selected from Friedreich's ataxia, amyotrophic lateral sclerosis, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, peripheral neuropathy and hearing loss.

[0064] The present invention further provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one, two, three or more other therapeutic agents.

[0065] The terms used herein have their ordinary meanings, and the meaning of such terms is independent at each occurrence thereof. Despite this and unless otherwise indicated, the following definitions apply throughout this specification and claims. Chemical name, common name and chemical structure are used interchangeably to describe identical structures. If chemical structure and chemical name are used to refer to a compound and there is ambiguity between the structure and the name, the structure shall prevail. Unless otherwise indicated, these definitions apply regardless of whether a term is used alone or in combination with other terms. Therefore, the definition of "alkyl" applies to the "alkyl" portion of "alkyl" as well as "hydroxyalkyl", "haloalkyl", "-O alkyl" and the like.

[0066] As used herein and throughout this disclosure, unless otherwise indicated, the following terms shall be understood to have the following meanings:

[0067] The term "alkyl" as used herein refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced by a bond. The alkyl group may be straight chain or branched. In one embodiment, the alkyl group contains from about 1 to about 6 carbon atoms (C 1-6Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, and neohexyl. In one embodiment, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched. Unless otherwise indicated, the alkyl group is unsubstituted.

[0068] The term "OC 1-6 "Alkyl" means a group in which the term "C 1-6 "Alkyl" is as defined above.

[0069] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and one of its hydrogen atoms being replaced by a key. An alkenyl group can be straight or branched. In one embodiment, an alkenyl group contains 2 to 6 carbon atoms (C2-C6 alkenyl). Examples of alkenyl groups include vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. Unless otherwise noted, an alkenyl group is unsubstituted.

[0070] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and one of its hydrogen atoms being replaced by a key. An alkynyl group can be straight or branched. In one embodiment, an alkynyl group contains 2 to 6 carbon atoms (C2-C6 alkynyl). In another embodiment, an alkynyl group contains 2 to 3 carbon atoms (C2-C3 alkynyl). Examples of alkynyl groups include ethynyl, propynyl, 2-butynyl, and 3-methylbutynyl. Unless otherwise noted, an alkynyl group is unsubstituted.

[0071] The term "aryl" as used herein refers to an aromatic monocyclic or polycyclic ring system. In one embodiment, the aryl group contains 6-12 carbon atoms (C 6-12 In another embodiment, the aryl group contains 6-10 carbon atoms (C 6-10 In one embodiment, the aryl group may be optionally fused to a cycloalkyl or cycloalkanoyl group. Examples of aryl groups include phenyl and naphthyl. In one embodiment, the aryl group is phenyl. As used herein, the term "aryloxy" refers to a group having the formula -Oaryl, wherein the term "aryl" is as defined above.

[0072] The term "cycloalkyl" as used herein refers to a non-aromatic monocyclic or polycyclic ring system. In one embodiment, the cycloalkyl group contains 3 to 12 ring carbon atoms (C 3-12 In another embodiment, the cycloalkyl group contains 3 to 8 ring carbon atoms (C 3-8 In another embodiment, the cycloalkyl group contains 3 to 6 ring atoms (C3-6 Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl groups include 1-decalinyl, norbornyl, and adamantyl. The ring carbon atoms of the cycloalkyl group may be functionalized as carbonyl groups. An illustrative example of such a cycloalkyl group (also referred to herein as a "cycloalkanoyl" group) includes cyclobutanoyl:

[0073]

[0074] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I.

[0075] The term "haloalkyl" as used herein refers to an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group have been replaced by halogen. In one embodiment, a haloalkyl group has 1 to 6 carbon atoms (C 1-6 In another embodiment, the haloalkyl group is substituted with 1 to 3 F atoms. Examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2Cl, and -CCl3.

[0076] The term "hydroxyalkyl" as used herein refers to an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group have been replaced by an -OH group. In one embodiment, the hydroxyalkyl group has 1 to 6 carbon atoms (C 1-6 Examples of hydroxyalkyl groups include -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, and -CH2CH(OH)CH3.

[0077] As used herein, the term "5-12 membered heteroaryl ring containing 1-4 heteroatoms independently selected from O, S and N" refers to an aromatic monocyclic or bicyclic ring system containing 5-12 ring atoms, wherein 1-4 ring atoms are independently O, S or N and the remaining ring atoms are carbon atoms. In one embodiment, the heteroaryl ring is a 5-8 membered heteroaryl ring containing 1-3 heteroatoms independently selected from O, S and N. The heteroaryl groups are attached via a ring carbon atom, and any nitrogen atom of the heteroaryl group can be optionally oxidized to the corresponding N-oxide. Examples of 5 or 6 membered monocyclic heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, imidazolyl, 1,2,4-triazinyl, and the like, and all isomeric forms thereof. In another embodiment, the heteroaryl is an aromatic bicyclic ring system comprising 9 or 10 ring atoms, wherein 1-3 ring atoms are independently O, N or S and the remaining ring atoms are carbon atoms. The 9 or 10 membered bicyclic heteroaryl groups are attached via ring carbon atoms, and any nitrogen atom of the heteroaryl group may be optionally oxidized to the corresponding N-oxide. Examples of 9- or 10-membered bicyclic heteroaryl groups include imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, benzimidazolyl, quinazolinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolinyl, benzazaindolyl, benzothiazolyl, and the like, and all isomeric forms thereof.

[0078] As used herein, the term "3-11 membered saturated or unsaturated heterocycle containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2" means a non-aromatic monocyclic or polycyclic saturated or partially unsaturated ring system containing 3-11 ring atoms, wherein 1-4 ring atoms are independently O, S or N and the remaining ring atoms are carbon atoms. The heterocycle may be attached via a ring carbon or ring nitrogen atom. In one embodiment, the heterocycle is monocyclic and has 3-9 ring atoms. In another embodiment, the heterocycle is monocyclic and has 3-6 ring atoms. In another embodiment, the heterocycle is bicyclic and has 7-11 ring atoms. In yet another embodiment, the heterocycle is monocyclic and has 5 or 6 ring atoms. In one embodiment, the heterocycle is monocyclic. In another embodiment, the heterocycle is bicyclic. There are no adjacent oxygen and / or sulfur atoms in the ring system. Any -NH group in the heterocyclic ring may be present in a protected form, such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group, and the like; such protected heterocyclic groups are considered part of this invention. The heterocyclic ring may also include a heterocyclic ring as defined above fused to an aryl (e.g., benzene) or heteroaryl ring. The nitrogen or sulfur atom of the heterocyclic ring may optionally be oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Examples of monocyclic heterocycles include oxetanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, δ-lactam, δ-lactone, silacyclopentane, silapyrrolidine, and the like, and all isomers thereof.

[0079] The ring carbon atoms of the heterocyclic group may be functionalized as carbonyl groups. An illustrative example of such a heterocyclic group is:

[0080]

[0081] In one embodiment, the heterocyclic group is a 5-membered monocyclic heterocycle. In another embodiment, the heterocyclic group is a 6-membered monocyclic heterocycle. The term "3-8 membered monocyclic heterocycle" refers to a monocyclic heterocycle having 3-8 ring atoms. The term "3-6 membered monocyclic heterocycle" refers to a monocyclic heterocycle having 3-6 ring atoms. The term "7-11 membered bicyclic heterocycle" refers to a bicyclic heterocyclic group having 7-11 ring atoms. Unless otherwise indicated, the heterocycle is unsubstituted.

[0082] As used herein, the term "substituted" means that one or more hydrogen atoms on the designated atom are replaced with a designated set of alternatives, provided that the designated atom's normal valency under the existing conditions is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A "stable compound" or "stable structure" is intended to mean a compound that is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0083] As used herein, the term "in substantially purified form" refers to the physical state of a compound after isolating the compound from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof. The term "in substantially purified form" also refers to the physical state of a compound after obtaining the compound from one or more purification methods described herein or known to a skilled artisan (e.g., chromatography, recrystallization, etc.), with sufficient purity to be characterized by standard analytical techniques described herein or known to a skilled artisan.

[0084] It should also be noted that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein are assumed to have the sufficient number of hydrogen atoms to satisfy the valences.

[0085] When a functional group in a compound is referred to as "protected," this means that the group is present in a modified form to prevent undesirable side reactions at the protected site when the compound is reacted. Suitable protecting groups are known to those of ordinary skill in the art and can be found in standard textbooks such as, for example, TW Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0086] When any substituent or variable (e.g., alkyl, R 6 When ) occurs more than one time in any constituent or in formula (I), its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0087] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results directly from combination of the specified ingredients in the specified amounts.

[0088] ICs used in this article 50 It refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximal response in an assay measuring such response.

[0089] As used herein, the terms "subject" and "patient" are used interchangeably. The term "subject" refers to mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys such as cynomolgus monkeys, chimpanzees, and humans), and, for example, humans. The subject may also be a domestic animal (e.g., horse, cow, pig, etc.) or a pet (e.g., dog or cat).

[0090] As used herein, the term "therapeutic agent" refers to any agent that can be used to treat or prevent a disorder or one or more symptoms thereof. The term "therapeutic agent" includes the compounds provided herein. In some cases, a therapeutic agent can be an agent that is known to be useful, has been used, or is currently being used to treat or prevent a disorder or one or more symptoms thereof.

[0091] As used herein, the term "effective amount" refers to an amount of a compound of formula (I) and / or another therapeutic agent or its composition that effectively produces the desired treatment, improvement, inhibition or preventive effect when administered to a patient suffering from a viral infection or a virus-related disorder. In the conjoint therapy of the present invention, an effective amount can represent each independent medicament or a combination as a whole, in which the amount of all medicaments administered is effective together, but the component medicaments of the combination may not exist alone in an effective amount." therapeutically effective amount" can vary with, in particular, the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated.

[0092] As used herein, the term "treating" any disease or disorder means improving a disease or disorder present in a subject. In some cases, "treating" includes improving at least one physical parameter that may be discernible to the subject. In other cases, "treating" includes regulating the disease or disorder physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters) or in both aspects. In other cases, "treating" includes delaying the onset of a disease or disorder.

[0093]

[00146] The term "preventing" as used herein with reference to a disease or disorder means reducing the likelihood or severity of the disease or disorder.

[0094] In one embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is H, C 1-6 Alkyl, C 3-6 Cycloalkyl or a 3-6 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl and C 3-6Each cycloalkyl group is independently optionally substituted with one or more halogens, and wherein the heterocycle is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-6 Alkyl and -OC 1-6 alkyl;

[0095] In another embodiment, R 1 is H or C optionally substituted by one or more halogens 1-6 In another embodiment, R 1 is H. In another embodiment, R 1 In another embodiment, R 1 It's ethyl.

[0096] In another embodiment, R 1 It is C 3-6 Cycloalkyl or a 3-6 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 3-6 The cycloalkyl group is optionally substituted with one or more halogens, and wherein the heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-6 Alkyl and -OC 1-6 alkyl;

[0097] In another embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is H, C 1-6 Alkyl, C 3-6 Cycloalkyl or a 3-6 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl and C 3-6 Each cycloalkyl group is independently optionally substituted with one or more halogens, and wherein the heterocycle is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-6 Alkyl and -OC 1-6 alkyl;

[0098] In another embodiment, R 2 is H or C optionally substituted by one or more halogens 1-6 In another embodiment, R 2 is H. In another embodiment, R 2 In another embodiment, R 2 It's ethyl.

[0099] In another embodiment, R 2 It is C 3-6 Cycloalkyl or a 3-6 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 3-6 The cycloalkyl group is optionally substituted with one or more halogens, and wherein the heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-6 Alkyl and -OC 1-6 alkyl;

[0100] In another embodiment, R 1 is H and R 2 is C optionally substituted by one or more halogens 1-6 alkyl.

[0101] In another embodiment, R 1 is H and R 2 It's methyl.

[0102] In another embodiment, R 1 is H and R 2 It's ethyl.

[0103] In another embodiment, R 1 is C optionally substituted by one or more halogens 1-6 Alkyl and R2 is H.

[0104] In another embodiment, R 1 is methyl and R 2 It’s H.

[0105] In another embodiment, R 1 is ethyl and R 2 It’s H.

[0106] In another embodiment, R 1 and R 2 are each independently C optionally substituted by one or more halogens 1-6 alkyl.

[0107] In another embodiment, R 1 and R 2 They are all methyl.

[0108] In another embodiment, R 1 is methyl and R 2 It's ethyl.

[0109] In another embodiment, R 1 is ethyl and R 2 It's methyl.

[0110] In another embodiment, R 1 and R 2 Together with the carbon to which they are bonded, they form a cyclopropyl, cyclobutyl, or cyclopentyl group;

[0111] In another embodiment, R 1 and R 2 Together with the carbon to which they are bonded they form a cyclopropyl group.

[0112] In another embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 It is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 6 replace.

[0113] In another embodiment, R 3 is H, C1-6 alkyl or C3-8 cycloalkyl, wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl groups are optionally substituted independently with one or more halogens.

[0114] In another embodiment, R 3 is H or C optionally substituted by one or more halogens 1-6 alkyl.

[0115] In another embodiment, R 3 is H or methyl optionally substituted by one or more halogens.

[0116] In another embodiment, R 3 is C optionally substituted by one or more halogens 3-8 Cycloalkyl.

[0117] In another embodiment, R 3 is optionally substituted by 1-3 substituents R 6 Substituted C 6-10 Aryl.

[0118] In another embodiment, R 3 is optionally substituted by 1-3 substituents R6 Substituted phenyl.

[0119] In another embodiment, R 3 is a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, and the heterocyclic ring is optionally substituted by 1-3 substituents R 6 replace.

[0120] In another embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 It is NR 7 R 8 NR 7 C(O)R 8 NR 7 S(O) n R 8 、CONR 9 R 10 or S(O) n NR 9 R 10 , where R 7 -R 10 and n are as defined above.

[0121] In another embodiment, R 4 It is NR 7 R 8 or NR 7 C(O)R 8 , where R 7 and R 8 As defined above.

[0122] In another embodiment, R 4 It is NR 7 S(O) n R 8 , where R 7 、R 8 and n are as defined above.

[0123] In another embodiment, R 4 It is CONR 9 R 10 or S(O) n NR 9 R 10 , where R 9 、R 10 and n are as defined above.

[0124] In another embodiment, R 4 It is NR 7 R8 , where R 7 and R 8 are independently H or C 1-6 alkyl.

[0125] In another embodiment, R 4 It is NR 7 R 8 , where R 7 Is H or C 1-6 Alkyl and R 8 It is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 11 Substituted, where R 11 As defined above.

[0126] In another embodiment, R 4 It is NR 7 R 8 , where R 7 Is H or C 1-6 Alkyl and R 8 It is C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl groups are optionally substituted independently with one or more halogens.

[0127] In another embodiment, R 4 It is NR 7 R 8 , where R 7 Is H or C 1-6 Alkyl and R 8 is optionally substituted by 1-3 substituents R 11 Substituted C 6-10 Aryl, where R 11 As defined above.

[0128] In another embodiment, R 4 It is NR 7 R 8 , where R 7 Is H or C 1-6 Alkyl and R 8is a 3-8 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, and the heterocyclic ring is optionally substituted by 1-3 substituents R 11 Substituted, where R 11 As defined above.

[0129] In another embodiment, R 4 It is NR 7 C(O)R 8 , where R 7 and R 8 are independently H or C 1-6 alkyl.

[0130] In another embodiment, R 4 It is NR 7 C(O)R 8 , where R 7 Is H or C 1-6 Alkyl and R 8 It is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 11 Substituted, where R 11 As defined above.

[0131] In another embodiment, R 4 It is NR 7 C(O)R 8 , where R 7 Is H or C 1-6 Alkyl and R 8 It is C 1-6 Alkyl or C 3-8 Cycloalkyl, wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl groups are optionally substituted independently with one or more halogens.

[0132] In another embodiment, R 4 It is NR 7 C(O)R 8 , where R 7 Is H or C 1-6 Alkyl and R 8is optionally substituted by 1-3 substituents R 11 Substituted C6- 10 Aryl, where R 11 As defined above.

[0133] In another embodiment, R 4 It is NR 7 C(O)R 8 , where R 7 is H or methyl and R 8 is optionally substituted by 1-3 substituents R 11 Substituted C 6-10 Aryl, where R 11 As defined above.

[0134] In another embodiment, R 4 It is NR 7 C(O)R 8 , where R 7 is H or methyl and R 8 is optionally substituted by 1-3 substituents R 11 Substituted phenyl, wherein R 11 As defined above.

[0135] In another embodiment, R 4 It is NR 7 C(O)R 8 , where R 7 Is H or C 1-6 Alkyl and R 8 is a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, and the heterocyclic ring is optionally substituted by 1-3 substituents R 11 Substituted, where R 11 As defined above.

[0136] In another embodiment, R 4 It is C(O)NR 9 R 10 , where R 9 and R 10 are independently H or C 1-6 alkyl.

[0137] In another embodiment, R 4 It is C(O)NR 9 R 10 , where R 9 and R 10 is independently H or methyl.

[0138] In another embodiment, R 4It is C(O)NR 9 R 10 , where R 9 Is H or C 1-6 Alkyl and R 10 It is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said C 6-10 The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 11 Substituted, where R 11 As defined above.

[0139] In another embodiment, R 4 It is S(O) n NR 9 R 10 , where R 9 and R 10 are independently H or C 1-6 Alkyl and n are as defined above.

[0140] In another embodiment, R 4 It is S(O) n NR 9 R 10 , where R 9 and R 10 is independently H or methyl and n is as defined above.

[0141] In another embodiment, R 4 It is S(O) n NR 9 R 10 , where R 9 Is H or C 1-6 Alkyl and R 10 It is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2; wherein the C 1-6 Alkyl and the C 3-8 Cycloalkyl is optionally substituted independently with one or more halogens, and wherein said C 6-10The aryl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 11 substituted, where n and R 11 As defined above.

[0142] In another embodiment, R 4 is optionally substituted by 1-3 substituents R 11 Substituted C 6-10 Aryl.

[0143] In another embodiment, R 4 is optionally substituted by 1-3 substituents R 11 Substituted phenyl.

[0144] In another embodiment, R 4 is a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, and the heterocyclic ring is optionally substituted by 1-3 substituents R 11 replace.

[0145] In another embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 Together with the carbon to which they are bonded, they form C 3-8 Cycloalkyl or a 3-11 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein said S is optionally oxidized to SO or SO2, and wherein said C 3-8 The cycloalkyl group and the 3-8 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 12 Substituted, where R 12 As defined above. In a sub-embodiment of this embodiment, R 12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 alkyl.

[0146] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form a radical optionally substituted by 1 to 3 substituents R 12 Substituted C 3-8 Cycloalkyl, where R 12 As defined above.

[0147] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form a radical optionally substituted by 1 to 3 substituents R 12 Substituted cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, wherein R 12 As defined above.

[0148] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form a radical optionally substituted by 1 to 3 substituents R 12 Substituted cyclopentyl, wherein R 12 As defined above.

[0149] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form a radical optionally substituted by 1 to 3 substituents R 12 Substituted cyclohexyl, wherein R 12 As defined above.

[0150] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form a 3-11 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein said S is optionally oxidized to SO or SO2, and wherein said 3-11 membered saturated or unsaturated heterocyclic ring is optionally substituted by 1-3 substituents R 12 Substituted, where R 12 As defined above.

[0151] In another embodiment, R 3 and R 4Together with the carbon to which they are bound, they form a 3-8 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein said S is optionally oxidized to SO or SO2, and wherein said 3-8 membered saturated or unsaturated heterocyclic ring is optionally substituted by 1-3 substituents R 12 Substituted, where R 12 As defined above. In a sub-embodiment of this embodiment, R 12 Selected from hydroxyl, =C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 alkyl.

[0152] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form azetidine, piperidine, pyrrolidine, morpholine, tetrahydrofuran or tetrahydropyran, said azetidine, piperidine, pyrrolidine, morpholine, tetrahydrofuran and tetrahydropyran being optionally substituted with 1 to 3 substituents R 12 Substituted, where R 12 As defined above. In a sub-embodiment of this embodiment, R 12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 alkyl.

[0153] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form tetrahydrofuran or tetrahydropyran, which are optionally substituted by 1 to 3 substituents R 12 Substituted, where R 12 As defined above.

[0154] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form azetidine, piperidine, pyrrolidine or morpholine, which are optionally substituted by 1 to 3 substituents R 12 Substituted, where R 12 As defined above.

[0155] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form a spirocyclic carbocyclic or heterocyclic ring selected from:

[0156]

[0157] wherein the asterisk indicates the point of attachment of the spirocyclic carbocyclic or heterocyclic ring to the cyanoenone, the spirocyclic carbocyclic or heterocyclic ring optionally being substituted by 1-3 substituents R 12 Substituted, where R 12 As defined above. In a sub-embodiment of this embodiment, R 12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 alkyl.

[0158] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form a spirocyclic carbocyclic or heterocyclic ring selected from:

[0159]

[0160] wherein the asterisk indicates the point of attachment of the spirocyclic carbocyclic or heterocyclic ring to the cyanoenone, the spirocyclic carbocyclic or heterocyclic ring optionally being substituted by 1-3 substituents R 12 Substituted, where R 12 As defined above. In a sub-embodiment of this embodiment, R 12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 alkyl.

[0161] In another embodiment are compounds having Formula Ia-Id:

[0162]

[0163] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 、R 2 and R 12 As defined above. In a sub-embodiment of this embodiment, R 12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 alkyl.

[0164] In another embodiment are compounds having Formula Ia-Id:

[0165]

[0166] or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 As defined above. In a sub-embodiment of this embodiment, R12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 alkyl.

[0167] In another embodiment is a compound of Formula Ia:

[0168]

[0169] or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 As defined above. In a sub-embodiment of this embodiment, R 12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 In a subembodiment of this embodiment, R 12 Yes-C(O)-C 6-10 Aryl, -C(O)-het, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 In a subembodiment of this embodiment, R 12 Yes-C(O)-C 6-10 Aryl, -C(O)-het, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a heterocycle selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, imidazolyl and pyrazolyl, wherein said C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and het is optionally substituted independently with one or more substituents selected from halogen.

[0170] In another embodiment is a compound of Formula Ib:

[0171]

[0172] or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 As defined above. In a sub-embodiment of this embodiment, R 12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -C(O)-het, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 In a subembodiment of this embodiment, R 12 Yes-C(O)-C 6-10 Aryl, -C(O)-het, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic ring is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 In a subembodiment of this embodiment, R 12 Yes-C(O)-C 6-10 Aryl, -C(O)-het, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a heterocycle selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, imidazolyl and pyrazolyl, wherein said C 3-6 Cycloalkyl, C 6-10Each occurrence of aryl and het is optionally substituted independently with one or more substituents selected from halogen, hydroxy, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -OC 1-6 Alkyl and -SC 1-6 alkyl.

[0173] In another embodiment, R 3 and R 4 Together with the carbon to which they are bonded, they form C 3-8 Cycloalkyl or a 3-11 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, wherein the C 3-8 The cycloalkyl group and the 3-11 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 12 substituted, and wherein in C 3-8 Two R on adjacent atoms of a cycloalkyl group or a 3-11-membered saturated or unsaturated heterocycloalkyl group 12 The substituents, together with the ring atoms to which they are bound, form a fused bicyclic ring system which is optionally substituted by one or more substituents R 21 replace;

[0174] In another embodiment, R 3 and R 4 Together with the carbon to which they are bonded, they form C 3-8 Cycloalkyl or a 3-8 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, wherein the C 3-8 The cycloalkyl group and the 3-8 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 12 substituted, and wherein in C 3-8 Two R on adjacent atoms of a cycloalkyl group or a 3-8 membered saturated or unsaturated heterocyclic ring 12 The substituents, together with the ring atoms to which they are bound, form a fused bicyclic ring system which is optionally substituted by one or more substituents R 21 replace;

[0175] In another embodiment, R 3 and R 4 Together with the carbon to which they are bound, they form a radical optionally substituted by 1 to 3 substituents R 12 Substituted C 3-8 Cycloalkyl, wherein C 3-8 Two R on adjacent atoms of a cycloalkyl group 12The substituents, together with the ring atoms to which they are bound, form a fused bicyclic ring system which is optionally substituted by one or more substituents R 21 replace;

[0176] In another embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 Together with the carbon to which they are bound, they form a 3-11 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, wherein said S is optionally oxidized to SO or SO2, wherein said 3-11 membered saturated or unsaturated heterocyclic ring is optionally substituted by 1-3 substituents R 12 substituted, and wherein two R on adjacent atoms of a 3-11 membered saturated or unsaturated heterocyclic ring 12 The substituents, together with the ring atoms to which they are bound, form a fused bicyclic ring system which is optionally substituted by one or more substituents R 21 replace;

[0177] In another embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 Together with the carbon to which they are bound, they form a 3-8 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein said S is optionally oxidized to SO or SO2, wherein said 3-8 membered saturated or unsaturated heterocyclic ring is optionally substituted by 1-3 substituents R 12 substituted, and wherein two R on adjacent atoms of a 3-8 membered saturated or unsaturated heterocyclic ring 12 The substituents, together with the ring atoms to which they are bound, form a fused bicyclic ring system which is optionally substituted by one or more substituents R 21 replace;

[0178] In another embodiment is a compound of Formula IIa having the structure:

[0179]

[0180] or a pharmaceutically acceptable salt or solvate thereof, wherein

[0181] X 1 Yes O, OCR 12a R 12a , CR 12a R 12a O、CR 12a R 12a 、(CR 12a R 12a )2、C(O)、NR 12a 、CHR12a NR 12a or NR 12a CR 12a R 12a ;

[0182] X 2 It is O, CR 12a R 12a , C(O) or NR 12a ;

[0183] X 3 、X 4 、X 5 and X 6 Each independently is N or CR 23 , the prerequisite is that X 3 -X 6 No more than 2 of them can be N and

[0184] Each R 12a are independently H or C 1-6 Alkyl and

[0185] R 23 is 1-3 substituents independently selected from H, halogen, hydroxyl, C 3-6 Alkyl and -OC 1-6 Alkyl, wherein the -C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently substituted with one or more halogens,

[0186] or a pharmaceutically acceptable salt or solvate thereof.

[0187] In another embodiment is a compound of Formula IIa:

[0188]

[0189] or a pharmaceutically acceptable salt or solvate thereof, wherein

[0190] X 1 Is O or CR 12a R 12a ;

[0191] X 2 It's CR 12a R 12a , C(O) or NR 12a ;

[0192] X 3 、X 4 、X 5 and X 6 Each independently is N or CR 23 , the prerequisite is that X3 -X 6 No more than 2 of them can be N;

[0193] Each R 12a are independently H, optionally substituted with hydroxyl -C(O)C 1-6 Alkyl or -C 1-6 alkyl, and

[0194] Each R 23 are independently H, halogen, -C 1-6 Alkyl or -C 1-6 Halogenated alkyl.

[0195] In another embodiment is a compound of Formula IIa:

[0196]

[0197] or a pharmaceutically acceptable salt or solvate thereof, wherein

[0198] X 1 is O, where each R 12a and X 2 -X 6 In another embodiment of this sub-embodiment, X 1 Is O and X 2 It's CR 12a R 12a , where each R 12a and X 3 -X 6 In another embodiment of this sub-embodiment, X 1 It's O, X 2 It's CR 12a R 12a , where each R 12a Independently selected from the previously defined options, X 3 -X 5 It's CR 23 , where each R 23 are independently selected from the options defined previously, and X 6 is N. In another embodiment of this subembodiment, X 1 It's O, X 2 It is CH2, X 3 -X 5 It's CR 23 , where each R 23 are independently selected from the options defined previously, and X 6 It's N.

[0199] In another embodiment is a compound of Formula IIa:

[0200]

[0201] or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 It's O, X 2 Yes (CR 12a R 12a )2, where each R 12a are independently selected from the previously defined options and each X 3 -X 6 In another embodiment of this sub-embodiment, X 1 It's O, X 2 is CH2CH2, and X 3 -X 6 It's CR 23 , where each R 23 Independently selected from the previously defined options.

[0202] In another embodiment is a compound of Formula IIa:

[0203]

[0204] or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 It's CR 12a , X 2 It's CR 12a , where each R 12a are independently selected from the options defined previously, and X 3 -X 6 Each is independently selected from the options defined previously. In another embodiment of this sub-embodiment, X 1 It's O, X 2 is CH2CH2, and X 3 -X 6 It's CR 23 , where each R 23 Independently selected from the previously defined options.

[0205] In another embodiment is a compound of Formula IIa:

[0206]

[0207] or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is C(O) and X 2 It is NR 12a , where R 12a As defined above, and X 3 -X 6Each is independently selected from the options defined previously. In another embodiment of this sub-embodiment, X 1 is C(O), X 2 It is NR 12a , where R 12a As defined above, and X 3 -X 6 It's CR 23 , where each R 23 As defined above. In another embodiment of this sub-embodiment, X 1 is C(O), X 2 is NCH3 and X 3 -X 6 It's CR 23 , where each R 23 As defined above.

[0208] In another embodiment is a compound having the formula:

[0209]

[0210] or a pharmaceutically acceptable salt or solvate thereof, wherein R 12a and R 23 As defined above. In a sub-embodiment of this embodiment, R 23 is 1 to 3 substituents independently selected from H, fluorine, chlorine, methyl and CF3.

[0211] In another embodiment is a compound having the formula:

[0212]

[0213] or a pharmaceutically acceptable salt or solvate thereof, wherein R 12a As defined above, and each R 23 In a sub-embodiment of this embodiment, R 12a is a methyl group and each R 23 Independently selected from H, fluorine, chlorine, methyl and CF3.

[0214] In another embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 Together with the carbon to which they are bonded, they form C 3-8 Cycloalkyl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, wherein the C 3-8The cycloalkyl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 12 substituted, and wherein in C 3-8 Two R on the same atom of a cycloalkyl group or a 3-9 membered saturated or unsaturated heterocyclic ring 12 The substituents, together with the ring atoms to which they are bound, form a spirobicyclic ring system which is optionally substituted by one or more substituents R 22 replace;

[0215] In another embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 Together with the carbon to which they are bonded, they form C 3-8 Cycloalkyl or a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the S is optionally oxidized to SO or SO2, wherein the C 3-8 The cycloalkyl group and the 3-9 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-3 substituents R 12 substituted, and wherein in C 3-8 Two R on a cycloalkyl or 3-8 membered saturated or unsaturated heterocyclic ring 12 The substituents, together with the ring atoms to which they are bound, form a bridged bicyclic ring system which is optionally substituted by one or more substituents R2 2 replace;

[0216] In another embodiment is a compound of formula (I) selected from:

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224] or a pharmaceutically acceptable salt or solvate thereof.

[0225] In another embodiment is a compound of formula (I) selected from:

[0226]

[0227]

[0228]

[0229]

[0230] or a pharmaceutically acceptable salt or solvate thereof.

[0231] In one embodiment, the variables of the compounds of formula (I) are selected independently of each other.

[0232] In another embodiment, the compound of Formula (I) is in substantially purified form.

[0233] Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 , see ACSSymposium Series, and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" refers to a compound (e.g., a drug precursor) that is converted in vivo to provide a compound of formula (I) or a pharmaceutically acceptable salt of said compound. The conversion can occur by various mechanisms (e.g., by metabolic or chemical processes), for example, by hydrolysis in the blood.

[0234] For example, if the compound of formula (I) contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as: (C 1-8 )alkyl, (C 2-12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalyl, 4-crotonyl lactonyl, γ-butyrolactone-4-yl, di-N,N-(C 1-2 )alkylamino(C 2-3 ) alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-2 )alkyl, N,N-di(C 1-2 )alkylcarbamoyl-(C 1-2 )alkyl and piperidino-, pyrrolidino- or morpholino (C 2-3 ) alkyl, etc.

[0235] Similarly, if the compound of formula (I) contains an alcohol functional group, a prodrug may be formed by replacing one or more hydrogen atoms of the alcohol group with groups such as: (C 1-6 )alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C1-6)alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinyl, (C 1-6 ) alkanoyl, α-amino (C 1-4 )alkyl, α-amino(C1-C4)alkylene-aryl, arylacyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from a naturally occurring L-amino acid or a glycosyl group (a group derived from the removal of a hydroxyl group in the hemiacetal form of a carbohydrate). Other examples of alcohol-derived prodrugs include: -P(O)(OH)2; -P(O)(-O-C1-C6 alkyl)2; -P(O)(-NH-(α-aminoacyl))(-O-aryl); -P(O)(-O-(C1-C6 alkylene)-S-acyl)(-NH-arylalkyl); and those described in: U.S. Patent No. 7,879,815; International Publication Nos. WO2005 / 003047, WO2008 / 082602, WO2010 / 0081628, WO2010 / 075517, and WO2010 / 075549; Mehellou, Chem. Med. Chem., 5 :1841-1842 (2005); Bobeck et al., Antiviral Therapy 15 : 935-950 (2010); Furman et al., Future Medicinal Chemistry, 1: 1429-1452 (2009); and Erion, Microsomes and Drug Oxidations, Proceedings of the International Symposium, 17th ed., Saratoga Springs, NY, United States, July 6-10, 2008, 7-12(2008).

[0236] If the compound of formula (I) contains an amine functional group, a prodrug may be formed by replacing the hydrogen atom of the amine group with a group such as, for example, R-carbonyl-, RO-carbonyl-, NRR'-carbonyl-, wherein R and R' are each independently (C 1-10 )alkyl, (C 3-7 )cycloalkyl, benzyl, natural α-aminoacyl, -C(OH)C(O)OY 1 , where Y 1 is H, (C1-C6) alkyl or benzyl, -C(OY 2 )Y 3 , where Y 2 Yes (C 1-4 ) alkyl and Y 3 Yes (C 1-6 ) alkyl; carboxyl (C 1-6 ) alkyl; amino (C 1-4 )alkyl or mono-N- or di-N,N-(C 1-6 )alkylaminoalkyl; -C(Y 4 )Y 5 , where Y 4 is H or methyl and Y 5 Is single-N- or double-N,N-(C 1-6 ) alkylaminomorpholino; piperidin-1-yl or pyrrolidin-1-yl, etc.

[0237] Pharmaceutically acceptable esters of the compounds of the present invention include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxyl group of a hydroxy compound, wherein the non-carbonyl portion of the carboxylic acid portion of the ester group is selected from a linear or branched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, tert-butyl, sec-butyl or n-butyl), an alkoxyalkyl group (e.g., methoxymethyl), an aralkyl group (e.g., benzyl), an aryloxyalkyl group (e.g., phenoxymethyl), an aryl group (e.g., phenyl) optionally substituted with, for example, halogen, C 1-4 Alkyl, -O-(C 1-4 (alkyl) or amino); (2) sulfonates, such as alkyl- or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonates, and (5) mono-, di-, or triphosphates. Phosphates can be further esterified, for example, with C 1-20 alcohol or its reactive derivatives, or esterified with 2,3-di(C 6-24 ) Acylglycerol esterification.

[0238] One or more compounds of the present invention may exist in unsolvated form as well as in a form solvated with a pharmaceutically acceptable solvent (such as water, ethanol, etc.), and the present invention is intended to cover both solvated and unsolvated forms. "Solvate" refers to the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes solution phase and isolatable solvates. Examples of solvates include ethanolates, methanolates, etc. "Hydrate" is a solvate in which the solvent molecule is water.

[0239] One or more compounds of the invention may optionally be converted into solvates. The preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3) , 601-611 (2004) describes the preparation of ethyl acetate solvate and water solvate of the antifungal drug fluconazole. The following documents describe similar preparation methods of solvates, hemisolvates, hydrates, etc.: EC van Tonder et al., AAPSPharmSciTechours., 5(1) , Article 12 (2004); and A.L. Bingham et al., Chem. Commun., 603-604 (2001). A typical method comprises dissolving the compound of the invention in a desired amount of a target solvent (an organic solvent or water or a mixture thereof) at above room temperature, cooling the solution at a rate sufficient to form crystals, and then isolating the crystals by standard methods. Analytical techniques (such as, for example, infrared spectroscopy) reveal the presence of solvent (or water) in the solvate (or hydrate) crystals.

[0240] The compounds of formula (I) can form salts, which are also within the scope of the present invention. The term "salt" as used herein refers to acidic salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. In addition, when the compound of formula (I) contains a basic moiety (such as pyridine or imidazole) and an acidic moiety (such as carboxylic acid), zwitterions ("inner salts") can be formed and are included within the scope of the term "salt" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is a non-pharmaceutically acceptable salt. Salts of compounds of formula (I) can be formed, for example, by reacting the compound of formula (I) with an amount of acid or base (such as an equal amount) in a medium (e.g., a medium in which the salt is precipitated), or in an aqueous medium, followed by lyophilization.

[0241] Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthenate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In addition, acids generally considered suitable for forming pharmaceutically acceptable salts from basic pharmaceutical compounds are discussed in, for example, P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977). 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on their website).

[0242] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, tert-butylamine, choline, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized using, for example, lower alkyl halides (e.g., chlorides, bromides and iodides of methyl, ethyl and butyl), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate and dibutyl sulfate), long-chain halides (e.g., chlorides, bromides and iodides of decyl, lauryl and stearyl), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.

[0243] All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

[0244] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the present invention (including those of the salts and solvates of the compounds), such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotamers, atropisomers (e.g., substituted biaryls), and diastereomeric forms, are contemplated as being within the scope of the present invention. If the compounds of formula (I) contain double bonds or fused rings, both the cis- and trans- forms, as well as mixtures, are included within the scope of the present invention.

[0245] The compounds of formula (I) may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. For example, the present invention includes all keto-enol and imine-enamine forms of the compounds.

[0246] Each stereoisomer of the compounds of the present invention may, for example, be substantially free of other isomers, or may be mixed, for example, as a racemate, or with all other stereoisomers or other selected stereoisomers. The chiral centers of the present invention may have an S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt," "solvate," and the like is intended to apply equally to salts and solvates of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the present invention.

[0247] By methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization, diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences. Enantiomers can be separated as follows: by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acyl chloride), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and converting (e.g., hydrolyzing) each diastereomer into the corresponding pure enantiomer. Stereochemically pure compounds can also be prepared by using chiral starting materials or by adopting salt resolution techniques. Enantiomers can also be directly separated using chiral chromatographic techniques.

[0248] In the compounds of formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from that which predominantly occurs in nature. The present invention is intended to include all suitable isotopic variants of the compounds of formula (I). For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2H). Protium is the dominant hydrogen isotope found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing half-life in vivo or reducing dosage requirements, or can provide compounds that can be used as standards for biological sample characterization. By conventional techniques well known to those skilled in the art, or by methods similar to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates, isotopically enriched compounds of formula (I) can be prepared without excessive experimentation. In one embodiment, one or more hydrogen atoms of the compound of formula (I) are replaced by deuterium.

[0249] The present invention is intended to include polymorphic forms of the compounds of formula (I) and salts or solvates of the compounds of formula (I).

[0250] Other embodiments of the present invention include the following:

[0251] (a) A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

[0252] (b) The pharmaceutical composition of (a), further comprising one or more other therapeutic agents selected from neurological or psychiatric drugs, anti-inflammatory drugs, immunomodulatory drugs and anti-cancer drugs.

[0253] (c) A combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one, two, three or more other therapeutic agents.

[0254] (d) A combination of (c) which is (i) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and (ii) one or more other therapeutic agents selected from neurological or psychiatric drugs, anti-inflammatory drugs, immunomodulatory drugs and anti-cancer drugs.

[0255] (e) A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

[0256] (f) A compound for use according to (e), wherein the treatment is the treatment or prevention of a disease mediated by activation of Nrf2 transcription in a subject.

[0257] (g) A compound for use as described in (e) or (f), wherein the treatment is the treatment or prevention of a neurological disorder, an inflammatory disorder, an autoimmune disorder or cancer in a subject.

[0258] (h) A compound for use as described in (g), wherein the treatment is the treatment or prevention of a neurodegenerative disease such as Friedreich's ataxia, amyotrophic lateral sclerosis, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, peripheral neuropathy or hearing loss in a subject.

[0259] (i) A compound for use as described in (e), (f), (g) or (h), wherein the compound is administered in combination with one or more other therapeutic agents.

[0260] (j) Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for treating or preventing a neurological disorder, an inflammatory disorder, an autoimmune disorder or cancer in a subject.

[0261] (k) The use of (j), wherein the neurodegenerative disease is Friedreich's ataxia, amyotrophic lateral sclerosis, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, peripheral neuropathy, or hearing loss in the subject.

[0262] (1) The use of (j) or (k), wherein the compound is administered in combination with one or more other therapeutic agents.

[0263] (m) a method for treating or preventing a neurological disorder, an inflammatory disorder, an autoimmune disorder or cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0264] (n) The method of (m), wherein the neurological disorder is a neurodegenerative disease selected from Friedreich's ataxia, amyotrophic lateral sclerosis, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, peripheral neuropathy and hearing loss.

[0265] (o) The method of (m) or (n), wherein the compound of formula (I) is administered in combination with an effective amount of one or more other therapeutic agents.

[0266] Other embodiments of the present invention include the pharmaceutical compositions, combinations and methods described above in (a)-(o), and the uses described below in the discussion, wherein the compound of the present invention used is a compound of one of the embodiments, aspects, categories, subclasses or features of the above-mentioned compounds. In all of these embodiments, the compound can optionally be used in the form of a pharmaceutically acceptable salt or solvate, as appropriate. It should be understood that reference to a compound will include the compound in its current form as well as different forms, such as polymorphs and solvates, where applicable.

[0267] It is further understood that the embodiments of the compositions and methods provided above as (a) through (o) are to be understood to encompass all embodiments of the compounds, including such embodiments resulting from combinations of the embodiments.

[0268] In another embodiment, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is used to treat or prevent a neurodegenerative disorder in a subject. In one embodiment, the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, other CAG-triplet repeat (or polyglutamine) diseases, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), diffuse Lewy body disease, chorea-acanthocytosis, primary lateral sclerosis, multiple sclerosis (MS), frontotemporal dementia, Friedreich's ataxia, acute head injury and epilepsy (inhibition of microglial activation). In another embodiment, the neurodegenerative disorder is Friedreich's ataxia, amyotrophic lateral sclerosis, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, peripheral neuropathy or hearing loss. In another embodiment, the neurodegenerative disorder is Alzheimer's disease. In another embodiment, the neurodegenerative disorder is Parkinson's disease. In another embodiment, the neurodegenerative disorder is amyotrophic lateral sclerosis.

[0269] In another embodiment is a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in treating or preventing an ophthalmic disorder in a subject. In one embodiment, the ophthalmic disorder is selected from retinal diseases such as macular degeneration, diabetic retinopathy, diabetic macular edema, retinitis pigmentosa, Stargardt disease, Ussher syndrome, Leber congenital amaurosis, choroideremia, rod-cone or cone-rod dystrophy, ciliary diseases, progressive retinal atrophy, degenerative retinal diseases, retinopathy of prematurity, retinal vascular diseases, cataracts, glaucoma, glaucomatous retinal neurodegeneration; ischemic optic neuropathy and ocular vascular diseases.

[0270] In another embodiment is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in treating a renal kidney disease in a subject. In one embodiment, the renal kidney disease is chronic or acute renal failure, acute kidney injury caused by pre-renal, intra-renal and post-renal causes, chronic kidney disease, diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), nephrotic syndrome or non-diabetic chronic kidney disease.

[0271] Therefore, the present invention also provides a method for treating or preventing a neurological disorder and / or reducing the likelihood or severity of symptoms of a neurological disorder in a patient, comprising administering to the patient an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0272] In another embodiment is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in inhibiting, treating, and / or reducing the likelihood of, or the severity of, an inflammatory disorder in a subject. In one embodiment, the inflammatory disorder is selected from (i) respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, and radiation pneumonitis; (ii) cardiovascular diseases such as atherosclerotic disease; (iii) metabolic diseases such as acute kidney injury, chronic kidney disease, acute liver injury, and chronic liver failure; (iv) multiple organ failure as a consequence of systemic sepsis and / or major trauma; (v) inflammatory arthritis such as gout; (vi) inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis; and (vii) inflammatory skin diseases such as atopic dermatitis.

[0273] Therefore, the present invention also provides a method for treating or preventing an inflammatory disorder and / or reducing the likelihood or severity of symptoms of an inflammatory disorder in a patient, comprising administering to the patient an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0274] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to inhibit, treat and / or reduce the likelihood of an autoimmune disorder or the severity of its symptoms in a subject. In one embodiment, the autoimmune disorder is selected from systemic lupus erythematosus (SLE), Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis, psoriasis and myositis.

[0275] Therefore, the present invention also provides a method for treating or preventing an autoimmune disorder and / or reducing the likelihood or severity of symptoms of an autoimmune disorder in a patient, comprising administering to the patient an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0276] In another embodiment is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for inhibiting, treating and / or reducing the likelihood of cancer or the severity of its symptoms in a subject. In one embodiment, the cancer is selected from liver cancer, breast cancer, gastric cancer, colorectal cancer, colon cancer, prostate cancer, gallbladder cancer, ovarian cancer, lung cancer, esophageal cancer, glioma, esophageal squamous cell carcinoma, endometrial cancer, papillary carcinoma, head and neck cancer, skin cancer, hepatocellular carcinoma, kidney and bladder cancer, pancreatic cancer and leukemia cancer. In a specific embodiment, the cancer is a metastasis originating from other cancers (such as colon cancer, pancreatic cancer, etc.).

[0277] Therefore, the present invention also provides a method for treating or preventing cancer and / or reducing the likelihood or severity of symptoms of cancer in a patient, comprising administering to the patient an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0278] In another aspect of the invention, the therapeutic use of the compounds and compositions of the invention may further comprise the administration of one or more additional therapeutic agents which are not compounds of formula (I).

[0279] In one embodiment, the compound of formula (I) is co-administered with one additional therapeutic agent. In another embodiment, the compound of formula (I) is co-administered with two additional therapeutic agents. In yet another embodiment, the compound of formula (I) is co-administered with two or more additional therapeutic agents.

[0280] In one embodiment, the additional therapeutic agent is a neurological or psychiatric drug such as a cognitive or memory enhancing agent.

[0281] In another embodiment, the additional therapeutic agent is an anti-inflammatory agent.

[0282] In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressant.

[0283] In another embodiment, the additional therapeutic agent is an anti-cancer agent.

[0284] In one embodiment, the additional therapeutic agent is a β-secretase inhibitor, e.g., vilrostat; an M1 mAChR agonist or PAM; an M4 mAChR agonist or PAM; an mGluR2 antagonist or NAM or PAM; an ADAM 10 or activator; a γ-secretase inhibitor, such as LY450139 and TAK 070; a γ-secretase modulator; a tau phosphorylation inhibitor; a glycine transport inhibitor; an LXR β agonist; an ApoE4 conformational modulator; an NR2B antagonist; an androgen receptor modulator; a blocker of Aβ oligomer formation; a 5-HT4 agonist, such as PRX-03140; a 5-HT6 antagonist, such as GSK 742467, SGS-518, FK-962, SL-65.0155, SRA-333 and zaliproden; 5-HT1a antagonists such as lecozotan; p25 / CDK5 inhibitors; NK1 / NK3 receptor antagonists; COX-2 inhibitors; LRRK2 inhibitors; CB-1 receptor antagonists or CB-1 receptor inverse agonists such as AVE1625; N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine, neramexane and EVT101; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, phenylhydroxyalanine, radotigid and ABT-089; growth hormone secretagogues such as ibuprofen, ibuprofen mesylate and caprelin; histamine H3 receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP1 6795; AMPA agonists or AMPA modulators, such as CX-717, LY 451395, LY404187, and S-18986; PDE IV inhibitors, including MEM1414, HT0712, and AVE8112; GABAA inverse agonists; GSK3β inhibitors, including AZD1080, SAR502250, and CEP16805; neuronal nicotinic agonists; selective M1 agonists; HDAC inhibitors; and microtubule affinity regulating kinase (MARK) ligands.

[0285] Examples of combinations of compounds include combinations with agents used to treat schizophrenia, such as sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, mild tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as adizalam, allobarbital, allomidone, alprazolam, amisulpride, amitriptyline, amobarbital, alobarbital, Moxapine, aripiprazole, benzazepam, benzotamine, brotizolam, bupropion, buspirone, butalbital, butalbital, caproulone, carbochloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, chlorpiperazine, clorazepate, chlordiazepoxide, chlorpromazine, clozapine, ciproazepam, desipramine, cyproheptadine, diazepam, chloralpyrine, divalproex sodium, diphenhydramine, doxepin, estazolam, ethchlorvinox, etomidate, fenobant, flunitrazepam, flupentixol, fluphenazine Flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, chloroquine, melatonin, mephobarbital, meprobamate, methaqualone, midaflutol, midazolam, nefazodone, nisolbamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paroxetine, pentobarbital, perazepam, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine The subject compounds may be administered in combination with physical methods such as phototherapy or electrical stimulation.

[0286] In another embodiment, the additional therapeutic agent is levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), an anticholinergic such as biperiden (optionally as its hydrochloride or lactate) and trihexyphenidyl (benzhexol) hydrochloride; a COMT inhibitor such as entacapone, an MAO-B inhibitor, an antioxidant, an A2a adenosine receptor antagonist, a cholinergic agonist, an NMDA receptor antagonist, a serotonin receptor antagonist, or a dopamine receptor agonist such as alentimod, bromocriptine, fenoldopam, lisuride, nagolide, pergolide, and pramipexole. It should be understood that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentimod hydrobromide, bromocriptine mesylate, fenoldopam mesylate, nagolide hydrochloride, and pergolide mesylate.

[0287] In another embodiment, the additional therapeutic agent is an anti-inflammatory agent. Anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs), nonspecific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants and methotrexate.

[0288] Examples of NSAIDs include ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib and / or etoricoxib.

[0289] In certain embodiments, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylate.

[0290] The anti-inflammatory agent can also be a corticosteroid. For example, the corticosteroid can be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate or prednisone.

[0291] In further embodiments, the anti-inflammatory agent is a gold compound such as aurothiobutane or auranofin.

[0292] The invention also includes embodiments wherein the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor (such as methotrexate) or a dihydroorotate dehydrogenase inhibitor (such as leflunomide).

[0293] Other embodiments of the invention relate to combinations wherein at least one anti-inflammatory agent is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist (such as etanercept, or infliximab, which is an anti-TNFα monoclonal antibody.

[0294] In another embodiment, the additional therapeutic agent is an anticancer agent. Examples of such agents include sorafenib besylate (Nexavar), radiation therapy, selective internal radiation therapy (e.g., SIR-Spheres and TheraSphere), ethiodized oil (Lipidol), pexastimogenedevacirepvec (Pexa-Vec, JX-594, Jennarex), mepacrine (Clevelane BioLabs), CC-223 (Celgene), CF102 (Can-Fite), SGI-110 (Astex), and G-202 (Genspera).

[0295] In one embodiment, the anticancer agent is selected from the group consisting of: vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothened inhibitors, alkylating agents, antitumor antibiotics, antimetabolites, retinoids, immunomodulators (including anticancer vaccines, CTLA-4, LAG-3), PD-1 antagonists, and BET bromodomain inhibitors.

[0296] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more preventive and / or therapeutic agents). The application of term "combination" does not limit the order in which therapy (e.g., preventive and / or therapeutic agents) is administered to the subject with disorder. The subject with disorder can be administered a second therapy (e.g., a preventive or therapeutic agent) before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks), simultaneously or afterwards (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks) administering the first therapy (e.g., a preventive or therapeutic agent, such as provided herein).

[0297] As used herein, the term "synergistic" includes a combination of a compound provided herein with another therapy (e.g., a prophylactic or therapeutic agent) that has been or is currently being used to prevent, control, or treat an obstacle, and the combination is more effective than the additive effect of the therapy. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) allows the use of one or more therapies at lower doses and / or the administration of the therapy to a subject with an obstacle at a lower frequency. The ability to use a lower dose of the therapy (e.g., a prophylactic or therapeutic agent) and / or the administration of the therapy at a lower frequency reduces the toxicity associated with the administration of the therapy to the subject without reducing the effectiveness of the therapy in the prevention or treatment of the obstacle. In addition, a synergistic effect can result in an improved effectiveness of the medicament in the prevention or treatment of the obstacle. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can avoid or mitigate the adverse or undesirable side effects associated with the use of any one therapy alone.

[0298] When the conjugate therapy of the present invention is administered to a patient, the therapeutic agent in the combination, or one or more pharmaceutical compositions comprising the therapeutic agent, can be administered in any order, such as, for example, sequentially, concurrently, together, simultaneously, etc. The amounts of the various active substances in such conjugate therapy can be different amounts (different doses) or the same amount (same dose). Therefore, for purposes of explanation, the compound of formula (I) and other therapeutic agent can be present in a single dose unit (e.g., capsule, tablet, etc.) in a fixed amount (dose).

[0299] In one embodiment, at least one compound of formula (I) is administered during the time that the additional therapeutic agent exerts its prophylactic or therapeutic effect, or vice versa.

[0300] In another embodiment, at least one compound of Formula (I) and the additional therapeutic agent are administered in doses commonly employed when such agents are used as monotherapy.

[0301] In another embodiment, at least one compound of Formula (I) and the additional therapeutic agent are administered in doses lower than the doses typically employed when such agents are used as monotherapy.

[0302] In yet another embodiment, at least one compound of Formula (I) and the additional therapeutic agent act synergistically and are administered in dosages lower than those normally employed when such agents are used as monotherapy.

[0303] In one embodiment, at least one compound of Formula (I) and the additional therapeutic agent are present in the same composition. In one embodiment, the composition is suitable for oral administration. In another embodiment, the composition is suitable for intravenous administration. In another embodiment, the composition is suitable for subcutaneous administration. In yet another embodiment, the composition is suitable for parenteral administration.

[0304] The active compounds provided herein can be combined or alternately administered with another therapeutic agent. In conjoint therapy, two or more medicaments of an effective dose are administered together, while in alternating or sequential step treatments, each medicament of an effective dose is administered sequentially or in sequence. The dosage administered will depend on the absorption, inactivation and excretion rate of the drug and other factors known to those skilled in the art. It should be noted that the dosage value will also vary with the severity of the disease to be alleviated. It should be further understood that for any particular subject, the specific dosage regimen and plan should be adjusted over time according to the professional judgment of the personnel administering the composition or supervising the administration of the composition.

[0305] At least one compound of formula (I) and other therapeutic agent can work cumulatively or synergistically. Synergistic combination can allow the use of one or more medicaments of lower dosage and / or less frequent administration of one or more medicaments of conjoint therapy. Lower dosage or less frequent administration of one or more medicaments can reduce the toxicity of therapy without reducing the effectiveness of therapy.

[0306] The dosage and administration regimen of other medicaments used in the conjoint therapy of the present invention can be determined by the attending clinician, and the dosage and administration regimen approved in the package insert are considered; The age, sex and general health of the patient; And the type and severity of viral infection or related disease or disorder. When co-administered, the compound of formula (I) and other medicaments can be administered simultaneously (that is, in the same composition or in a separated composition one immediately after another) or sequentially. This is particularly useful in the following cases: when the components of the combination are given with different dosing schedules, for example, one component is administered once a day and another component is administered once every six hours, or when preferred pharmaceutical compositions are different, for example, one is a tablet and the other is a capsule. Therefore, it is advantageous to include a medicine box of a separated dosage form.

[0307] Typically, the total daily dose of at least one compound of Formula (I) individually or when used as a conjoint therapy can be in the range of about 1 to about 2500mg per day, although changes are inevitable according to therapeutic goals, patients, and routes of administration. In one embodiment, the dosage is about 10 to about 1000mg / days, which is administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is about 1 to about 500mg / days, which is administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is about 1 to about 100mg / days, which is administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is about 1 to about 50mg / days, which is administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is about 500 to about 1500mg / days, which is administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is about 500 to about 1000 mg / day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is about 100 to about 500 mg / day, administered in a single dose or in 2-4 divided doses.

[0308] Due to their activity, the compounds of formula (I) are useful in veterinary and human medicine.As mentioned above, the compounds of formula (I) are useful for treating or preventing neurodegenerative diseases, inflammatory diseases, autoimmune diseases or cancer in a patient.

[0309] When administered to a patient, the compound of formula (I) can be used as a component of a composition comprising a pharmaceutically acceptable carrier or vehicle. The present invention provides a pharmaceutical composition comprising an effective amount of a compound of at least one formula (I) or a pharmaceutically acceptable salt, solvate or enantiomer thereof and a pharmaceutically acceptable carrier or diluent. In the pharmaceutical composition and purposes of the present invention, active ingredient is usually mixed with a suitable carrier material for administration, and the carrier material is suitably selected in the following aspects: intended form of administration (i.e. oral tablets, capsules (solid-filled, semi-solid-filled or liquid-filled), powders for construction, oral gels, elixirs, dispersible particles, syrups, suspensions, etc.), and in accordance with conventional pharmaceutical practice. For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with any oral non-toxic pharmaceutically acceptable inert carrier, and the carrier is such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethanol (liquid form) etc. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may contain from about 0.5% to about 95% of the composition of the present invention. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

[0310] In addition, when desired or required, suitable binders, lubricants, disintegrants and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural gums and synthetic gums, such as gum arabic, sodium alginate, carboxymethyl cellulose, polyethylene glycol and wax. Among lubricants, lubricants that can be mentioned for these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include starch, methyl cellulose, guar gum and the like. Sweeteners, flavorings and preservatives may also be included when necessary.

[0311] Liquid form preparations include solutions, suspensions, and emulsions, and may include water or water-propylene glycol solutions for parenteral injection.

[0312] Liquid form preparations may also include solutions for intranasal administration.

[0313] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.Such liquid forms include solutions, suspensions, and emulsions.

[0314] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed evenly therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0315] In addition, the compositions of the present invention can be formulated in a sustained release form to provide a controlled rate release of any one or more components or active ingredients to optimize the therapeutic effect, i.e., antiviral activity, etc. Suitable dosage forms for sustained release include multilayer tablets containing layers with different disintegration rates; or controlled release polymer matrices impregnated with the active ingredient and formed into tablet form; or capsules containing such impregnated or encapsulated porous polymer matrices.

[0316] In one embodiment, one or more compounds of Formula (I) are administered orally.

[0317] In another embodiment, one or more compounds of Formula (I) are administered intravenously.

[0318] In one embodiment, the pharmaceutical preparation comprising a compound of formula (I) is in unit dosage form. In such form, the preparation is subdivided into unit doses containing an effective amount of the active ingredient.

[0319] Compositions can be prepared according to conventional mixing, granulation or coating methods, respectively, and in one embodiment, the compositions of the present invention can contain from about 0.1% to about 99% of the compound of formula (I) by weight or volume. In various embodiments, the compositions of the present invention can contain from about 1% to about 70% or from about 5% to about 60% of the compound of formula (I) by weight or volume in one embodiment.

[0320] The amount of the compound of formula (I) in a unit dose of the product can be varied or adjusted from about 1 mg to about 2500 mg. In various embodiments, the amount is from about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, and 1 mg to about 100 mg.

[0321] For convenience, if necessary, the total daily dose can be divided and administered in batches throughout the day. In one embodiment, the daily dose is administered in a single dose. In another embodiment, the total daily dose is administered in two divided doses over a 24-hour period. In another embodiment, the total daily dose is administered in three divided doses over a 24-hour period. In yet another embodiment, the total daily dose is administered in four divided doses over a 24-hour period.

[0322] The amount and frequency of the compound of formula (I) will be regulated according to the judgment of the attending clinician, and factors such as the severity of the patient's age, condition and body shape and the symptom being treated will be considered. Generally, the daily total dose of the compound of formula (I) is in the range of about 0.1 to about 2000mg every day, although it is inevitable to change according to treatment goals, patients and route of administration. In one embodiment, the dosage is about 1 to about 200mg / days, which is used in a single dose or in 2-4 divided doses. In another embodiment, the dosage is about 10 to about 2000mg / days, which is used in a single dose or in 2-4 divided doses. In another embodiment, the dosage is about 100 to about 2000mg / days, which is used in a single dose or in 2-4 divided doses. In another embodiment, the dosage is about 500 to about 2000mg / days, which is used in a single dose or in 2-4 divided doses. Example

[0323] The following examples illustrate the present invention. For all examples, standard post-processing and purification methods known to those skilled in the art can be utilized. Unless otherwise noted, all temperatures are expressed in degrees Celsius. Unless otherwise noted, all reactions are carried out at room temperature. The synthetic methods explained herein are intended to illustrate applicable chemistry by using specific examples.

[0324] Abbreviations used are those conventional in the art or the following:

[0325] ACN acetonitrile

[0326] Aryl

[0327] Aq Water-based

[0328] Boc tert-butyloxycarbonyl protecting group

[0329] ℃ degrees Celsius

[0330] CDCl3 deuterated chloroform

[0331] CHCl3 chloroform

[0332] CO2 carbon dioxide

[0333] DBDMH 1,3-dibromo-5,5-dimethylhydantoin

[0334] DCM dichloromethane

[0335] DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

[0336] DIEA N,N-diisopropylethylamine

[0337] DMAP 4-dimethylaminopyridine

[0338] DMF N,N-dimethylformamide

[0339] DMSO dimethyl sulfoxide

[0340] DMSO-d6 deuterated dimethyl sulfoxide

[0341] Et2O ether

[0342] EtOAc

[0343] EtOH

[0344] Eq equivalent

[0345] g grams

[0346] h hour

[0347] H2O water

[0348] H2O2 Hydrogen peroxide

[0349] HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- Methylammonium hexafluorophosphate N-oxide

[0350] HCl

[0351] HPLC high-performance liquid chromatography

[0352] KOtBu Potassium tert-butoxide

[0353] L liter

[0354] LCMS liquid chromatography and mass spectrometry

[0355] LDA lithium diisopropylamide

[0356] LiHMDS Lithium bis(trimethylsilyl)amide

[0357] M Moore

[0358] MHz Megahertz

[0359] MeI iodomethane

[0360] MeOH methanol

[0361] MS

[0362] mmol millimole

[0363] mg milligrams

[0364] min

[0365] mL milliliters

[0366] N2 nitrogen

[0367] NaH sodium hydride

[0368] NaHCO3 sodium bicarbonate

[0369] NaOMe sodium methoxide

[0370] NaOH sodium hydroxide

[0371] NaOtBu sodium tert-butoxide

[0372] nBuLi n-butyllithium solution

[0373] nM nanomolar

[0374] N equivalent concentration

[0375] NH4Cl ammonium chloride

[0376] NH3H2O ​​ammonia water

[0377] NH4OH ammonium hydroxide

[0378] NMR Nuclear Magnetic Resonance

[0379] HO-NH2HCl Hydroxylamine hydrochloride

[0380] Pd(OAc)2 Palladium(II) acetate

[0381] Pd-PEPPSI-IHepCl dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridine palladium(II)

[0382] PhSeCl phenylselenyl chloride

[0383] Pyr Pyridine

[0384] rt room temperature

[0385] RuPhos Pd G2 Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino [(1,1′-biphenyl)]palladium(II)

[0386] sat. saturated

[0387] SM starting material

[0388] SFC Supercritical Fluid Chromatography

[0389] SPhos Pd G4 Methanesulfonate (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl) (2′-Methylamino-1,1′-biphenyl-2-yl)palladium(II)

[0390] tBuOH tert-butyl alcohol

[0391] T3P Propylphosphonic Anhydride

[0392] TEA triethylamine

[0393] TFA trifluoroacetic acid

[0394] THF Tetrahydrofuran

[0395] TLC thin layer chromatography

[0396] Prep.TLC

[0397] TsCl p-Toluenesulfonyl chloride (toluenesulfonyl chloride)

[0398] TsCN p-Toluenesulfonyl cyanide (Toluenesulfonyl cyanide)

[0399] μL microliter

[0400] vol volume

[0401] VT variable temperature

[0402] General synthetic scheme

[0403] Although the present invention has been described in conjunction with the specific examples set forth below, many alternatives, modifications, and variations thereof will be apparent to those skilled in the art. In some cases, the order in which the steps of the reaction schemes are carried out may be altered to facilitate the reaction or to avoid undesirable reaction products. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise described.

[0404] Several methods for preparing compounds of the present invention are described in the following Schemes and Examples. Unless otherwise indicated, all variables are as previously defined.

[0405] Solution 1 :

[0406]

[0407] Optionally substituted cyano enone 5 can be synthesized using a four-step procedure in Scheme 1. Formylation of the optionally substituted ketone 1 provides 3, and subsequent ring closure provides the isoxazole 4. Ring opening and subsequent oxidation provide the cyano enone 5.

[0408] Option 2 :

[0409]

[0410] In Scheme 2, optionally substituted cyano enone 10 can be synthesized using a five-step procedure. Optionally substituted ketone 6 can be alkylated under basic conditions to provide 7. Formylation and subsequent ring closure provide isoxazole 9. Ring opening and subsequent oxidation provide cyano enone 10.

[0411] Option 3 :

[0412]

[0413] In Scheme 3, optionally substituted cyano enone 14 can be synthesized using a three-step procedure. Optionally substituted ketone 11 can be alkylated under basic conditions to provide 12. α-cyanation followed by oxidation provides cyano enone 14.

[0414] Option 4 :

[0415]

[0416] In Scheme 4, spiro-azetidine is used for illustrative purposes. Similar chemical methods can be used to functionalize other amines. When R3 and R4 are spirocyclic amines, a two-step procedure can be used to functionalize the amine substituent. Protected amine 15 can be deprotected under acidic conditions to provide amine 16. Amine 16 can be used in many reactions. Sulfonylation using sulfonyl chloride provides sulfonamide 17. Alternatively, amide 18 can be formed using acid chloride or carboxylic acid. Alternatively, alkylation with alkyl halide provides alkylamine 19. Finally, palladium-catalyzed CN coupling reaction with aryl halide provides arylamine 20.

[0417] Option 5 :

[0418]

[0419] In Scheme 5, optionally substituted spirocyclic cyanoenone 25 can be synthesized using a 5-step procedure. Optionally substituted spirocyclic ketone 21 can be alkylated under basic conditions to provide 22. The amine can be deprotected under acidic conditions to provide amine 23. Palladium-catalyzed CN coupling reaction with an aryl halide provides arylamine 24. α Cyanation followed by oxidation afforded the spirocyclic cyanoketene 25.

[0420] Option 6 :

[0421]

[0422] In Scheme 6, optionally substituted spirocyclic indolinone 31 can be synthesized using a 5-step procedure. Optionally substituted indolinone 26 can be alkylated with methyl acrylate under basic conditions to provide 27, which can be cyclized under basic conditions to produce 28. The ketone can be alkylated under basic conditions to provide 29. Alpha cyanation followed by oxidation provides spirocyclic indolinone 31.

[0423] Option 7 :

[0424]

[0425] In Scheme 7, optionally substituted spirodihydroisobenzofuran 40 can be synthesized using an 8-step procedure. Lithiation of optionally substituted bromobenzene 33 with ketone 32 provides diol 34, which can be closed to spirodihydroisobenzofuran 35 with TsCl or TfO under basic conditions. Deprotection under acidic conditions provides ketone 36. Alternatively, diol 34 can be closed and deprotected in one pot using TFA to provide ketone 36. Ketone 36 can be alkylated under basic conditions to provide 37. Formylation and subsequent ring closure provide isoxazole 39. Ring opening and subsequent oxidation provide spirodihydroisobenzofuran 40. Optionally, alpha-cyanation of 37 followed by oxidation provides spirodihydroisobenzofuran 40. Alternatively, to 32, a ketone with R1 and R2 preinstalled as methyl groups can be used, omitting the conversion from 36 to 37.

[0426] Synthesis of intermediates

[0427] Racemic compounds purified by reverse phase or normal phase chromatography were further purified by chiral SFC. Where indicated, enantiomer 1 represents the first eluting peak and enantiomer 2 represents the second eluting peak. Otherwise, the compound is achiral or racemic.

[0428] Option 8 :

[0429]

[0430] Intermediate 1: 9,9-Dimethyl-8-oxo-2-azaspiro[4.5]dec-6-ene-7-carbonitrile, HCl

[0431] Step 1 8- oxo -2- azaspiro [4.5] decane -2- tert-butyl formate (829mg, 3.27mmol) is dissolved in tBuOH (16mL). Under a nitrogen atmosphere, potassium tert-butoxide (918mg, 8.18mmol) is slowly added, and the mixture is stirred at room temperature for 1h. Iodomethane (0.430mL, 6.87mmol) is added dropwise, and the mixture is stirred at room temperature overnight. Water (20mL) is added, and the aqueous phase is extracted with EtOAc (3x). The organic layer merged is washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Residue is purified by column chromatography (0-50% Et2O / hexane) on silica gel to produce 7,7- dimethyl -8- oxo -2- azaspiro [4.5] decane -2- tert-butyl formate as oil. MS: 226 (M+H-tBu).

[0432] Step 2: To a suspension of sodium hydride (151 mg, 3.76 mmol) in THF (5.5 mL) was added 7,7-dimethyl-8-oxo-2-azaspiro [4.5] decane-2-tert-butyl formate (921 mg, 3.27 mmol) in THF (5.5 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C for 20 minutes. Ethyl formate (0.793 mL, 9.82 mmol) was then added and the reaction mixture was warmed to room temperature and stirred overnight. 0.5 equivalents of NaH were added to the mixture, and the reaction was stirred at room temperature for 2 h. The mixture was quenched with saturated NH4Cl (aqueous solution) and extracted with EtOAc (2x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl (Z)-9-(hydroxymethylene)-7,7-dimethyl-8-oxo-2-azaspiro[4.5]decane-2-carboxylate as a liquid, which was used without further purification. MS: 254 (M+H-tBu).

[0433] Step 3 To a solution of (Z)-9-(hydroxymethylene)-7,7-dimethyl-8-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.01 g, 3.27 mmol) in 10:1 EtOH:HO (8 mL) was added a solution of hydroxylamine hydrochloride (0.25 g, 3.6 mmol) in 10:1 EtOH:HO (8 mL). The reaction mixture was stirred at 40 ° C for 5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was basified with saturated NaHCO (aqueous solution) and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to produce tert-butyl 7,7-dimethyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,3′-pyrrolidine]-1′-carboxylate as an oily solid, which was used without further purification. MS: 251 (M+H-tBu).

[0434] Step 4: To a solution of 7,7-dimethyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,3′-pyrrolidine]-1′-carboxylic acid tert-butyl ester (1.0 g, 3.3 mmol) in MeOH (16 mL) was added sodium methoxide (30% in MeOH, 1.87 mL, 9.79 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with EtOAc, and neutralized with 1M HCl aqueous solution (9.8 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% Et2O / hexane) to produce 9-cyano-7,7-dimethyl-8-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester as foam. MS: 251 (M+H-tBu).

[0435] Step 5 To a solution of tert-butyl 9-cyano-7,7-dimethyl-8-oxo-2-azaspiro[4.5]decane-2-carboxylate (843 mg, 2.75 mmol) in THF (5.5 mL) was added palladium(II) acetate (618 mg, 2.75 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and then diluted with DCM (5 mL) and 1:1 water: brine (5 mL). The organic layer was collected by a phase separator and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-80% Et2O / hexane) to produce tert-butyl 7-cyano-9,9-dimethyl-8-oxo-2-azaspiro[4.5]dec-6-ene-2-carboxylate as an oily foam. MS: 249 (M+H-tBu).

[0436] Alternative Step 5Benzene selenyl chloride (80mg, 0.42mmol) in DCM (0.5mL) solution was added to pyridine (34 μL, 0.42mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes, followed by addition of 9-cyano-7,7-dimethyl-8-oxo-2-azaspiro [4.5] decane-2-tert-butyl formate (64mg, 0.209mmol) in DCM (1mL). The reaction mixture was stirred at 0°C for 1h, and subsequently washed with 1M HCl aqueous solution (2mL). Each phase was separated, and the organic phase was treated with hydrogen peroxide (30% in water, 430 μL, 4.2mmol) at 0°C. The reaction mixture was stirred vigorously for 15 minutes, then each phase was separated, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% Et2O / hexanes) to give tert-butyl 7-cyano-9,9-dimethyl-8-oxo-2-azaspiro[4.5]dec-6-ene-2-carboxylate as an oily foam. MS: 249 (M+H-tBu).

[0437] Alternative step 5: To a solution of compound 5 (40.0 g, 124 mmol, 1.0 equiv) in toluene (0.4 L) was added DDQ (42.2 g, 186 mmol, 1.5 equiv) at 25°C. The reaction was stirred at 110°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to produce a residue. Purification by column chromatography (SiO2, petroleum ether: ethyl acetate = 100: 1-50: 1) provided $ (23.0 g, 67.5 mmol, 54.4% yield, 94% purity) as a light yellow solid. 1 HNMR: ET33537-23-P1A1 (400MHz, CDCl3) δ7.61 (s, 1H), 3.72-3.79 (m, 3H), 3.62 (s, 1H), 3.21-3.26 (m , 1H), 3.15-3.19(m, 1H), 2.01-2.05(m, 1H), 1.82-.86(m, 1H), 1.48(s, 9H), 1.30(s, 3H), 1.20(s, 3H).

[0438] Step 6: 7- cyano -9,9- dimethyl -8- oxo -2- azaspiro [4.5] dec- 6- alkene -2- tert-butyl formates (443mg, 1.45mmol) is dissolved in DCM (14mL). HCl (4.0M in dioxane, 3.64mL, 14.5mmol) is added, and the mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure to produce 9,9- dimethyl -8- oxo -2- azaspiro [4.5] dec- 6- alkene -7- formonitrile, HCl as foam, which is used without further purification. MS: 205 (M+H).

[0439] Table 1 The following intermediates were prepared using a procedure similar to that described above for Intermediate 1. For oxidation conditions, 1 = palladium(II) acetate and 2 = phSeCl, pyridine, H2O2

[0440]

[0441]

[0442] Option 9 :

[0443]

[0444] Intermediate 5: 9,9-Dimethyl-8-oxo-2-azaspiro[4.5]dec-6-ene-7-carbonitrile, HCl

[0445] Intermediate 6: 9,9-Dimethyl-8-oxo-2-azaspiro[4.5]dec-6-ene-7-carbonitrile, HCl

[0446] Step 1 tert-Butyl 7-cyano-9,9-dimethyl-8-oxo-2-azaspiro[4.5]dec-6-ene-2-carboxylate (1.1 g, 3.6 mmol) was purified by chiral SFC (OJ-H column, 15% MeOH / 85% CO2 with 0.1% NH4OH modifier) ​​to afford two products as solids:

[0447] Tert-butyl 7-cyano-9,9-dimethyl-8-oxo-2-azaspiro[4.5]dec-6-ene-2-carboxylate (Enantiomer 1). MS: 249 (M+H-tBu).

[0448] Tert-butyl 7-cyano-9,9-dimethyl-8-oxo-2-azaspiro[4.5]dec-6-ene-2-carboxylate (Enantiomer 2). MS: 249 (M+H-tBu).

[0449] Step 2: To 7-cyano-9,9-dimethyl-8-oxo-2-azaspiro [4.5] dec-6-ene-2-carboxylic acid tert-butyl ester (enantiomer 1, 405 mg, 1.33 mmol) dissolved in DCM (10 mL) was added HCl (4.0 M in dioxane, 3.33 mL, 13.3 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to produce 9,9-dimethyl-8-oxo-2-azaspiro [4.5] dec-6-ene-7-carbonitrile, HCl (intermediate 5) as a solid, which was used without further purification. MS: 205 (M+H).

[0450] Note that enantiomer 2 was deprotected and isolated as intermediate 6 using the same procedure described in step 2.

[0451] Table 2 : The following intermediates were prepared using a similar procedure as described above for intermediates 5 and 6

[0452]

[0453] Plan 10 :

[0454]

[0455] Intermediate 9: 8,8-dimethyl-7-oxo-2-azaspiro[ 3 .5] Ren-5- 6-ene Formonitrile, H Cl

[0456] Step 1 : To a solution of tert-butyl 7-oxo-2-azaspiro [3.5] nonane-2-formate (1.25 g, 5.22 mmol) in tBuOH (26 mL) was added potassium tert-butoxide (1.46 g, 13.1 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. Iodomethane (0.685 mL, 11.0 mmol) was added to the mixture, and the reaction was stirred at room temperature overnight. The reaction was quenched with water (100 mL) and the mixture was extracted with EtOAc (3x75 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% EtOAc / hexane) to provide tert-butyl 6,6-dimethyl-7-oxo-2-azaspiro [3.5] nonane-2-formate as a solid. MS: 212 (M+H-tBu).

[0457] Step 2: at -78 ℃ to LDA (2.0M in THF, 2.32mL, 4.64mmol), dropwise add 6,6-dimethyl-7-oxo-2-azaspiro [3.5] nonane-2-t-butyl formates (620mg, 2.32mmol) in THF (4mL).Mixture was stirred at -78 ℃ for 30 minutes.A solution of 4-methylbenzenesulfonyl cyanide (420mg, 2.32mmol) in THF (3mL) was added dropwise, and the mixture was stirred at -78 ℃ for another 30 minutes.The reaction was quenched with 2M NH4OH (1.2mL) and warmed to room temperature.Then the mixture was neutralized to a pH of about 7 with the 1M HCl aqueous solution, and extracted with EtOAc (3x5mL).The organic layer merged was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-30% EtOAc / hexanes) to afford tert-butyl 8-cyano-6,6-dimethyl-7-oxo-2-azaspiro[3.5]nonane-2-carboxylate as a solid. MS: 237 (M+H-tBu).

[0458] Step 3 : To a solution of pyridine (314 μL, 3.90mmol) in DCM (2.5mL) was added a solution of phenylselenyl chloride (747mg, 3.90mmol) in DCM (2.5mL) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes, followed by the addition of a solution of 8-cyano-6,6-dimethyl-7-oxo-2-azaspiro [3.5] nonane-2-tert-butyl formate (570mg, 1.95mmol) in DCM (5mL). The reaction mixture was stirred at 0°C for 1h, then washed with 1M HCl aqueous solution (8mL), then washed with water (16mL). The phases were separated, and the organic phase was treated with hydrogen peroxide (30% in water, 4.0mL, 39mmol) at 0°C. The reaction mixture was vigorously stirred for 15 minutes, then separated, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-40% EtOAc / hexanes) to give tert-butyl 6-cyano-8,8-dimethyl-7-oxo-2-azaspiro[3.5]non-5-ene-2-carboxylate as a solid. MS: 235 (M+H-tBu).

[0459] Step 4To a solution of tert-butyl 6-cyano-8,8-dimethyl-7-oxo-2-azaspiro[3.5]non-5-ene-2-carboxylate (465 mg, 1.60 mmol) in DCM (16 mL) was added HCl (4 M in THF, 4.0 mL, 16 mmol). The mixture was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure to yield 8,8-dimethyl-7-oxo-2-azaspiro[3.5]non-5-ene-6-carbonitrile as the HCl salt. MS: 191 (M+H).

[0460] Option 11:

[0461]

[0462] Intermediate 10: 7,7-Dimethyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,3′-pyrrolidine] hydrochloride

[0463] Step 1: To a solution of tert-butyl 7,7-dimethyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,35-pyrrolidine]-11-carboxylate (2 g, 6.53 mmol) in 2-MeTHF (10 mL) was added hydrochloride (4 M in dioxane, 30 mL). The resulting mixture was stirred at 18 ° C for 2 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo. The residue was co-evaporated with THF (15 mL×5) to provide 7,7-dimethyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,3′-pyrrolidine] hydrochloride (1.585 g, 6.53 mmol, 100% yield) as a light yellow solid. 12 H 18 N2O[M+H] + MS ESI calculated value: 207.14, found: 207.10. 1 H-NMR (300MHz, DMSO-d6) δ9.39 (s, 2H), 8.38 (s, 1H), 3.32-3.14 (m, 2H), 3.11-3.01 (m, 1H), 2.96-2.83 (m, 1H), 2.57 (d, J=15.7Hz, 1H), 2.42 (d, J=15.7Hz, 1H), 1.91-1.75 (m, 4H), 1.29 (s, 3H), 1.26 (s, 3H).

[0464] Table 3 : The following intermediates were prepared using a similar procedure as described above for Intermediate 10.

[0465]

[0466] Plan 11 :

[0467]

[0468] Intermediate 13: N-methyl-N-(1-methyl-4-oxocyclohexyl)benzamide

[0469] Step 1 : To 8- methyl -1,4- dioxaspiro [4.5] decane -8- amine (1.89g, 11.0mmol) in DCM (10mL) solution, add triethylamine (6.12mL, 44.1mmol) and benzoyl chloride (2.56mL, 22.1mmol). The reaction is stirred at room temperature overnight. The mixture is quenched with HCl aqueous solution (1M, 10mL) and extracted with DCM (2x). The combined organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is passed through column chromatography (0-70% Et2O / hexane) on silica gel to be provided as solid N- (8- methyl -1,4- dioxaspiro [4.5] decane -8- yl) benzamide. MS: 276 (M+H).

[0470] Step 2 To N-(8-methyl isophthalic acid, 4-dioxaspiro [4.5] last -8-yl) benzamide (2.76g, 10.0mmol) in DCM (10mL) solution, add sodium hydride (1.00g, 25.1mmol) and iodomethane (2.18mL, 35.1mmol).Reactant mixture is stirred at room temperature overnight.Reactant mixture is quenched with the HCl aqueous solution (1M, 10mL), and extracted with DCM (2x).By the organic layer merged through anhydrous sodium sulfate drying, filter, and under reduced pressure concentrate to be provided as solid N-methyl-N-(8-methyl isophthalic acid, 4-dioxaspiro [4.5] last -8-yl) benzamide, it is used without further purification.MS: 290(M+H).

[0471] Step 3 : A solution of N-methyl-N-(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)benzamide (2.9g, 10mmol) in acetone (11mL), HCl (37% by weight in H2 O, 5.5mL) and water (5.5mL) was stirred at room temperature overnight. The reaction mixture was neutralized with an aqueous NaOH solution (2M) and extracted with EtOAc (2x). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Residue was purified by column chromatography (0-100% Et2 O / hexane) on silica gel to provide N-methyl-N-(1-methyl-4-oxocyclohexyl)benzamide as a solid. MS: 246 (M+H).

[0472] Plan 12 :

[0473]

[0474] Intermediate 14: N,N-dimethyl-4-oxo-1-phenylcyclohexane-1-carboxamide

[0475] Step 1 To 4-oxo-1-phenylcyclohexane-1-methyl-formiate (1.4g, 6.0mmol) in THF (18mL) and MeOH (9mL) solution, add sodium hydroxide (2.0M in water, 9.0mL, 18mmol).Reactant mixture is stirred at room temperature overnight.Then the saturated NH of reaction mixture is quenched by the Cl aqueous solution (10mL), and extracted with EtOAc (2x).By the organic layer merged through anhydrous sodium sulfate drying, filter, and under reduced pressure concentrate to be provided as solid 4-oxo-1-phenylcyclohexane-1-formic acid, it is used without further purification.MS:219(M+H).

[0476] Step 2 A solution of 4-oxo-1-phenylcyclohexane-1-carboxylic acid (1.3 g, 6.0 mmol), dimethylamine (2.0 M in THF, 4.5 mL, 9.0 mmol), N,N-diisopropylethylamine (2.1 mL, 12 mmol) and HATU (2.85 g, 7.50 mmol) in DMF (7.5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with aqueous HCl (1 M), saturated NaHCO aqueous solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20-90% Et2O / hexane) to provide N,N-dimethyl-4-oxo-1-phenylcyclohexane-1-carboxamide as a solid. MS: 246 (M+H).

[0477] Plan 13 :

[0478]

[0479] Intermediate 15: 6,6-Dimethyl-1,4-dioxaspiro[4.5]decan-8-one

[0480] Step 1:To a solution of cyclohexane-1,4-diol (100 g, 860 mmol) in DMF (2.5 L) was added NaH (68.9 g, 1.72 mol) at 0°C. Benzyl bromide (161 g, 946 mmol) was then added dropwise, and the resulting solution was stirred at ambient temperature for 12 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (3x). The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: petroleum ether (1:50 to 1:3) to produce 4-(benzyloxy)cyclohexane-1-ol. 1 H NMR (400MHz, CDCl3) δ7.23-7.39 (m, 5H), 4.53 (d, J=5.6Hz, 2H), 3.63-3.79 (m, 1H), 3.34-3.52 (m, 1H), 1.96- 2.10 (m, 2H), 1.85-1.94 (m, 1H), 1.63-1.77 (m, 2H), 1.54-1.62 (m, 1H), 1.24-1.48 (m, 3H), 1.24-1.48 (m, 1H).

[0481] Step 2: To a solution of 4-(benzyloxy)cyclohexan-1-ol (7.00 g, 33.9 mmol) in DCM (140.0 mL) was added PCC (10.9 g, 50.9 mmol) and (10.9 g). The resulting mixture was stirred for 12 h. The reaction mixture was filtered and washed with saturated sodium bicarbonate solution (2x). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: petroleum ether (1:5 to 1:3) to provide 4-(benzyloxy)cyclohexane-1-one. MS: 205 (M+H).

[0482] Step 3: To a solution of 4-(benzyloxy)cyclohexane-1-one (100 g, 489 mmol) in t-BuOH (1.0 L) was added potassium tert-butoxide (137 g, 1.22 mol). The resulting mixture was stirred at ambient temperature for 1 h. Iodomethane (145 g, 1.03 mol) was added dropwise and the mixture was stirred at ambient temperature for 1 h. The mixture was then quenched with saturated aqueous NH4Cl solution (5.0 L) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine (1.0 L) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: petroleum ether (1: 100 to 5: 100) to produce 4-(benzyloxy)-2,2-dimethylcyclohexane-1-one. MS: 233 (M+H).

[0483] Step 4:To a solution of 4-(benzyloxy)-2,2-dimethylcyclohexane-1-one (132 g, 568 mmol) in toluene (2.0 L) was added 4-methylbenzenesulfonic acid (7.81 g, 45.3 mmol) and ethane-1,2-diol (105 g, 1.70 mol) at ambient temperature. The resulting mixture was refluxed under azeotropic conditions for 12 h. After cooling, the mixture was poured into a saturated sodium bicarbonate solution (3.0 L) and extracted with ethyl acetate (3x). The combined organic layers were washed with brine (800 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ACN / H2O, containing 10 mM NH4HCO3 as a modifier) ​​to produce 8-(benzyloxy)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane. MS: 277 (M+H).

[0484] Step 5: To a solution of 8-(benzyloxy)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane (55.0 g, 199 mmol) in methanol (500 mL) was added Pd / C (10%, 25.0 g) at ambient temperature under a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 h under a H2 atmosphere (20 psi). The mixed reaction was filtered and the filtrate was concentrated under reduced pressure to provide 6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol, which was used in the next step without further purification. MS: 187 (M+H).

[0485] Step 6: To a solution of 6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol (51.0 g, 273 mmol) in dichloromethane (1.0 L) was added PCC (106 g, 493 mmol) and (106 g). The resulting mixture was stirred for 2 h. The reaction mixture was filtered and washed with saturated sodium bicarbonate solution (3x). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: petroleum ether (1:50 to 1:30) to provide 6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-one. MS: 185 (M+H).

[0486] Plan 14 :

[0487]

[0488] Intermediate 16: 5′-Chloro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-4-one

[0489] Step 1To (2-bromo-5-chlorophenyl) methanol (2.22g, 10.0mmol) in THF (30mL) was added n-butyl lithium (2.5M in hexane, 8.0mL, 20mmol) at -78 ° C. The suspension obtained was stirred at -78 ° C for 45 minutes. A solution of 1,4-dioxaspiro [4.5] decane-8-one (1.56g, 10.0mmol) in THF (3mL) was added, and the reaction mixture was stirred at -78 ° C for 1h. The reaction mixture was then quenched with saturated NH4Cl aqueous solution (10mL), warmed to room temperature, and extracted with EtOAc (3x). The organic layer merged was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% MeOH / DCM) to afford 8-(4-chloro-2-(hydroxymethyl)phenyl)-1,4-dioxaspiro[4.5]decan-8-ol as an oil. MS: 281 (M+H-H2O).

[0490] Step 2 Toluenesulfonyl chloride (1.34g, 7.03mmol), triethylamine (1.95mL, 14.1mmol) and 4-dimethylaminopyridine (0.057g, 0.47mmol) are added in the solution of 8-(4-chloro-2-(hydroxymethyl) phenyl)-1,4-dioxaspiro [4.5] decane-8-alcohol (1.4g, 4.7mmol) in DCM (16mL).Reactant mixture is stirred at room temperature overnight.Then the reaction mixture is quenched with the HCl aqueous solution (1M, 10mL), and extracted with DCM (2x).The organic layer merged is filtered through anhydrous sodium sulfate drying, and is under reduced pressure concentrated. The residue was purified by column chromatography on silica gel (0-60% Et2O / hexanes) to afford 5-chloro-3H-dispiro[isobenzofuran-1,1'-cyclohexane-4',2"-[1,3]dioxolane] as a solid. MS: 281 (M+H).

[0491] Step 3 A solution of 5-chloro-3H-dispiro[isobenzofuran-1,1′-cyclohexane-4′,2″-[1,3]dioxolane] (765 mg, 2.72 mmol) in acetone (3.6 mL), THF (3.6 mL), hydrochloric acid (37 wt % in H2O, 1.8 mL) and water (1.8 mL) was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous NaOH (2 M) and extracted with EtOAc (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-70% Et2O / hexanes) to afford 5′-chloro-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-4-one as a solid. MS: 237 (M+H).1 H NMR (600MHz, CDCl3) δ7.29 (s, 1H), 7.26 (width s, 1H), 7.04 (d, J = 8.0Hz, 1H), 5.14 (s, 2H), 2.94-2.85 (m, 2H), 2.44-2.38 (m, 2H), 2.18-2.10 (m, 4H).

[0492] Table 2 : The following intermediates were prepared using a similar procedure as described above for Intermediate 16.

[0493]

[0494] Plan 15 :

[0495]

[0496] Intermediate 20: 3′-Methyl-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-4-one

[0497] Step 1 : To a solution of 1-(2-bromophenyl)ethane-1-ol (1.97 g, 9.80 mmol) in THF (30 mL) was added n-butyllithium (2.5 M in hexane, 7.84 mL, 19.6 mmol) at -78 ° C. The resulting suspension was stirred at -78 ° C for 1 h. A solution of 1,4-dioxaspiro[4.5]decane-8-one (1.53 g, 9.80 mmol) in THF (3 mL) was added, and the reaction mixture was stirred at -78 ° C for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% Et2O / hexanes) to afford 8-(2-(1-hydroxyethyl)phenyl)-1,4-dioxaspiro[4.5]decan-8-ol as an oil. MS: 261 (M+H-H2O).

[0498] Step 2 : A solution of 8- (2- (1- hydroxyethyl) phenyl) -1,4- dioxaspiro [4.5] decane -8- alcohol (1.25 g, 4.49 mmol) in DCM (9 mL) and TFA (9 mL) was stirred at room temperature overnight. The reaction mixture was quenched with an aqueous NaOH solution (2 M) and extracted with DCM (3x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-45% Et2O / hexane) on silica gel to provide 3'-methyl -3'H- spiro [cyclohexane -1,1'- isobenzofuran] -4- one as a solid. MS: 217 (M+H).

[0499] Table 3 : The following intermediates were prepared using a similar procedure as described above for Intermediate 20.

[0500]

[0501] Plan 15 :

[0502]

[0503] Intermediate 22: 5′-(Trifluoromethyl)-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-4-one

[0504] Step 1 : To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (3 g, 11.8 mmol) in THF (35 mL) was added n-butyllithium (2.5 M in hexane, 9.41 mL, 23.5 mmol) at -78 ° C. The resulting suspension was stirred at -78 ° C for 1 h. A solution of 1,4-dioxaspiro[4.5]decane-8-one (1.84 g, 11.8 mmol) in THF (4 mL) was added, and the reaction mixture was stirred at -78 ° C for 3 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% Et2O / hexanes) to afford 8-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)-1,4-dioxaspiro[4.5]decan-8-ol as an oil. MS: 315 (M+H-H2O).

[0505] Step 2 Toluenesulfonyl chloride (1.8g, 9.4mmol), triethylamine (2.6mL, 18.8mmol) and 4-dimethylaminopyridine (77mg, 0.63mmol) are added in the solution of 8-(2-(hydroxymethyl)-4-(trifluoromethyl) phenyl)-1,4-dioxaspiro [4.5] decane-8-alcohol (2.09g, 6.29mmol) in DCM (21mL).Reactant mixture is stirred at room temperature overnight.Then the reaction mixture is quenched with the HCl aqueous solution (1M, 10mL), and extracted with DCM (2x).The organic layer merged is filtered through anhydrous sodium sulfate drying, and is under reduced pressure concentrated. The residue was purified by column chromatography on silica gel (0-60% Et2O / hexanes) to afford 5-(trifluoromethyl)-3H-dispiro[isobenzofuran-1,1′-cyclohexane-4′,2″-[1,3]dioxolane] as an oil. MS: 315 (M+H).

[0506] Step 3 A solution of 5-(trifluoromethyl)-3H-dispiro[isobenzofuran-1,1′-cyclohexane-4′,2″-[1,3]dioxolane] (1.2 g, 3.8 mmol) in DCM (6.5 mL) and TFA (6.5 mL) was stirred at room temperature overnight. The reaction mixture was quenched with aqueous NaOH (2 M, 10 mL) and extracted with DCM (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-70% Et2O / hexanes) to afford 5′-(trifluoromethyl)-3′H-spiro[cyclohexane-1,1′-isobenzofuran]-4-one as an oil. MS: 271 (M+H).

[0507] Option 16:

[0508]

[0509] Intermediate 23: 7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridin]-4-one

[0510] Step 1: To a stirred mixture of (3-bromopyridin-2-yl)methanol (8 g, 42.5 mmol) and 1,4-dioxaspiro[4.5]decane-8-one (6.65 g, 42.5 mmol) in THF (110 mL) was added N-butyllithium (2.5 M in hexane, 34.0 mL, 85 mmol) at -78 ° C. The mixture was stirred at 0 ° C for 2 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic phases were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by RP-Combi-Flash chromatography using the following conditions: column: C18 gel column (330 g), 20-45 μm, 19×150 mm; mobile phase A: 5 mM aqueous NH4HCO3; mobile phase B: MeCN; gradient: 20% for 7 min, up to 35% in 20 min; flow rate: 100 mL / min; detector: UV 254 and 210 nm; RT: 15 min to give 8-(2-(hydroxymethyl)pyridin-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.6 g, 6.03 mmol, 14% yield) as a yellow oil. MS: m / z=266.15 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 8.46-7.45 (m, 1H), 7.56-7.32 (m, 1H), 7.23-7.20 (m, 1H), 5.03 (s, 2H), 4.03-3.95 (m, 4H), 2.20-2.07 (m, 4H), 1.95-1.88 (m, 2H), 1.72-1.69 (m, 2H).

[0511] Step 2: To a stirred mixture of 8-(2-(hydroxymethyl)pyridin-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.6 g, 6.03 mmol) in DCM (5 mL) was added 4-dimethylaminopyridine (0.074 g, 0.603 mmol), triethylamine (1.831 g, 18.09 mmol) and trifluoromethanesulfonic anhydride (2.55 g, 9.05 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by LCMS. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×40 mL). The combined organic phases were washed with brine (40 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 60-75% EA / PE to give 7H-dispiro[furo[3,4-b]pyridine-5,1′-cyclohexane-4′,2″-[1,3]dioxolane] (800 mg, 3.24 mmol, 53% yield) as a yellow oil. MS: m / z = 248.20 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.48-8.47 (m, 1H), 7.49-7.47 (m, 1H), 7.20-7.17 (m, 1H), 5.06 (s, 2H), 4.04-3.97 (m, 4H), 2.13-1.94 (m, 4H), 1.90-1.76 (m, 2H), 1.75-1.72 (m, 2H).

[0512] Step 3:To a stirred mixture of 7H-dispiro[furo[3,4-b]pyridine-5,1′-cyclohexane-41,2″-[1,3]dioxolane] (800 mg, 3.24 mmol) in THF (5 mL) was added hydrochloric acid (5 mL, 18.00 mmol, 2 M) at ambient temperature. The mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by LCMS. After the reaction was complete, the mixture was quenched with saturated NaHCO (15 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by RP-Flash chromatography using the following conditions: Column: C 18 gel column (80 g), 20-35 μm, 19×150 mm; Mobile phase A: 5 mM Aqueous NH4HCO3; Mobile phase B: MeCN; Gradient: 0% for 5 min, 38% over 20 min, 38% for 2.2 min. Flow rate: 70 mL / min; Detectors: UV254 and 210 nm; RT: 15 min to afford 7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridin]-4-one (500 mg, 2.460 mmol, 76% yield) as a white solid. MS: m / z = 204.20 [M+H] + . 1 H NMR (300 MHz, CHLOROFORM-d) δ 8.56-8.54 (m, 1H), 7.47-7.44 (m, 1H), 7.25-7.21 (m, 1H), 5.17 (s, 2H), 3.01-2.89 (m, 2H), 2.46-2.38 (m, 2H), 2.26-2.09 (m, 4H).

[0513] Option 17:

[0514]

[0515] Intermediate 24: 3H-spiro[benzofuran-2,1′-cyclohexane]-4′-one

[0516] Step 1Under nitrogen atmosphere, 12 (0.163 g, 0.64 mmol) was added to a suspension of magnesium stick (1.56 g, 64.0 mmol) in ether (20 mL), followed by 1-(bromomethyl)-2-fluorobenzene (0.24 g, 1.28 mmol). A high-intensity heat gun was used to initiate the reaction, followed by the slow addition of 1-(bromomethyl)-2-fluorobenzene (4.84 g, 25.6 mmol) in ether (5.0 mL) at a rate that maintained a gentle reflux. After the addition was complete, the reaction mixture was refluxed for 3 hours, cooled to room temperature, and a solution of 1,4-dioxaspiro[4.5]decane-8-one (2.0 g, 12.81 mmol) in ether (5.0 mL) and tetrahydrofuran (5.0 mL) was slowly added under vigorous stirring. After the addition was complete, the reaction mixture was placed at room temperature for 3 hours. NH4Cl aqueous solution (50 mL) was added, and the mixture was stirred at room temperature overnight, extracted with ethyl acetate (3x150 mL), washed with water (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EA:PE = 0%-30% to produce 8-(2-fluorobenzyl)-1,4-dioxaspiro[4.5]decan-8-ol (3.00 g, 11.27 mmol, 88% yield) as a light yellow solid. 1 H NMR (300 MHz, chloroform-d): δ 7.28-7.21 (m, 2H), 7.14-7.04 (m, 2H), 3.97 (d, J=1.8 Hz, 4H), 2.86 (d, J=1.8 Hz, 2H), 1.98-1.72 (m, 4H), 1.70-1.62 (m, 4H).

[0517] Step 2 : by 8-(2-fluorobenzyl)-1,4-dioxaspiro [4.5] decane-8-alcohol (2.4g, 9.01mmol) and sodium hydride (60 % by weight dispersion in mineral oil, 511mg, 11.73mmol) in toluene (21mL) 110 ℃ of heating 5 minutes.Add DMF (7mL) and mixture was stirred 30 minutes at 110 ℃, then it is cooled to room temperature.Reaction mixture is quenched with water (100mL), and extracted with ethyl acetate (3x100mL).The organic layer merged is washed with salt solution (2x200mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with EA:PE = 5%-40% to afford 3H-dispiro[1-benzofuran-2,1′-cyclohexane-4′,2″-[1,3]dioxolane] (1.9 g, 7.71 mmol, 86% yield) as a pale yellow solid. MS: m / z = 247.10 [M+H] + . 1H NMR (300 MHz, chloroform-d): δ 7.23-7.11 (m, 2H), 6.86-6.77 (m, 2H), 4.06-3.96 (m, 4H), 3.03 (s, 2H), 2.10-2.00 (m, 4H), 1.93-1.68 (m, 4H).

[0518] Step 3 To a solution of 3H-dispiro[1-benzofuran-2,1′-cyclohexane-41,2″-[1,3]dioxolane] (1.9 g, 7.71 mmol) in tetrahydrofuran (8 mL) was added 1N aqueous HCl (8.0 mL, 97 mmol) dropwise at 0° C. under argon atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 3 h. The reaction mixture was quenched with water (50 mL) and the pH of the solution was adjusted with 1N The NaHCO3 aqueous solution was adjusted to 6-7. The reaction mixture was extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with EA: PE = 5-40% to provide 3H-spiro [benzofuran -2,1 '- cyclohexane] -4 '- one (1.3 g, 6.43 mmol, 83% yield) as a light yellow solid. MS: m / z = 203.05 [M + H] + . 1 H NMR (300 MHz, chloroform-d): δ 7.21-7.15 (m, 2H), 6.92-6.82 (m, 2H), 3.12 (s, 2H), 2.93-2.82 (m, 2H), 2.42-2.32 (m, 4H), 2.08-1.98 (m, 2H).

[0519] Table 4 : The following intermediates were prepared using a similar procedure as described above for Intermediate 24.

[0520]

[0521] Plan 18 :

[0522]

[0523] Intermediate 26: Spiro[cyclohexane-1,3′-isochroman]-4-one

[0524] Step 1Under nitrogen atmosphere, to a suspension of magnesium stick (2.45g, 101mmol) in ether (40.0mL), I2 (0.26g, 1.024mmol) was added, followed by 1-bromo-2-(bromomethyl) benzene (0.34g, 1.35mmol). A high-intensity heat gun was used to initiate the reaction, followed by a slow addition of 1-bromo-2-(bromomethyl) benzene (5.04g, 20.17mmol) in ether (10.0mL) at a speed that maintained a gentle reflux. After addition was complete, the reaction mixture was refluxed for 3 hours, cooled to room temperature, and under vigorous stirring, a solution of 1,4-dioxaspiro[4.5]decane-8-one (2.1g, 13.45mmol) in ether (10.0mL) and tetrahydrofuran (10.0mL) was slowly added. After addition was complete, the reaction mixture was placed at room temperature for 3 hours. NH4Cl aqueous solution (40 mL) was added and the mixture was stirred at room temperature overnight, extracted with ethyl acetate (200 mL×3), washed with H2O (300 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0%-30% ethyl acetate / petroleum ether to produce 8-(2-bromobenzyl)-1,4-dioxaspiro[4.5]decane-8-ol (3.3 g, 10.09 mmol, 75% yield) as a light yellow solid. 1 H NMR (300 MHz, chloroform-d): δ 7.59 (dd, J=8.0, 1.3 Hz, 1H), 7.38-7.18 (m, 2H), 7.17-7.06 (m, 1H), 3.97 (s, 4H), 3.04 (s, 2H), 1.98-1.58 (m, 8H).

[0525] Step 2 : At -78 DEG C, n-butyllithium (2.5M in n-hexane, 4.89mL, 12.22mmol) is added dropwise to a solution of 8-(2-bromobenzyl)-1,4-dioxaspiro [4.5] decane-8-ol (2.0g, 6.11mmol) in tetrahydrofuran (15.0mL). The resulting solution is stirred at 0 DEG C for 1h under a nitrogen atmosphere. At -78 DEG C, dimethylformamide (2.37mL, 30.6mmol) is added to the mixture, and the resulting solution is stirred at 0 DEG C for 1.5h. The reaction mixture is quenched with saturated ammonium chloride (50mL), and extracted with ethyl acetate (100mL×3). The combined organic layer is washed with brine (100mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude 2-((8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)methyl)benzaldehyde (1.689 g, 6.11 mmol, 100% yield) as a light yellow oil, which was used directly in the next step.

[0526] Step 3 : To a mixture of 2-((8-hydroxy-1,4-dioxaspiro[4.5]decane-8-yl)methyl)benzaldehyde (1.689 g, 0.00 mmol) in methanol (8.0 mL) was added sodium borohydride (0.35 g, 9.17 mmol) at ambient temperature, and the mixture was stirred at this temperature under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a gradient of 1:100 to 1:20 methanol / dichloromethane to produce 8-(2-(hydroxymethyl)benzyl)-1,4-dioxaspiro[4.5]decane-8-ol (1.3 g, 4.67 mmol, 76% yield) as a colorless oil. 16 H 22 O4[M+Na] + MS ESI calculated value 301.14, found 301.15. 1 H NMR (300 MHz, chloroform-d): δ 7.42-7.35 (m, 1H), 7.35-7.23 (m, 2H), 7.23-7.14 (m, 1H), 4.65 (s, 2H), 3.98 (s, 4H), 2.92 (s, 2H), 1.93-1.58 (m, 8H).

[0527] Step 4 : Phosphoric acid (85% in water, 1.5 mL, 5.39 mmol) was added to a solution of 8-(2-(hydroxymethyl)benzyl)-1,4-dioxaspiro[4.5]decane-8-ol (1.5 g, 5.39 mmol) in toluene (15 mL) at ambient temperature. The mixture was stirred at 110 ° C for 1 h. The toluene was then removed by distillation, and the resulting residue was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 10%-60% ethyl acetate / petroleum ether to provide spiro[cyclohexane-1,3′-isochroman]-4-one (800 mg, 3.70 mmol, 67% yield) as a light yellow solid. 14 H 16 O2[M+H] + MS ESI calculated value 217.12, found 217.10. 1H NMR (300 MHz, chloroform-d): δ 7.31-7.16 (m, 2H), 7.15-7.05 (m, 2H), 4.87 (s, 2H), 2.79 (s, 2H), 2.78-2.67 (m, 2H), 2.37-2.12 (m, 4H), 1.88-1.76 (m, 2H).

[0528] Scheme 19:

[0529]

[0530] Intermediate 27: 1′,4′-dihydro-2′H-spiro[cyclohexane-1,3′-quinoline]-2′,4-dione

[0531] Step 1: To a solution of 1-methyl-4-oxocyclohexane-1-formic acid (2g, 12.81mmol) in DCM (25ml) was added N,N-dimethylformamide (0.099ml, 1.281mmol) and oxalyl chloride (1.625g, 12.81mmol) at 0°C. The resulting mixture was stirred at 25°C for 2h. After the reaction was complete, the reaction mixture was concentrated in a vacuum. Residue was co-evaporated 3 times with DCM to provide 1-methyl-4-oxocyclohexane-1-formyl chloride (2.237g, 12.81mmol, 100% yield) as a light yellow solid.

[0532] Step 2: To a solution of 1-methyl-4-oxocyclohexane-1-carbonyl chloride (2.237g, 12.81mmol) in DCM (25mL), N,N-diisopropylethylamine (3.31g, 25.6mmol) and 2-bromoaniline (4.41g, 25.6mmol) in DCM (1mL) was added. The resulting mixture was stirred at 25°C for 16h. The reaction mixture was concentrated in a vacuum. The residue was purified by silica gel column chromatography using a gradient of 10%-70% ethyl acetate / petroleum ether as eluent. The fractions containing the desired product were merged and concentrated under reduced pressure to provide N-(2-bromophenyl)-1-methyl-4-oxocyclohexane-1-formamide (3.6g, 11.61mmol, 91% yield) as a light yellow solid. 14 H 16 BrNO2[M+H] + MS ESI calculated value 310.04, found 310.00. 1H-NMR (300MHz, chloroform-d) δ8.34 (dd, J=8.3, 1.6Hz, 1H), 8.04 (brs, 1H), 7.56 (dd, J=8.0, 1.5Hz, 1H), 7.39- 7.30 (m, 1H), 7.07-6.96 (m, 1H), 2.70-2.53 (m, 2H), 2.53-2.33 (m, 4H), 1.96-1.78 (m, 2H), 1.47 (s, 3H).

[0533] Option 20:

[0534]

[0535] Intermediate 28: 3,3-Dimethyl-5′,6′-dihydrospiro[cyclohexane-1,8′-imidazo[2,1-c][1,4]oxazine]- 4-Keto

[0536] Step 1: To a solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazole (5.59 g, 24.69 mmol) in THF (30 mL) was added n-butyllithium (2.5 M in n-hexane, 9.87 mL, 24.69 mmol) at -78 ° C, and the mixture was stirred for 30 min. A solution of 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-one (3.79 g, 20.57 mmol) in THF (21 mL) was then added to the above mixture at -78 ° C, and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude 8-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazol-2-yl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol (8.44 g), which was used directly in the next step. 21 H 38 N2O4Si[M+H] + MS ESI calculated value 411.26, found 411.25.

[0537] Step 2:To a solution of 8-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazol-2-yl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol (8.44 g, 20.57 mmol) in THF (66 mL) was added hydrofluoride (70% in pyridine, 25.6 mL) at 0° C., and the solution was stirred at 0° C. for 20 min and at room temperature for 1 h. The reaction mixture was quenched with saturated sodium bicarbonate (100 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography using the following conditions: Column AQ C 18 Spherical 20-35 μm; mobile phase: 0%-30% acetonitrile / water, UV 210 nm. The collected fractions were combined and concentrated under reduced pressure to produce 8-(1-(2-hydroxyethyl)-1H-imidazol-2-yl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol (3.18 g, 10.72 mmol, 52.1% yield) as a white solid. 15 H 24 N2O4[M+H] + MS ESI calculated value: 279.17, found: 279.20. 1 H-NMR (400 MHz, chloroform-d) δ 7.07 (d, J = 1.2 Hz, 1H), 6.69 (d, J = 1.2 Hz, 1H), 5.10 (s, 1H), 4.96 (t, 1H), 4.32-4.22 (m, 2H), 3.98-3.76 (m, 4H), 3.72-3.62 (m, 2H), 2.37-2.21 (m, 1H), 2.11-1.76 (m, 5H), 1.11 (s, 3H), 0.67 (s, 3H).

[0538] Step 3: To a solution of 8-(1-(2-hydroxyethyl)-1H-imidazol-2-yl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-ol (3.177 g, 10.72 mmol) in DCM (78 mL) was added 4-dimethylaminopyridine (0.131 g, 1.072 mmol), triethylamine (3.25 g, 32.2 mmol) and p-toluenesulfonyl chloride (3.07 g, 16.08 mmol) at room temperature, and the mixture was stirred for 16 h. The reaction mixture was quenched with water (60 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using the following conditions: Column AQ C 18Spherical 20-40 μm; mobile phase: 0%-50% acetonitrile / water, UV 210 nm. The collected fractions were combined and concentrated under reduced pressure to produce 2-(2-(8-hydroxy-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-yl)-1H-imidazol-1-yl)ethyl 4-methylbenzenesulfonate (3.3 g, 7.32 mmol, 68.3% yield) as a yellow oil. 22 H 30 N2O6S[M+H] + MS ESI calculated value 451.18, found value 451.25. 1 H-NMR (400 MHz, chloroform-d) δ 7.68 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 1.5 Hz, 1H), 6.87 (d, J = 1.4 Hz, 1H), 4.55-4.51 (m, 2H), 4.35-4.25 (m, 2H), 4.01-3.92 (m , 2H), 3.92-3.88 (m, 2H), 2.44 (s, 3H), 2.43-2.32 (m, 1H), 2.16 (d, J=14.3Hz, 1H), 2 .07-2.02 (m, 1H), 1.88-1.80 (m, 1H), 1.74-1.60 (m, 2H), 1.20 (s, 3H), 0.80 (s, 3H).

[0539] Step 4: To a mixture of sodium hydride (60% in mineral oil, 0.439 g, 10.99 mmol) in DMF (25 mL) was added a solution of 4-methylbenzenesulfonic acid 2-(2-(8-hydroxy-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-yl)-1H-imidazol-1-yl)ethyl ester (3.3 g, 7.32 mmol) in DMF (25 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 min and at room temperature for 4 h. The reaction mixture was quenched with NH4Cl (60 mL) and extracted with ethyl acetate (70 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 1-70% EtOAc / petroleum ether to afford 2′,2′-dimethyl-5,6-dihydrodispiro[imidazo[2,1-c][1,4]oxazine-8,4′-cyclohexane-1′,2″-[1,3]dioxolane] (786 mg, 2.82 mmol, 38.6% yield) as a white solid. 15 H 22 N2O3[M+H] + MS ESI calculated value: 279.16, found: 279.15.1 H NMR (400 MHz, chloroform-rhenium δ 7.03 (s, 1H), 6.81-6.76 (m, 1H), 4.10-3.90 (m, 8H), 2.49 (t, J = 13.3 Hz, 1H), 2.26 (d, J = 14.7 Hz, 1H), 2.09 (td, J = 13.7, 3.8 Hz, 1H), 1.95 (dd, J = 14.0, 3.4 Hz, 1H), 1.85 (dd, J = 14.8, 3.2 Hz, 1H), 1.59-1.51 (m, 1H), 1.24 (s, 3H), 0.89 (s, 3H).

[0540] Step 5: To a solution of HCl (1.5 M in water, 10 mL, 15.00 mmol) was added a solution of 2′,2′-dimethyl-5,6-dihydrodispiro[imidazo[2,1-c][1,4]oxazine-8,4′-cyclohexane-1′,2″-[1,3]dioxolane] (786 mg, 2.82 mmol) in THF (10 mL) at room temperature, and the solution was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated sodium bicarbonate (20 mL) and washed with acetic acid. The product was concentrated under reduced pressure. The mixture was stirred for 2 hours and then dried over 40 minutes. The mixture was stirred for 2 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 3 hours. 13 H 18 N2O2[M+H] + MS ESI calculated value 235.14, found value 235.15. 1 H-NMR (300 MHz, chloroform-d) δ 7.02 (d, J = 1.3 Hz, 1H), 6.83 (d, J = 1.3 Hz, 1H), 4.29-3.87 (m, 4H), 3.07-2.84 (m, 1H), 2.65-2.01 (m, 5H), 1.34 (s, 3H), 1.10 (s, 3H).

[0541] Option 21:

[0542]

[0543] Intermediate 29: 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 Tetradecan-12-ol

[0544] Intermediate 30: 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradecan-12-one

[0545] Intermediate 31: 1′,3,3-trimethyl-1′,4′-dihydrospiro [ Cyclohexane-1,6′-furo[3,4-c]pyrazole]-4- ketone

[0546] Step 1: To a solution of (3-(benzyloxy)propyl)triphenylphosphonium bromide (10.06 g, 20.46 mmol) in THF (23 mL) was added n-butyl lithium (2.5 M in hexane, 8.19 mL, 20.46 mmol) at 0°C, and the solution was stirred at 25°C for 2 hours. A solution of 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-one (2.9 g, 15.74 mmol) in THF (5 mL) was then added dropwise to the above solution at 0°C. The resulting mixture was stirred at 25°C for 6 hours. After the reaction was completed, the reaction mixture was quenched with aqueous NH4Cl solution and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), then washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 10% to 40% ethyl acetate / petroleum ether as eluent. The fractions containing the desired product were combined and concentrated under reduced pressure to provide 8-(3-(benzyloxy)propylidene)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane (4.05 g, 12.80 mmol, 81% yield) as a light yellow solid. 20 H 28 O3[M+H] + MS ESI calculated value 317.20, found 317.15. 1 H-NMR (400 MHz, chloroform-d) δ 7.40-7.29 (m, 5H), 5.26 (t, J = 7.2 Hz, 0.5H), 5.13 (t, J = 7.3 Hz, 0.5H), 4.51 (s, 2H), 4.01-3.87 (m, 4H), 3.49-3.40 (m, 2H), 2.40-2.28 (m, 2H), 2.28-2.15 (m, 2H), 2.14 (s, 1H), 2.07 (s, 1H), 1.67-1.55 (m, 2H), 0.94 (s, 3H), 0.92 (s, 3H).

[0547] Step 2:To a solution of 8-(3-(benzyloxy)propylidene)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane (3.5 g, 11.06 mmol) in DCM (175 mL) and 0.5 M aqueous sodium bicarbonate solution (53 mL) was added m-CPBA (85%, 2.863 g, 14.10 mmol) at 0°C under an argon atmosphere. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was diluted with DCM (250 mL), then washed with 0.5 M aqueous sodium bicarbonate solution (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by RP-Combi-Flash using the following conditions: Column: AQ-C 18 OBD column, 330 g; mobile phase A: 10 mM NH4HCO3 aqueous solution, mobile phase B: MeCN; flow rate: 100 mL / min; gradient: 0%-100% in 35 min. Detector: UV 254 and 210 nm; fractions containing the desired product were combined and concentrated under reduced pressure to provide 2-(2-(benzyloxy)ethyl)-5,5-dimethyl-1,7,10-trioxadispiro[2.2.4 6 .2 3 ] dodecane (2.96 g, 8.90 mmol, 80.5% yield). 20 H 28 O4[M+Na] + MS ESI calculated value 355.20, found 355.25. 1 H-NMR (300 MHz, chloroform-d) δ 7.43-7.30 (m, 5H), 4.62-4.47 (m, 2H), 4.10-3.88 (m, 4H), 3.82-3.53 (m, 2H), 2.95-2.72 (m, 1H), 2.26-1.50 (m, 8H), 1.13-0.94 (m, 6H).

[0548] Step 3: 2-(2-(benzyloxy)ethyl)-5,5-dimethyl-1,7,10-trioxadispiro[2.2.4 6 .2 3] Dodecane (1.00g, 3.01mmol) is dissolved in MeOH (150mL), and the mixture obtained is evacuated, and argon atmosphere is applied at ambient temperature. Then palladium hydroxide on carbon (20%, 800mg, 1.14mmol) is added under argon atmosphere. The suspension is degassed under vacuum and purged with hydrogen 3 times. The reaction solution is stirred at room temperature for 4 hours under 1 atmosphere of hydrogen. The suspension is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using a gradient of 10%-40% ethyl acetate / petroleum ether as eluent. The fractions containing the desired product are merged, and concentrated under reduced pressure to provide 2-(5,5-dimethyl-1,7,10-trioxadispiro[2.2.4 6 .2 3 ] dodecan-2-yl)ethan-1-ol (684 mg, 2.82 mmol, 93.8% yield). 13 H 22 O4[M+H] + MS ESI calculated value 243.15, found value 243.10. 1 H-NMR (400MHz, DMSO-d6) δ4.60 (t, J=4.3Hz, 0.5H), 5.57 (t, J=4.3Hz, 0.5H), 3.98-3.77 (m, 4H), 3. 63-3.43 (m, 2H), 2.79-2.70 (m, 1H), 1.79-1.34 (m, 8H), 0.98 (s, 1.5H), 0.93 (s, 3H), 0.90 (s, 1.5H).

[0549] Step 4: To a solution of 2-(5,5-dimethyl-1,7,10-trioxadispiro[2.2.46.23]dodecane-2-yl)ethane-1-ol (510 mg, 2.105 mmol) in DCM (5 mL) was added (1S)-(+)-10-camphorsulfonic acid (98 mg, 0.421 mmol). The resulting mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 10%-40% ethyl acetate / petroleum ether as eluent. The fractions containing the desired product were combined and concentrated under reduced pressure to provide 4-hydroxy-7,7-dimethyl-1-oxaspiro[4.5]decane-8-one (320 mg, 1.614 mmol, 77% yield) as a colorless oil. 11 H 18 O3[M+H] + MS ESI calculated value 199.13, found 199.20. 1H-NMR (400MHz, DMSO-d6) δ4.99 (d, J=4.9Hz, 0.5H), 4.93 (d, J=4.1Hz, 0.5H), 3.93-3.72 (m, 3H), 2.73 (ddt, J=13.9, 8 .4, 5.8Hz, 1H), 2.24-2.02(m, 2H), 1.90-1.62(m, 5H), 1.20(s, 1.5H), 1.19(s, 1.5H), 0.97(s, 1.5H), 0.94(s, 1.5H).

[0550] Step 5: To a solution of 4-hydroxy-7,7-dimethyl-1-oxaspiro[4.5]decane-8-one (310 mg, 1.564 mmol) and ethylene glycol (97 mg, 1.564 mmol) in toluene (15 mL) was added p-toluenesulfonic acid (269 mg, 1.564 mmol). The resulting mixture was heated to reflux for 16 hours using a Dean-Stark separator to remove water. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (100 mL), then washed with saturated aqueous sodium bicarbonate solution (10 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to produce 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradecan-12-ol (400 mg, crude), which was used in the next step without further purification. 13 H 22 O4[M+H] + MS ESI calculated value 243.15, found 243.20. 1 H-NMR (400MHz, DMSO-d6) δ 4.90-4.70 (m, 1H), 3.93-3.60 (m, 7H), 2.15-2.00 (m, 1H), 1.83-1.30 (m, 7H), 1.08 (s, 3H), 0.82 (s, 1.5H), 0.78 (s, 1.5H).

[0551] Step 6: To 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5] Tetradecan-12-ol (400 mg, 1.564 mmol, crude) was added to a solution of DCM (10 mL) with Dess-Martin periodinane (1400 mg, 3.30 mmol). The resulting mixture was stirred at 25 ° C for 2 hours. After the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0%-30% ethyl acetate / petroleum ether as eluent to provide 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradecan-12-one (220 mg, 0.916 mmol, 58.6% yield over two steps). 13 H 20 O4[M+H] + MS ESI calculated value 241.14, found value 241.20. 1 H-NMR (400 MHz, chloroform-d) δ 4.28-4.05 (m, 2H), 4.04-3.85 (m, 4H), 2.51 (t, J = 7.3 Hz, 2H), 2.00 (td, J = 13.4, 4.2 Hz, 1H), 1.85-1.71 (m, 2H), 1.71-1.49 (m, 2H), 1.41 (dd, J = 14.1, 2.9 Hz, 1H), 1.22 (s, 3H), 0.90 (s, 3H).

[0552] Step 7: To 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ] To a solution of tetradecane-12-one (240 mg, 0.999 mmol) in diethyl ether (1 mL) were added potassium methoxide (140 mg, 1.998 mmol) and ethyl formate (148 mg, 1.998 mmol). The resulting mixture was stirred at 25 ° C for 2 hours. The reaction progress was monitored by LCMS and TLC. After the reaction was completed, the reaction was quenched with saturated NH4Cl aqueous solution (2 mL). The mixture was concentrated in vacuo. The residue was purified by RP-Combi-Flash using the following conditions: Column: AQ-C 18 OBD column, 40 g; mobile phase A: water (0.1% TFA), mobile phase B: MeCN; flow rate: 40 mL / min; gradient: 5%-60% in 35 min; detector: UV 254 and 210 nm; fractions containing the desired product were combined and concentrated under reduced pressure to provide 11-(hydroxymethylene)-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5]Tetradecan-12-one (256 mg, 0.954 mmol, 96% yield). 14 H 20 O5[M+H] + MS ESI calculated value 269.13, found value 269.10

[0553] Step 8: To 11-(hydroxymethylene)-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradecan-12-one (256 mg, 0.954 mmol) in ethanol (5 mL) was added methylhydrazine dihydrochloride (227 mg, 1.908 mmol) and AcOH (229 mg, 3.82 mmol). The resulting mixture was stirred at 85 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to produce crude 2,2′,2′-trimethyl-2,4-dihydrodispiro[furo[3,4-c]pyrazole-6,4′-cyclohexane-1′,2″-[1,3]dioxolane] (266 mg, 0.954 mmol, 100% yield) as a brown solid, which was used directly in the next step without further purification. 15 H 22 N2O3[M+H] + MS ESI calculated value: 279.16, found: 279.15.

[0554] Step 9: To a solution of 2,2′,2′-trimethyl-2,4-dihydrodispiro[furo[3,4-c]pyrazole-6,4′-cyclohexane-1′,2″-[1,3]dioxolane] (266 mg, 0.954 mmol) in THF (2 mL) was added hydrochloric acid (2M in water, 3 mL, 6.00 mmol). The resulting mixture was stirred at 25° C. for 2 hours. The progress of the reaction was monitored by LCMS and TLC. After the reaction was complete, the reaction was quenched with sodium bicarbonate (0.5 g, 6 mmol) and the mixture was concentrated in vacuo. The residue was purified by RP-Combi-Flash using the following conditions: Column: AQ-C 18 OBD column, 40 g; mobile phase A: water (0.1% TFA), mobile phase B: MeCN; flow rate: 40 mL / min; gradient: 5%-60% in 35 min. Detectors: UV 254 and 210 nm; fractions containing the desired product were combined and concentrated under reduced pressure to provide 2′,3,3-trimethyl-2′,4′-dihydrospiro[cyclohexane-1,61-furo[3,4-c]pyrazol]-4-one (90 mg, 0.384 mmol, 40.3% yield) as a yellow oil. 13 H18 N2O2[M+H] + MS ESI calculated value 235.14, found value 235.20. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.18 (s, 1H), 4.94-4.84 (m, 2H), 3.78 (s, 3H), 3.21-3.09 (m, 1H), 2.35-2.27 (m, 1H), 2.24-2.12 (m, 2H), 2.10-1.98 (m, 2H), 1.42 (s, 3H), 1.09 (s, 3H).

[0555] Option 22:

[0556]

[0557] Intermediate 32: 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradecan-11-one

[0558] Intermediate 33: Trifluoromethanesulfonic acid 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 Tetradeca]1-ene-11- esters

[0559] Step 1: To a solution of 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-one (48.0 g, 260 mmol) in THF (1.0 L) was added allylmagnesium bromide (1 M, 521 mL) dropwise at -78 ° C. The reaction was stirred for 3 h at -78 ° C. The mixture was then quenched with saturated NH4Cl aqueous solution (1.0 L) and extracted with MTBE (3x). The combined organic layers were washed with water (2x), dried over sodium sulfate and concentrated under reduced pressure to provide 8-allyl-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-ol, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ5.73-5.87(m, 1H), 4.96-5.15(m, 2H), 3.77-4.02(m, 5H), 2.07-2.15(m, 2H) , 1.96-2.05(m, 1H), 1.51-1.72(m, 3H), 1.35-1.43(m, 2H), 1.16-1.22(m, 3H), 0.76-0.83(m, 3H).

[0560] Step 2:To a solution of 8-allyl-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol (55.0 g, 243 mmol) in a 4:1 solution of water / acetone (1.0 L) was added OSO4 (0.75 g, 2.95 mmol) at 0°C. The resulting solution was stirred at room temperature for 12 h. The reaction was then quenched with saturated aqueous Na2SO3 (0.5 L) and extracted with ethyl acetate (8x). The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate:petroleum ether (1:20 to 1:1) to produce 3-(8-hydroxy-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-1,2-diol. 1 H NMR (400MHz, DMSO-d6) δ4.76-4.83 (m, 1H), 4.53-4.64 (m, 1H), 4.34-4.42 (m, 1H), 3.76-3.97 (m, 5H), 3.20-3 .34(m, 2H), 1.89-2.03(m, 1H), 1.57-1.73(m, 2H), 1.34-1.56(m, 5H), 1.16-1.24(m, 3H), 0.79-0.89(m, 3H).

[0561] Step 3: To a solution of 3-(8-hydroxy-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-1,2-diol (41.0 g, 158 mmol) in THF (0.8 L) was added triethylamine (87.7 mL, 630 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (21.7 g, 189 mmol) was added portionwise. The reaction was stirred for 3 h and heated to 50° C. for another 20 h. The mixture was then diluted with ethyl acetate (250 mL), quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: petroleum ether (1:50 to 1:0) to produce 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4.2]tetradecan-11-ol. 1 H NMR (400MHz, DMSO-d6) δ4.75-4.82(m, 1H), 4.19-4.28(m, 1H), 3.73-3.91(m, 6H), 3.48-3.56(m, 1H ), 1.59-1.92(m, 5H), 1.51-1.58(m, 2H), 1.40-1.48(m, 2H), 1.02-1.10(m, 3H), 0.78-0.84(m, 3H).

[0562] Step 4: To a solution of 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4.2]tetradecan-11-ol (26.0 g, 107 mmol) in dichloromethane (0.8 L) was added PCC (41.6 g, 193 mmol) at ambient temperature. The resulting mixture was stirred for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: petroleum ether (1:100 to 1:5) to provide 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4.2]tetradecan-11-one. 1 H NMR (400MHz, DMSO-d6) δ 3.87-4.00 (m, 6H), 2.24-2.54 (m, 2H), 1.67-1.92 (m, 4H), 1.45-1.64 (m, 2H), 1.04-1.14 (m, 3H), 0.80-0.90 (m, 3H).

[0563] Step 5: To a solution of 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4.2]tetradecan-11-one (11.0 g, 45.8 mmol) in THF (0.3 L) was added NaHMDS (2 M, 34.3 mL, 68.6 mmol) at -78 ° C, and the resulting solution was stirred for 2 h. Comin's reagent (26.9 g, 68.6 mmol) was then added, and the mixture was stirred at -78 ° C for another 1 h. The reaction was then warmed to room temperature and stirred for 1 h. The mixture was then quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate (3x). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: petroleum ether (0-30%) to give 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4.2]tetradec-11-en-11-yl trifluoromethanesulfonate. 1 H NMR (400MHz, CDCl3) δ5.52-5.62 (m, 1H), 4.47-4.60 (m, 2H), 3.78-3.92 (m, 4H), 1.89-1. 99 (m, 1H), 1.63-1.83 (m, 3H), 1.41-1.57 (m, 3H), 1.08-1.11 (m, 3H), 0.79-0.83 (m, 3H).

[0564] Option 23:

[0565]

[0566] Intermediate 34: 2-(6,6-dimethyl 1,4,9-trioxadispiro [ 4.2.4 8 .2 5 ]Tetradec-11-en-11-yl)pyrazine

[0567] Step 1: To trifluoromethanesulfonic acid 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 To a stirred solution of tetradecene-11-ene-11-yl ester (600 mg, 1.611 mmol) in THF (6 mL) was added bis(triphenylphosphine)palladium dichloride (II) (56.6 mg, 0.081 mmol), 2N aqueous sodium carbonate solution (4 mL) and 2-(tributylstannyl)pyrazine (1190 mg, 3.22 mmol). The reaction mixture was degassed 3 times with nitrogen and stirred at 80 ° C for 16 h under a nitrogen atmosphere. The reaction progress was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL × 3). The combined organic layer was then washed with brine (60 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 10%-60% ethyl acetate / petroleum ether as eluent. Fractions containing the desired product were combined and concentrated under reduced pressure to afford 2-(6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]tetradec-11-en-11-yl)pyrazine (330 mg, 1.037 mmol, 64.3% yield). 17 H 22 N2O3[M+H] + MS ESI calculated value 303.17, found 303.10. 1 H NMR (300 MHz, chloroform-d) δ 8.69 (s, 1H), 8.54 (s, 1H), 8.44 (s, 1H), 6.51 (t, J = 2.2 Hz, 1H), 5.10 (d, J = 2.1 Hz, 2H), 4.09-3.88 (m, 4H), 2.19-2.01 (m, 1H), 2.01-1.76 (m, 3H), 1.69-1.52 (m, 2H), 1.26 (s, 3H), 0.93 (s, 3H).

[0568] Option 24:

[0569]

[0570] Intermediate 35: 6,6-dimethyl-11-phenyl-1,4,9-trioxadispiro [ 4.2.4 8 .2 5 ]Tetradec-11-ene

[0571] Step 1:At room temperature, 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 To a solution of tetradecene-11-ene-11-yl ester (600 mg, 1.611 mmol) in 1,4-dioxane (6 mL) was added phenylboronic acid (236 mg, 1.934 mmol), K2CO3 (557 mg, 4.03 mmol) and water (0.6 mL). Pd(dppf)Cl2.CH2Cl2 (132 mg, 0.161 mmol) was then added to the above mixture. The system was replaced 3 times with nitrogen and stirred at 100 ° C for 2 h under nitrogen. The reaction mixture was quenched with water (60 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine (saturated, 2x50 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-20% ethyl acetate / petroleum ether to provide 6,6-dimethyl-11-phenyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradec-11-ene (450 mg, 1.498 mmol, 93% yield). 19 H 24 O3[M+H] + MS ESI calculated value 301.18, found 301.10. 1 H NMR (300 MHz, chloroform-d) δ 7.37-7.27 (m, 5H), 6.01 (t, J = 2.1 Hz, 1H), 4.99 (d, J = 2.1 Hz, 2H), 4.01-3.92 (m, 4H), 2.07 (td, J = 12.7, 4.5 Hz, 1H), 1.88 (td, J = 13.0, 4.1 Hz, 1H), 1.82-1.73 (m, 2H), 1.63-1.52 (m, 2H), 1.23 (s, 3H), 0.90 (s, 3H).

[0572] Table 5 The following intermediate was prepared using a procedure similar to that described above for intermediate 35:

[0573]

[0574] Option 25:

[0575]

[0576] Intermediate 37: (Z)-10-benzylidene-6,6-dimethyl-1,4,9-trioxadi[4.2.4 8 .2 ５ ]Tetradecane-11- ketone

[0577] Step 1: At 0 ° C, 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradecan-11-one (480 mg, 1.998 mmol) and benzaldehyde (212 mg, 1.998 mmol) in EtOH (4 mL) was added aqueous NaOH solution (5% in H2O, 0.8 mL, 1.998 mmol). The resulting mixture was stirred at 0 ° C for 1 hour. The mixture was filtered with EtOH (3×10 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by RP-Flash chromatography eluting with 0-55% acetonitrile / water to provide (Z)-10-benzylidene-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradecan-11-one (300 mg, 0.913 mmol, 45.7% yield). 20 H 24 O4[M+H] + MS ESI calculated value 329.18, found 329.20. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.83-7.74 (m, 2H), 7.45-7.30 (m, 3H), 6.34 (s, 1H), 4.11-3.92 (m, 4H), 2.58 (s, 2H), 2.42-2.14 (m, 1H), 2.12-1.85 (m, 4H), 1.71-1.57 (m, 1H), 1.36 (s, 3H), 0.98 (s, 3H).

[0578] Option 26:

[0579]

[0580] Intermediate 38: 10-methyl-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 Tetradecan-11-ol

[0581] Step 1: At 0 ° C, 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5] To a stirred mixture of tetradecane-11-one (480 mg, 1.998 mmol) and benzaldehyde (212 mg, 1.998 mmol) in EtOH (4 mL) was added aqueous NaOH solution (5% in H2O, 0.8 mL, 1.998 mmol). The resulting mixture was stirred at 0 ° C for 1 hour. The mixture was filtered with EtOH (3×10 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by RP-Flash chromatography eluting with 0-55% acetonitrile / water to provide (Z)-10-benzylidene-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradecan-11-one (300 mg, 0.913 mmol, 45.7% yield). 20 H 24 O4[M+H] + MS ESI calculated value 329.18, found 329.20. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.83-7.74 (m, 2H), 7.45-7.30 (m, 3H), 6.34 (s, 1H), 4.11-3.92 (m, 4H), 2.58 (s, 2H), 2.42-2.14 (m, 1H), 2.12-1.85 (m, 4H), 1.71-1.57 (m, 1H), 1.36 (s, 3H), 0.98 (s, 3H).

[0582] Step 2: To (Z)-10-benzylidene-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ] To a stirred mixture of tetradecane-11-one (300 mg, 0.913 mmol) in MeOH (5 mL) was added palladium hydroxide on carbon (128 mg, 0.913 mmol). The resulting mixture was stirred at room temperature for 3 h under H2. The solid was filtered off and washed with MeOH (50 mL). The filtrate was concentrated under vacuum. The residue was dissolved in MeOH (3 mL) and sodium borohydride (46.4 mg, 1.226 mmol) was added at 0 ° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by adding NH4Cl aqueous solution (30 mL), diluted with ethyl acetate (30 × 3 mL), and the organic layer was washed with water (60 mL) and brine (60 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by RP-Flash chromatography eluting with 0-50% acetonitrile / water to afford 10-benzyl-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8.2 5 ]Tetradecan-11-ol (190 mg, 0.572 mmol, 69.9% yield). 20 H 28 O4[M+H] + MS ESI calculated value 333.21, found 333.20. 1 H NMR (300MHz, chloroform-d) δ7.34-7.29(m, 3H), 7.28-7.17(m, 2H), 4.15-4.03(m, 1H), 3.99-3.90(m, 4H), 3.09-2.79(m, 2H), 2.13-1.59(m, 8H), 1 .54-1.39(m, 2H), 1.25(s, 1H), 1.19(s, 0.6H), 1.12(s, 0.6H), 1.05(s, 0.6H), 0.91(s, 1H), 0.90(s, 0.6H), 0.88(s, 0.6H), 0.85(s, 0.6H).

[0583] Step 3: At -10 °C, 10-benzyl-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ] To a stirred mixture of tetradecane-11-ol (260 mg, 0.782 mmol) in DCM (3 mL) was added pyridine (93 mg, 1.173 mmol) and trifluoromethanesulfonic anhydride (0.387 mL, 2.346 mmol). The resulting mixture was stirred at -10 ° C for 30 min. The reaction was quenched by adding NaHCO3 aqueous solution (30 mL), extracted with DCM (3 × 50 mL), and the organic layer was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide a crude product 10-benzyl-6,6-dimethyl-1,4,9-trioxadispiro[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4- 8 .2 5 ]Tetradec-10-ene (252 mg, 0.827 mmol, 100% yield), which was used directly in the next step. 20 H 26 O3[M+H] + MS ESI calculated value 315.20, found value 315.30.

[0584] Scheme 27:

[0585]

[0586] Intermediate 39: 6,6-dimethyl-12-methylene-1,4,9-trioxadispiro[4.2.4 8 .2 5 Tetradecane

[0587] To a solution of methyltriphenylphosphonium bromide (2973 mg, 8.32 mmol) in THF (3 mL) was added n-BuLi (2.5 M in hexane, 3.33 mL, 8.32 mmol) at 0°C, and the mixture was stirred at 30°C for 30 min. 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ] A solution of tetradecane-12-one (500mg, 2.081mmol) in THF (3.00mL) was added to the above mixture. The sealed tubular bottle was irradiated in a microwave at 80°C for 8 hours on a Biotage Smith synthesizer. The reaction process was monitored by LCMS and TLC. After the reaction was completed, the reaction mixture was quenched with NH4Cl aqueous solution (5mL). The mixture was concentrated in a vacuum. The residue was diluted with ethyl acetate (80mL), then washed with brine (5mL×3) and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in a vacuum, and the residue was purified by silica gel column chromatography using a gradient of ethyl acetate / petroleum ether of 0%-30% as eluent. The fractions containing the desired product were combined and concentrated under reduced pressure to provide 6,6-dimethyl-12-methylene-1,4,9-trioxadispiro[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4-[4.2.4- 8 .2 5 ]Tetradecane (400 mg, 1.678 mmol, 81% yield). 14 H 22 O3[M+H] + MS ESI calculated value: 239.16, found: 239.20. 1 H-NMR (400 MHz, chloroform-d) δ 4.95-4.87 (m, 1H), 4.86-4.78 (m, 1H), 4.05-3.88 (m, 4H), 3.87-3.75 (m, 2H), 2.67-2.49 (m, 2H), 2.14-1.92 (m, 1H), 1.76-1.59 (m, 3H), 1.56-1.43 (m, 2H), 1.21 (s, 3H), 0.85 (s, 3H).

[0588] Scheme 28:

[0589]

[0590] Intermediate 40: 6,6-dimethyl-10-phenyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradec-11-ene

[0591] Step 1:To a solution of 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-one (6 g, 32.6 mmol) in tetrahydrofuran (60 mL) was added vinylmagnesium bromide (1 M in THF, 42.3 mL, 42.3 mmol) at 0 ° C under an argon atmosphere. The resulting mixture was stirred at 25 ° C for 1 h. The solution was neutralized by adding saturated NH4Cl aqueous solution (60 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0-10%) to provide 6,6-dimethyl-8-vinyl-1,4-dioxaspiro[4.5]decane-8-ol (5.2 g, 22.05 mmol, 67.7% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ5.94 (dd, J=17.3, 10.7Hz, 1H), 5.26 (dd, J=17.3, 1.2Hz, 1H), 5.03 (dd, J=10.6, 1.2Hz, 1H), 4.14-3.84 (m, 4H), 2.12 (td, J=13 .2, 3.9Hz, 1H), 1.89 (td, J=13.5, 4.1Hz, 1H), 1.78 (d, J=14.4Hz, 1H), 1. 65-1.48 (m, 2H), 1.42 (dd, J=14.4, 2.9Hz, 1H), 1.28 (s, 3H), 0.90 (s, 3H).

[0592] Step 2: To a solution of 6,6-dimethyl-8-vinyl-1,4-dioxaspiro[4.5]decane-8-ol (1 g, 4.71 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60% in mineral oil, 0.414 g, 10.36 mmol) at 25 ° C under an argon atmosphere. The resulting mixture was stirred at 66 ° C for 0.5 h. The reaction was then cooled to room temperature and 3-bromoprop-1-ene (1.425 g, 11.78 mmol) was added to the mixture. The resulting mixture was stirred at 66 ° C for another 2 h. The solution was neutralized by adding saturated NH4Cl aqueous solution (10 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (0-10%) to afford 8-(allyloxy)-6,6-dimethyl-8-vinyl-1,4-dioxaspiro[4.5]decane (1 g, 3.96 mmol, 84% yield) as a yellow oil. 1H NMR (300MHz, chloroform-d) δ5.92-5.80(m, 1H), 5.79-5.70(m, 1H), 5.35-5.21(m, 1H), 5.20-5.04(m, 3H), 4.15-3.84( m, 4H), 3.82-3.81 (m, 2H), 2.10-1.70 (m, 4H), 1.63-1.52 (m, 1H), 1.50-1.48 (m, 1H), 1.24 (s, 3H), 0.90 (s, 3H).

[0593] Step 3: To a solution of 8-(allyloxy)-6,6-dimethyl-8-vinyl-1,4-dioxaspiro[4.5]decane (1 g, 3.96 mmol) in toluene (10 mL) was added benzyl-bis(tricyclohexylphosphine)dichlororuthenium (0.065 g, 0.079 mmol) at 25°C under an argon atmosphere. The resulting mixture was stirred at 25°C for 4 h. Ethoxyethylene (2.86 g, 39.6 mmol) was then added. The mixture was stirred for 15 min and then heated to reflux overnight. After cooling to room temperature, the solution was diluted with brine (10 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (0-10%) to afford 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradec-10-ene (400 mg, 1.783 mmol, 45.0% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.20 (t, J = 2.5 Hz, 1H), 4.76 (q, J = 2.6 Hz, 1H), 4.04-3.81 (m, 4H), 2.37 (t, J = 2.4 Hz, 2H), 2.06-1.45 (m, 6H), 1.16 (s, 3H), 0.90 (s, 3H).

[0594] Step 4: At 25 °C under argon atmosphere, 6,6-dimethyl-1,4,9-trioxadispiro[4.2.4 8 .2 5]Tetradec-10-ene (500 mg, 2.229 mmol) was added to a solution of tetrakis(triphenylphosphine)palladium(0) (258 mg, 0.223 mmol), triethylamine (338 mg, 3.34 mmol) and iodobenzene (682 mg, 3.34 mmol) in MeCN (5 mL). The resulting mixture was stirred at 100 ° C for 16 h. The solution was neutralized by adding saturated NH4Cl aqueous solution (5 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified as follows: Column: XBridge Prep C 18 OBD column, 19×150 mm, 5 μm; mobile phase A: water, mobile phase B: MeCN; flow rate: 30 mL / min; gradient: from 0% B to 70% B, 65% B in 30 min; detector: UV220 / 254 nm, to provide 6,6-dimethyl-10-phenyl-1,4,9-trioxadispiro[4.2.4 8 .2 5 ]Tetradec-11-ene (400 mg, 1.198 mmol, 53.8% yield). 19 H 24 O3[M+H] + MS ESI calculated value 301.17, found 301.25. 1 H NMR (300MHz, DMSO-d6) δ7.36-7.25 (m, 5H), 5.92-5.87 (m, 2H), 5.75 (dd, J=4.0, 2.2Hz, 1H), 3.93- 3.83(m, 4H), 1.92-1.88(m, 2H), 1.73-1.55(m, 2H), 1.55-1.47(m, 2H), 1.15(s, 3H), 0.85(s, 3H).

[0595] Scheme 29:

[0596]

[0597] Intermediate 41: 3,3-Dimethyl-6′H,8′H spiro [ Cyclohexane-1,5′-imidazo[2,1-c][1,4]oxazine]-4- ketone

[0598] Step 1:To a suspension of 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-one (500 mg, 2.71 mmol) and ammonium carbonate (1304 mg, 13.57 mmol) in ethanol / water (1:1) (300 mL) was added sodium cyanide (133 mg, 2.71 mmol). The reaction mixture was heated at 50°C for 12 h. After the disappearance of the starting material as determined by TLC monitoring, the mixture was heated to 80°C to decompose the excess (NH4)2CO3. NaOH (434 mg, 10.86 mmol) was then added and the ethanol was removed under reduced pressure, and the resulting solution was refluxed overnight. The mixture was cooled to room temperature. The mixture was neutralized by adding 2M HCl. The mixture was lyophilized twice to produce 8-amino-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (crude 2.71 mmol) as a white solid, which was used directly in the next step without further purification. 11 H 19 NO4[M+H] + The MSESI calculated value was 230.13 and the measured value was 230.15.

[0599] Step 2: To a solution of 8-amino-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (621 mg, 2.71 mmol) in diethyl ether (50 mL) was added LAH (206 mg, 5.42 mmol). The resulting mixture was stirred at 38° C. for 6 hours. The progress of the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was cooled to 0° C. and then quenched with aqueous NH 4 Cl solution (1 mL) and the mixture was stirred for 5 minutes. 15% aqueous NaOH solution (1 mL) was then added and the mixture was stirred for another 5 minutes. 3 mL of water was then added and the mixture was stirred for 15 minutes until room temperature. Finally, 3 g of NaSO 4 was added, the mixture was stirred for 15 minutes and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient of 0% to 20% MeOH (10% NH 3 .H 2 O) / DCM as eluent. The fractions containing the desired product were combined and concentrated under reduced pressure to afford (8-amino-6,6-dimethyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (400 mg, 1.858 mmol, 68.6% yield) as a white solid. 11 H 21 NO3[M+H] + MS ESI calculated value 216.15, found 216.20. 1H-NMR (300MHz, DMSO-d6) δ4.08 (s, 1H), 3.93-3.71 (m, 4H), 3.17 (s, 2H), 3.00 (s, 2H), 1.92 (td, J=12.7, 4 .0Hz, 1H), 1.56-1.32 (m, 3H), 1.30-1.16 (m, 1H), 1.19 (s, 3H), 1.11 (dd, J=13.8, 2.4Hz, 1H), 0.77 (s, 3H).

[0600] Step 3: A mixture of (8-amino-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methanol (380 mg, 1.765 mmol) in ethyl acetate (7 mL) and saturated Na2CO3 aqueous solution (7 mL) was cooled to 0 ° C and 2-chloroacetyl chloride (399 mg, 3.53 mmol) was added. The resulting mixture was stirred at 0 ° C for 1 h. The desired product was mainly detected on LCMS and TLC. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to produce crude 2-chloro-N-(8-(hydroxymethyl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-yl)acetamide (630 mg, 1.765 mmol) as a white solid, which was used in the next step without further purification. 13 H 22 ClNO4[M+H] + MS ESI calculated values: 292.12, 294.12, found: 292.05, 294.05. 1 H-NMR (400 MHz, chloroform-d) δ 6.63 (s, 1H), 4.03 (d, J = 2.4 Hz, 2H), 4.00-3.88 (m, 4H), 3.68 (s, 2H), 2.11-1.97 (m, 2H), 1.86-1.72 (m, 2H), 1.71-1.54 (m, 2H), 1.14 (s, 3H), 0.92 (s, 3H).

[0601] Step 4:To a solution of 2-chloro-N-(8-(hydroxymethyl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-yl)acetamide (600 mg, 2.056 mmol) in t-BuOH (20 mL) was added potassium 2-methylpropane-2-olate (254 mg, 2.262 mmol) at room temperature. The resulting mixture was stirred at 30 ° C for 3 h. The main desired product was detected on LCMS. The reaction mixture was diluted with NH4Cl (5 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 10%-40% ethyl acetate / petroleum ether as eluent. The fractions containing the desired product were combined and concentrated under reduced pressure to provide 6,6-dimethyl-1,4,12-trioxa-9-azabispiro[4.2.5 8 .2 5 ] Pentadecane-10-one (500 mg, 1.958 mmol, 95% yield). 13 H 21 NO4[M+H] + MS ESI calculated value 256.15, found value 256.15. 1 H-NMR (400 MHz, chloroform-d) δ 6.19 (s, 1H), 4.22-4.06 (m, 2H), 4.01-3.87 (m, 4H), 3.72 (d, J = 11.6 Hz, 1H), 3.52 (d, J = 11.6 Hz, 1H), 1.96-1.85 (m, 1H), 1.80-1.61 (m, 5H), 1.06 (s, 3H), 0.97 (s, 3H).

[0602] Step 5: 6,6-dimethyl-1,4,12-trioxa-9-azadispiro[4.2.5 8 .2 5 A mixture of pentadecane-10-one (340 mg, 1.332 mmol), 2,2-diethoxyethane-1-amine (1.162 mL, 7.99 mmol) and perchlorostannane (1 M in DCM, 0.40 mL, 0.40 mmol) in toluene (3.6 mL) was heated to 150 ° C, and the resulting mixture was stirred in a sealed test tube for 48 hours. The product was mainly detected on LCMS. The reaction mixture was concentrated in vacuo to produce a residue (1.332 mmol) as a black solid, which was used directly in the next step without further purification. 15 H 22 N2O3[M+H] + MS ESI calculated value: 279.16, found: 279.10.

[0603] Step 6: To a solution of 2′,2′-dimethyl-6H,8H-dispiro[imidazo[2,1-c][1,4]oxazine-5,4′-cyclohexane-1′,2″-[1,3]dioxolane] (371 mg, 1.332 mmol) in THF (3 mL) was added HCl (2 M in water, 4 mL, 8.00 mmol). The mixture was stirred at 25° C. for 3 h. The mixture was neutralized by the addition of NaHCO The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient of 0% to 10% methanol / DCM as eluent. The fractions containing the desired product were combined and concentrated under reduced pressure to provide 3,3-dimethyl-65H,8′H-spiro[cyclohexane-1,51-imidazo[2,1-c][1,4]oxazine]-4-one (50 mg, 0.213 mmol, 16.02% yield) as a white solid. 13 H 18 N2O2[M+H] + MS ESI calculated value 235.15, found value 235.10. 1 H-NMR (300 MHz, chloroform-d) δ 7.06 (s, 1H), 6.99 (s, 1H), 4.90 (s, 2H), 4.19 (d, J = 12.3 Hz, 1H), 4.02 (d, J = 12.3 Hz, 1H), 2.80-2.63 (m, 1H), 2.62-2.47 (m, 1H), 2.48-2.28 (m, 2H), 2.24 (s, 2H), 1.27 (s, 3H), 1.23 (s, 3H).

[0604] Option 30:

[0605]

[0606] Intermediate 42: 5,5-dimethyl-1,7,10-trioxadispiro[2.2.4 6 .2 3 ]Dodecane

[0607] To trimethylsulfonium iodide (3.59g, 17.59mmol) and 6,6-dimethyl-1,4-dioxaspiro [4.5] decane-8-one (2.0g, 10.86mmol) in dry DMSO (54.2mL) was added potassium tert-butoxide (1.827g, 16.28mmol), and the resulting reaction mixture was stirred at room temperature under an inert atmosphere overnight. The reaction was cooled to 0 ° C and quenched with H o (20mL). The organic phase was extracted with MTBE (3x25mL). The combined organic layer was washed with H o (2x20mL), then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to provide 5,5-dimethyl-1,7,10-trioxadispiro [2.2.4 6 .2 3 ] Dodecane (1.78 g, 83% IY). 1 H NMR (400 MHz, chloroform-d) δ 3.98-3.95 (m, 4H), 2.58 (m, 2H), 1.94-1.87 (m, 1H), 1.84-1.77 (m, 1H), 1.76-1.65 (m, 2H), 1.64-1.57 (m, 1H), 1.51 (d, J=13.6 Hz, 1H), 1.07 (s, 3H), 0.97 (s, 3H).

[0608] Option 31:

[0609]

[0610] Intermediate 43: 4-(4-methoxybenzyl)-8,8-dimethyl-1-oxa-4-azaspiro[5.5]undecane-3,9- diketone

[0611] Step 1: To 5,5-dimethyl-1,7,10-trioxadispiro[2.2.46.23]dodecane (1.0 g, 5.04 mmol) in methanol (10.01 mL) was added (4-methoxyphenyl)methylamine (1.450 mL, 11.10 mmol), and the resulting reaction mixture was stirred at 60 ° C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (0-5% MeOH / DCM) on silica gel to provide 8-(((4-methoxybenzyl)amino)methyl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-ol (1.11 g, 66% IY) as a clear oil. MS=336[M+H]. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.23 (m, 2H), 6.86 (m, 2H), 3.97-3.83 (m, 4H), 3.80 (s, 3H), 3.76 (s, 2H), 2.49 (s, 2H), 2.12-2.04 (m, 1H), 1.65-1.52 (m, 2H), 1.52-1.43 (m, 2H), 1.43-1.38 (m, 1H), 1.25 (s, 3H), 0.84 (s, 3H).

[0612] Step 2: To a solution of 8-(((4-methoxybenzyl)amino)methyl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-ol (1.11 g, 3.31 mmol) and triethylamine (0.484 mL, 3.47 mmol) in anhydrous THF (44.1 mL) was added 2-chloroacetyl chloride (0.264 mL, 3.31 mmol) at 0 ° C under a nitrogen stream. The resulting reaction mixture was stirred at 0 ° C for 1 h, then stirred at room temperature for 3 h under an inert atmosphere. The reaction mixture was diluted with H2O (15 mL), and the organic phase was extracted with DCM (3x20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to provide 2-chloro-N-((8-hydroxy-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methyl)-N-(4-methoxybenzyl)acetamide as a clear oil. MS = 412 [M+H]. The crude material was used in the next step without any further purification.

[0613] Step 3: To a solution of 2-chloro-N-((8-hydroxy-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methyl)-N-(4-methoxybenzyl)acetamide (1.36 g, 3.30 mmol) in anhydrous THF (33.3 mL) was added NaH (60% in mineral oil) (172 mg, 4.29 mmol) at 0 ° C under a stream of nitrogen. The reaction mixture was stirred at 0 ° C for 15 min, then stirred at 60 ° C under an inert atmosphere overnight. The reaction mixture was quenched with H o (20 mL) at 0 ° C. The organic phase was extracted with DCM (3x30 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% MTBE / heptane) to afford 12-(4-methoxybenzyl)-6,6-dimethyl-1,4,9-trioxa-12-azadispiro[4.2.5 8 .2 5 ] Pentadec-11-one, which solidified upon exposure to air (822 mg, 66% IY). MS=376[M+H]. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.17 (m, 2H), 6.85 (m, 2H), 4.55-4.46 (m, 2H), 4.27-4.15 (m, 2H), 3.98-3.82 (m, 4H), 3.80 (s, 3H), 3.02-2.92 (m, 2H), 1.97-1.90 (m, 1H), 1.85-1.80 (m, 1H), 1.78-1.73 (m, 1H), 1.54-1.40 (m, 2H), 1.31 (m, 1H), 1.18 (s, 3H), 0.81 (s, 3H).

[0614] Step 4: 12-(4-methoxybenzyl)-6,6-dimethyl-1,4,9-trioxa-12-azadispiro[4.2.5 8 .2 5 ] Pentadecane-11-one (200mg, 0.533mmol) was dissolved in TFA (4.0mL, 52.2mmol), and the resulting reaction mixture was sealed and stirred at 80°C for 3h. The reaction mixture was cooled to room temperature and neutralized with a saturated NaHCO3 aqueous solution. The organic phase was extracted with DCM (3x15mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% MTBE / heptane) to provide 4-(4-methoxybenzyl)-8,8-dimethyl-1-oxa-4-azaspiro[5.5]undecane-3,9-dione (142mg, 80% IY) as a clear oil. MS=332[M+H]. 1 H NMR (400MHz, chloroform-d) δ7.20-7.16 (m, 2H), 6.88-6.84 (m, 2H), 4.61 (d, J=14.4 Hz, 1H), 4.47 (d, J=14.4Hz, 1H), 4.36-4.22 (m, 2H), 3.80 (s, 3H), 3.10-3.00 (m, 2H), 2.84-2.76 (m, 1H), 2.26-2.15 (m, 2H), 2.06 (dd, J=14.8, J'=3.6Hz , 1H), 1.62-1.53 ​​(m, 1H), 1.41 (d, J=14.8Hz, 1H), 1.28 (s, 3H), 1.00 (s, 3H).

[0615] Option 32:

[0616]

[0617] Intermediate 44: 3′,3′,4-Trimethyl-3,4-dihydrospiro[benzo[b][1,4]oxazine-21′-cyclohexane]-4′-one

[0618] Step 1: To a solution of 2-bromoaniline (837 mg, 4.86 mmol) in anhydrous THF (6 mL) in a microwave vial was added sodium hydride (389 mg, 9.73 mmol) (60% in mineral oil) at 0° C. under a stream of nitrogen, and the resulting suspension was stirred at 0° C. for 305 s. Then, 5,5-dimethyl-1,7,10-trioxadispiro[2.2.4 6 .2 3 ] dodecane (643mg, 3.24mmol) in anhydrous THF (6mL).The resulting reaction mixture is sealed and stirred at 75 ° C overnight. After LCMS control, another aliquot of sodium hydride (389mg, 9.73mmol) (60% in mineral oil) is added, and the reaction mixture is stirred at 75 ° C until completion. The reaction mixture is quenched with H2O at 0 ° C, and the organic phase is extracted with EtOAc (3x15mL). The combined organic layer is dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (0-50% MTBE / heptane) on silica gel to provide 8- (((2- bromophenyl) amino) methyl) -6,6- dimethyl -1,4- dioxaspiro [4.5] decane -8- alcohol as a slightly yellow oil, which solidifies (1.06g, 88% IY) after exposure to air. MS=371[M+H]. 1 H NMR (400MHz, chloroform-d) δ7.43 (d, J=7.9Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 6.62 (t, J=7.4Hz, 1H), 4.00-3.88 (m, 4H), 3.12 (s, 2H), 2.12-2.05 (m, 1H), 1.84-1.72 (m, 2H), 1.68 (d, J=14.2Hz, 1H), 1.59-1.54 (m, 1H), 1.54-1.49 (m, 1H), 1.26 (s, 3H), 0.88 (s, 3H).

[0619] Step 2:In a microwave vial, cesium carbonate (2.52g, 7.72mmol) was added to a solution of 8-(((2-bromophenyl)amino)methyl)-6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-ol (1.43g, 3.86mmol) in anhydrous toluene (19.31mL), and the resulting mixture was degassed for 10min. Then, palladium acetate (II) (0.130g, 0.579mmol) and [1,1′-binaphthyl]-2-yldi-tert-butylphosphine (0.308g, 0.772mmol) were added under a stream of nitrogen. The reaction mixture was sealed and stirred at 100°C overnight under an inert atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through diatomaceous earth under vacuum. The residue was purified by column chromatography on basic alumina (0-50% MTBE / heptane) to afford 2′,2′-dimethyl-3,4-dihydrodispiro[benzo[b][1,4]oxazine-2,4′-cyclohexane-1′,2″-[1,3]dioxolane (420 mg, 38% IY) as a pale white solid. MS=290 [M+H]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.78 (t, J = 7.4 Hz, 2H), 6.70 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 4.05-3.89 (m, 4H), 3.05 (s, 2H), 2.24-2.16 (m, 1H), 1.87-1.82 (m, 1H), 1.76-1.72 (m, 2H), 1.57-1.49 (m, 2H), 1.23 (s, 3H), 0.85 (s, 3H).

[0620] Step 3:To a solution of 2′,2′-dimethyl-3,4-dihydrodispiro[benzo[b][1,4]oxazine-2,4′-cyclohexane-1′,2″-[1,3]dioxolane] (250 mg, 0.864 mmol) in anhydrous THF (8 mL) in a microwave vial was added sodium hydride (138 mg, 3.46 mmol) (60% in mineral oil) at 0° C. under a stream of nitrogen, and the resulting suspension was stirred at 0° C. for 1 h. Then, iodomethane (0.161 mL, 2.59 mmol) was added, and the resulting reaction mixture was sealed and stirred at 45° C. for 48 h. After LCMS control, another aliquot of sodium hydride (138 mg, 3.46 mmol) was added. , 3.46mmol) and iodomethane (0.161mL, 2.59mmol), and the reaction was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature and quenched with H2O (15mL) at 0 ° C. The organic phase was extracted with DCM (3x15mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% MTBE / heptane) to provide 2', 2', 4-trimethyl-3, 4-dihydrodispiro [benzo [b] [1, 4] oxazine -2, 4'- cyclohexane -1', 2 "- [1, 3] dioxolane (212mg, 81% IY) as a clear oil. MS = 304 [M + H]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.86 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.71-6.67 (m, 2H), 4.02-3.88 (m, 4H), 2.92 (d, J = 5.0 Hz, 2H), 2.89 (s, 3H), 2.24-2.16 (m, 1H), 1.86-1.81 (m, 1H), 1.77-1.69 (m, 2H), 1.58-1.53 ​​(m, 2H), 1.23 (s, 3H), 0.85 (s, 3H).

[0621] Step 4:2′,2′,4-Trimethyl-3,4-dihydrodispiro[benzo[b][1,4]oxazine-2,4′-cyclohexane-1′,2″-[1,3]dioxolane] (212 mg, 0.699 mmol) was dissolved in trifluoroacetic acid (5247 μl, 68.5 mmol), and the resulting reaction mixture was sealed and stirred at 80° C. for 3 h. The reaction mixture was cooled to room temperature and neutralized with saturated aqueous NaHCO 3 solution. The organic phase was extracted with DCM (3×15 mL). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to afford 3′,3′,4-trimethyl-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1′-cyclohexane]-4′-one as a dark solid. MS=260[M+H]. 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.90 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.75-6.70 (m, 2H), 3.15-3.06 (m, 1H), 2.99 (s, 2H), 2.92 (s, 3H), 2.29-2.20 (m, 2H), 2.16-2.11 (m, 1H), 1.87-1.78 (m, 1H), 1.63 (d, J = 14.7 Hz, 1H), 1.35 (s, 3H), 1.05 (s, 3H). The crude material was used in the next step without any further purification.

[0622] Plan 33 :

[0623]

[0624] Intermediate 45: 1′-(Cyclopropylmethyl)spiro[cyclohexane-1,3′-indoline]-2′,4-dione

[0625] Step 1: To a stirred solution of spiro[cyclohexane-1,3′-indoline]-2′,4-dione (860 mg, 4 mmol) in DMF (6 mL) was added (bromomethyl)cyclopropane (701 mg, 5.19 mmol) and Cs2CO3 (2083 mg, 6.39 mmol) at room temperature. The reaction mixture was then stirred at 50°C for 1 h. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (100 mL×2). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (0-50% EtOAc / PE) to provide 1′-(cyclopropylmethyl)spiro[cyclohexane-1,3′-indoline]-2′,4-dione as a solid. MS: 270 (M+1). 1H-NMR (400 MHz, chloroform-d) δ 7.33-7.29 (m, 1H), 7.26-7.24 (m, 1H), 7.10-7.08 (m, 1H), 6.99-6.97 (m, 1H), 3.64 (d, J = 6.8 Hz, 2H), 3.20-3.14 (m, 2H), 2.51-2.47 (m, 2H), 2.18-2.15 (m, 4H), 1.22-1.18 (m, 1H), 0.56-0.52 (m, 2H), 0.42-0.38 (m, 2H).

[0626] Table 6 : The following intermediates were prepared using a similar procedure to that described above for intermediate 45.

[0627]

[0628]

[0629] Plan 34 :

[0630]

[0631] Intermediate 49: 2-Phenyl-2-azaspiro[4.5]decane-1,8-dione

[0632] Step 1: THF (15.5mL) and LDA (12.8mL, 25.7mmol) are added in degassed 100mL RBF and are cooled to-78 ℃.While stirring, 1,4-dioxaspiro [4.5] decane-8-ethyl formate (5g, 23mmol) solution in THF (31mL) is added dropwise in flask.Mixture was stirred 30 minutes at-78 ℃.At-78 ℃, solution of bromoacetonitrile (1.95ml, 28.0mmol) in THF (31mL) is added in flask, and will react at-78 ℃ and stir 2h.The reaction is quenched with saturated ammonium chloride aqueous solution, and extracted with EtOAc (3x).The organic layer washed with salt water merging, through anhydrous sodium sulfate drying, filtered, and under reduced pressure concentrated. The residue was purified by column chromatography on silica gel (0-30% EtOAc / hexanes) monitored with ELSD to afford ethyl 8-(cyanomethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as an oil. MS: 254 (M+1).

[0633] Step 2:Sodium borohydride (2.15 g, 56.7 mmol) was added portionwise to a mixture of 8-(cyanomethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (2.87 g, 11.3 mmol) and cobalt(II) chloride (0.736 g, 5.67 mmol) in THF (44 mL) and water (22 mL) at 0 ° C. The mixture was stirred at room temperature overnight. The reaction was quenched with 2M NH4OH (5 mL) and the mixture was filtered. The solid was washed with 2:1THF: water and the filtrate was concentrated under reduced pressure. The aqueous solution was extracted with DCM (3x) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% MeOH / DCM) to provide 1,4-dioxa-10-azabispiro[4.2.4 8 .2 5 ]Tetradecan-9-one. MS: 212 (M+1).

[0634] Step 3: 1,4-dioxa-10-azabisspiro[4.2.4 8 .2 5 ]Tetradecan-9-one (908mg, 4.30mmol) was dissolved in DMF (43mL). Bromobenzene (0.675ml, 6.45mmol), N,N-dimethylethylenediamine (0.939ml, 8.60mmol), copper (I) iodide (1.23g, 6.45mmol) and potassium phosphate (1.62g, 7.61mmol) were added and the mixture was heated at 100°C overnight. The reaction was cooled to room temperature, poured into ice water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc / hexane) to provide 10-phenyl-1,4-dioxa-10-azadispiro[4.2.4 8 .2 5 ]Tetradecan-9-one. MS: 288 (M+1).

[0635] Step 4: To 10-phenyl-1,4-dioxa-10-azadispiro[4.2.4 8 .2 5]To a solution of tetradecane-9-one (1.4 g, 4.9 mmol) in acetone (24 mL) were added p-toluenesulfonic acid monohydrate (2.04 g, 10.7 mmol) and water (4.39 ml, 244 mmol). The mixture was heated at 70 ° C overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% EtOAc / hexane) to provide 2-phenyl-2-azaspiro[4.5]decane-1,8-dione as a solid. MS: 244 (M+1).

[0636] Plan 35 :

[0637]

[0638] Intermediate 50: 2-Phenyl-2-azaspiro[4.5]decane-3,8-dione

[0639] Step 1: Add 1,4-dioxa-10-azadispiro[4.2.4 8 .2 5 ]Tetradecan-11-one (1g, 4.7mmol), copper (I) iodide (1.35g, 7.1mmol), potassium phosphate (1.80g, 8.38mmol), bromobenzene (0.744mL, 7.1mmol) and N,N-dimethylethylenediamine (1.03mL, 9.46mmol). DMF (48mL) was added and the mixture was stirred at 100°C overnight. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30-100% EtOAc / hexane) to provide 10-phenyl-1,4-dioxa-10-azadispiro[4.2.4 8 .2 5 ]Tetradecan-11-one. MS: 288 (M+1).

[0640] Step 2: To 10-phenyl-1,4-dioxa-10-azadispiro[4.2.4 8 .2 5]To a solution of tetradecane-11-one (1.19 g, 4.16 mmol) in acetone (21 mL) was added p-toluenesulfonic acid monohydrate (1.74 g, 9.15 mmol) and water (3.75 ml, 208 mmol). The mixture was heated at 70 ° C overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with DCM (3x), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20-100% EtOAc / hexane) to provide 2-phenyl-2-azaspiro[4.5]decane-3,8-dione as a solid. MS: 244 (M+1).

[0641] Scheme 36:

[0642]

[0643] Intermediate 51: 2-Phenyl-2-azaspiro[4.5]decan-8-one

[0644] Step 1 : To a solution of 1,4-dioxa-10-azabisspiro[4.2.48.25]tetradecane-11-one (1.08g, 5.11mmol) in THF (10mL) was added lithium aluminum hydride (0.388g, 10.22mmol) at 0°C under N2 atmosphere. The resulting mixture was stirred at room temperature for 16h. The mixture was then quenched by adding water (0.39mL), 15% NaOH aqueous solution (0.39mL) and water (1.17mL) at 0°C. The resulting mixture was stirred at room temperature for 1h. The mixture was then filtered. The filtrate was concentrated under reduced pressure to produce 1,4-dioxa-10-azabisspiro[4.2.48.25]tetradecane (900mg, 4.56mmol, 89% yield) as a light yellow oil. 11 H 19 NO2[M+H] + MS ESI calculated value 198.14, found value 198.25. 1 H NMR (300 MHz, chloroform-d): δ 3.96 (s, 4H), 2.99 (t, J=6.9 Hz, 2H), 2.74 (s, 2H), 1.74-1.56 (m, 10H).

[0645] Step 2To a mixture of 1,4-dioxa-10-azadispiro[4.2.48.25]tetradecane (18 g, 91 mmol), [2′-(amino-n)[1,1′-biphenyl]-2-yl-c][[2′,6′-bis(1-methylethoxy)[1,1′-biphenyl]-2-yl]dicyclohexylphosphine-p]chloro-palladium (7.09 g, 9.12 mmol) and Ruphos (4.26 g, 9.12 mmol) in 1,4-dioxane (180 mL) was added bromobenzene (17.19 g, 109 mmol) and sodium 2-methylpropane-2-olate (17.54 g, 182 mmol) under N₂ atmosphere. The resulting mixture was heated to 70° C. and stirred for 16 h. The mixture was then cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with 0-30% ethyl acetate / petroleum ether to yield 10-phenyl-1,4-dioxa-10-azadispiro[4.2.48.25]tetradecane (13.5 g, 49.4 mmol, 54.1% yield) as a white solid. 17 H 23 NO2[M+H] + MS ESI calculated value 274.17, found 274.20. 1 H NMR (300MHz, chloroform-d): δ7.30-7.18 (m, 2H), 6.68 (t, J=7.5Hz, 1H), 6.57 (d, J=8.1Hz, 2H), 3. 97 (s, 4H), 3.37 (t, J=6.9Hz, 2H), 3.18 (s, 2H), 1.89 (t, J=6.9Hz, 2H), 1.80-1.60 (m, 8H).

[0646] Step 3 : To a solution of 10-phenyl-1,4-dioxa-10-azabispiro[4.2.48.25]tetradecane (13.4 g, 49.0 mmol) in THF (123 mL) was added hydrochloric acid (2 M, 123 mL, 245 mmol) at 0 ° C. The resulting mixture was stirred at 25 ° C for 5 h. The pH value of the mixture was then adjusted to 8 with saturated NaHCO3 aqueous solution. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL×3). The combined organic phases were washed with brine (250 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to produce 2-phenyl-2-azaspiro[4.5]decane-8-one (11.24 g, 49.0 mmol, 100% yield) as a yellow solid. 15 H 19 NO[M+H] + MS ESI calculated value: 230.15, found: 230.20.1 H NMR (300MHz, chloroform-d): δ7.35-7.20 (m, 2H), 6.72 (t, J=7.2Hz, 1H), 6.66-6.55 (m, 2H ), 3.46 (t, J=6.9Hz, 2H), 3.32 (s, 2H), 2.43 (t, J=6.9Hz, 4H), 2.12-1.83 (m, 6H).

[0647] Scheme 37:

[0648]

[0649] Intermediate 52: 2-Phenyl-2-azabispiro[4.1.47.35]tetradecan-12-one

[0650] Step 1: A mixture of 2-phenyl-2-azaspiro[4.5]decane-8-one (690 mg, 3.01 mmol), 1,4-dibromobutane (682 mg, 3.16 mmol) and 2-methylpropane-2-alcoholate potassium (709 mg, 6.32 mmol) in toluene (12 mL) was heated to reflux and stirred for 4 h. The mixture was then cooled to room temperature and diluted with ethyl acetate (40 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography using the following conditions: column: C 18 Gel column, 80 g, 20-45 μm, 100 A; mobile phase A: water, mobile phase B: MeCN; gradient: 0% B for 5 min, 45% B in 5 min, 45% B to 95% B in 30 min, 95% B for 5 min; flow rate: 65 mL / min; RT = 25 min; detector: UV 254 and 210 nm. Fractions containing product were collected and evaporated to provide 2-phenyl-2-azabispiro[4.1.47.35]tetradecan-12-one (340 mg, 1.200 mmol, 39.9% yield) as a brown solid. 19 H 25 NO[M+H] + MS ESI calculated value: 284.19, found: 284.20. 1 H NMR (300 MHz, chloroform-d): δ 7.32-7.24 (m, 2H), 6.70 (t, J=7.2 Hz, 1H), 6.65-6.54 (m, 2H), 3.51-3.18 (m, 4H), 2.64-2.40 (m, 2H), 2.29-1.31 (m, 14H).

[0651] Scheme 38:

[0652]

[0653] Intermediate 53: 7,7-Diethyl-2-phenyl-2-azaspiro[4.5]decan-8-one

[0654] Step 1 : at 25 ℃ to 2-phenyl-2-azaspiro [4.5] decane-8-one (1000mg, 4.36mmol) and potassium tert-butoxide (489mg, 4.36mmol) in toluene (10mL) dropwise add iodoethane (1428mg, 9.16mmol).The mixture that obtains is stirred 4h at 60 ℃.After reaction finishes, by reaction mixture NH4Cl aqueous solution (10mL) cancellation and with ethyl acetate (300mL) dilution, then wash with salt solution (50mL), through anhydrous sodium sulfate drying and filter.Filtrate is concentrated under reduced pressure, and with resistates by silica gel column chromatography, use the gradient of ethyl acetate / petroleum ether of 0%-20% as eluent. The fractions containing the desired product were combined and concentrated under reduced pressure to afford 7,7-diethyl-2-phenyl-2-azaspiro[4.5]decan-8-one (460 mg, 1.612 mmol, 37.0% yield) as a yellow oil. 19 H 27 NO[M+H] + MS ESI calculated value: 286.21, found: 286.15. 1 H-NMR (400 MHz, chloroform-d) δ 7.28-7.22 (m, 2H), 6.75-6.67 (m, 1H), 6.63-6.55 (m, 2H), 3.49-3.32 (m, 3H), 3.22 (d, J = 9.2 Hz, 1H), 2.55-2.33 (m, 2H), 2.05-1.99 (m, 2H), 1.98-1.89 (m, 1H), 1.87 (d, J = 1.8 Hz, 2H), 1.85-1.75 (m, 1H), 1.75-1.64 (m, 2H), 1.58-1.49 (m, 2H), 0.87-0.72 (m, 6H).

[0655] Option 39:

[0656]

[0657] Intermediate 54: 7-phenyl-7-azabispiro[2.1.45.33]dodecan-12-one

[0658] Step 1To a solution of 2-phenyl-2-azaspiro[4.5]decane-8-one (2 g, 8.72 mmol) and potassium 2-methylpropane-2-olate (2.94 g, 26.2 mmol) in toluene (30 mL) was added (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (4.64 g, 10.47 mmol) at room temperature. The resulting mixture was stirred at 110 ° C for 16 h. Water (200 mL) was added to the reaction and extracted with ethyl acetate (400 mL). The organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-25% ethyl acetate / petroleum ether to provide a yellow oil, which was further purified by RP-Flash chromatography eluting with 40-80% acetonitrile / water to provide 7-phenyl-7-azabispiro[2.1.45.33]dodecan-12-one (236 mg, 0.924 mmol, 10.60% yield) as a colorless oil. 17 H 21 NO[M+H] + MS ESI calculated value 256.16, found value 256.15. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.26-7.21 (m, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.59 (d, J = 7.8 Hz, 2H), 3.49-3.40 (m, 2H), 3.37 (d, J = 9.2 Hz, 1H), 3.27 (d, J = 9.2 Hz, 1H), 2.63-2.45 (m, 2H), 2.15-1.94 (m, 4H), 1.84 (s, 2H), 1.43-1.15 (m, 2H), 0.71-0.59 (m, 2H).

[0659] Option 40:

[0660]

[0661] Intermediate 55: 7-Ethyl-7-methyl-2-phenyl-2-azaspiro[4.5]decan-8-one

[0662] Step 1: To a stirred mixture of 2-phenyl-2-azaspiro [4.5] decane-8-one (2g, 8.72mmol) in toluene (20mL) was added iodoethane (1.224g, 7.85mmol) and potassium tert-butoxide (1.174g, 10.47mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred at 60°C for 3h. The reaction was quenched by adding saturated NH4Cl aqueous solution (20mL) and extracted with EtOAc (20mL×3). The organic layer was washed with brine (50mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate / petroleum ether to provide 7-ethyl-2-phenyl-2-azaspiro [4.5] decane-8-one (760mg, 2.95mmol, 33.9% yield) as a yellow oil. 17 H 23 NO[M+H] + MS ESI calculated value 258.28, found value 258.10. 1 H NMR (300MHz, chloroform-d) δ7.39-7.21 (m, 2H), 6.75 (t, J=7.3Hz, 1H), 6.67 (d, J=8.1Hz, 2H), 3.55-3.38 (m, 4H), 2.53 -2.18(m, 3H), 2.17-1.99(m, 1H), 1.99-1.71(m, 4H), 1.62-1.47(m, 1H), 1.30-1.14(m, 1H), 1.04-0.70(m, 4H).

[0663] Step 2 : 7- ethyl -2- phenyl -2- azaspiro [4.5] decane -8- ketone (760mg, 2.95mmol) in toluene (8mL) solution is added iodomethane (461mg, 3.25mmol) and potassium tert-butoxide (398mg, 3.54mmol). The resulting mixture is stirred at 60 DEG C for 2h, then quenched with NH4Cl (10mL), and extracted with EtOAc (30mL × 3). The combined organic layer is dried over Na2SO4 and concentrated in vacuo. The crude material is purified by silica gel column chromatography, eluted with 0-50% EtOAc / petroleum ether to provide 7- ethyl -7- methyl -2- phenyl -2- azaspiro [4.5] decane -8- ketone (320mg, 1.179mmol, 39.9% yield) as a colorless oil. 18 H 25 NO[M+H] + MS ESI calculated value 272.19, found 272.15. 1H NMR (300 MHz, chloroform-d) δ 7.33-7.21 (m, 2H), 6.76 (t, J=7.3 Hz, 1H), 6.70-6.64 (m, 2H), 3.68-3.13 (m, 4H), 2.57-2.32 (m, 1H), 2.15-1.88 (m, 3H), 1.87-1.37 (m, 6H), 1.13-1.07 (m, 3H), 0.91-0.79 (m, 3H).

[0664] Option 41:

[0665]

[0666] Intermediates 56 and 57: 6,6-dimethyl-8,11-dioxadispiro[3.2.4 7 .2 4 ] tridecan-2-one, 56 and 2-methyl Oxy-2,6,6-trimethylspiro[3.5]nonan-7-one, 57

[0667] Step 1 To a mixture of methyltriphenylphosphonium bromide (58.2 g, 163 mmol) in THF (100 mL) was added potassium tert-butoxide (18.27 g, 163 mmol) at 0 ° C under nitrogen. The mixture was stirred for 30 min at 0 ° C, and 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-one (10 g, 54.3 mmol) was added thereto. The resulting mixture was warmed to 25 ° C and stirred for 3 h, then quenched with water (200 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic fractions were washed with brine (250 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 1-10% ethyl acetate / petroleum ether to afford 6,6-dimethyl-8-methylene-1,4-dioxaspiro[4.5]decane (8.6 g, 47.2 mmol, 87% yield) as a colorless oil. 1 H-NMR (300 MHz, chloroform-d) δ 4.73 (s, 1H), 4.64 (s, 1H), 4.05-3.91 (m, 4H), 2.26 (t, J = 6.6 Hz, 2H), 2.13 (s, 2H), 1.68 (t, J = 6.6 Hz, 2H), 0.95 (s, 6H).

[0668] Step 2: Under nitrogen at 25 DEG C to 6,6-dimethyl-8-methylene-1,4-dioxaspiro [4.5] decane (7.6g, 41.7mmol) and zinc-copper partner (16.13g, 125mmol) in Et2O (65mL) in a mixture of slowly add trichloroacetyl chloride (15.16g, 83mmol) in Et2O (15mL) solution.The mixture is stirred for 1.5h, then quenched and filtered at 0 DEG C with sodium bicarbonate solution (200mL).The filtrate is extracted with ethyl acetate (2x 200mL).The organic fractions merged are washed with salt water (200mL), dried over anhydrous sodium sulfate and filtered.The filtrate is concentrated under reduced pressure to provide a brown oil.Ammonium chloride (4.46g, 83mmol) and zinc (8.18g, 125mmol) are added to a solution of the oil in MeOH (80ml) at 0 DEG C. The mixture was warmed to 25°C and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 1-14% ethyl acetate / petroleum ether to provide 6,6-dimethyl-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecane-2-one (4.1 g, 18.28 mmol, 43.8% yield). 1 H-NMR (400 MHz, chloroform-d) δ 4.02-7.52 (m, 4H), 2.97-2.72 (m, 4H), 1.83-1.60 (m, 6H), 1.03-1.00 (m, 6H).

[0669] Step 3 : At 0 ° C to 6,6-dimethyl-8,11-dioxadispiro [3.2.4 7 .2 4 ] To a solution of tridecane-2-one (250 mg, 1.115 mmol) in THF (2 mL) was added methylmagnesium bromide (1 M in THF, 2.229 mL, 2.229 mmol), and the mixture was stirred for 10 min. The mixture was then stirred at room temperature for 3 h and monitored by LCMS and TLC. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to produce 2,6,6-trimethyl-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecane-2-ol (250 mg, 1.040 mmol, 93% yield). 14 H 24 O3[M+H-H2O]+ MS ESI calculated value 223.17, found 223.25. 1 H NMR (300MHz, DMSO-d6) δ4.67 (s, 0.3H), 4.57 (s, 0.7H), 3.94-3.73 (m, 4H), 1.8 7-1.69 (m, 5H), 1.60-1.40 (m, 5H), 1.22 (s, 0.5H), 1.20 (s, 2.5H), 0.85 (s, 6H).

[0670] Step 4 To a solution of sodium hydride (60% in mineral oil, 80 mg, 1.997 mmol) in DMF (1.0 mL) was added 2,6,6-trimethyl-8,11-dioxadispiro[3.2.4 7 .2 4 ] A solution of tridecane-2-ol (192 mg, 0.799 mmol) in DMF (0.5 mL) and iodomethane (283 mg, 1.997 mmol) in DMF (0.5 mL) was added, and the mixture was stirred for 10 min. The reaction was stirred at 25 ° C for 5 h and monitored by LCMS and TLC. The reaction was quenched with saturated NH4Cl aqueous solution (5 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1-60% ethyl acetate / petroleum ether to provide 2-methoxy-2,6,6-trimethyl-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecane (140 mg, 0.550 mmol, 68.9% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.97-3.86 (m, 4H), 3.13 (s, 3H), 1.97 (m, 2H), 1.83-1.65 (m, 5H), 1.58 (m, 3H), 1.27 (s, 3H), 0.92 (s, 6H).

[0671] Step 5 : To hydrochloric acid (2M in water, 2.00 mL, 4.00 mmol) was added 2-methoxy-2,6,6-trimethyl-8,11-dioxadispiro[3.2.4 7 .2 4] tridecane (140 mg, 0.550 mmol) in THF (2.00 mL) was added, and the mixture was stirred for 10 min. The reaction was stirred at 25 ° C for 3 h and monitored by LCMS and TLC. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1-60% ethyl acetate / petroleum ether to provide 2-methoxy-2,6,6-trimethylspiro[3.5]nonane-7-one (85 mg, 0.404 mmol, 73.4% yield) as a yellow oil. 13 H 22 O2[M+H] + MS ESI calculated value 211.16, found value 211.10. 1 HNMR (300 MHz, CHLOROFORM-d) δ 3.17 (s, 1H), 3.16 (s, 2H), 2.47-2.37 (m, 2H), 2.20-2.06 (m, 2H), 2.04-1.70 (m, 6H), 1.36 (s, 1H), 1.33 (s, 2H), 1.09 (s, 6H).

[0672] Option 42:

[0673]

[0674] Intermediate 58: 7,7-Dimethyl-N-phenyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,1′-cyclobutane]- 3′-amine

[0675] Step 1 : At 0 ° C under nitrogen to 6,6-dimethyl-8,11-dioxadispiro [3.2.4 7 .2 4 ] To a mixture of tridecane-2-one (500 mg, 2.229 mmol) in MeOH (15 mL) was added NaBH4 (169 mg, 4.46 mmol). The mixture was stirred for 10 min. The resulting mixture was warmed to 25 ° C and stirred for 1.5 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2x40 mL). The combined organic fractions were washed with brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 1-23% ethyl acetate / petroleum ether to provide 6,6-dimethyl-8,11-dioxadispiro[3.2.4 7 .2 4]Tridecane-2-ol (408 mg, 1.803 mmol, 81% yield). 13 H 22 O3[M+H] + MS ESI calculated value: 227.16, found: 227.25. 1 H-NMR (400 MHz, chloroform-d) δ 4.46-4.18 (m, 1H), 4.02-3.84 (m, 4H), 2.41-2.20 (m, 2H), 1.81-1.68 (m, 3H), 1.68-1.58 (m, 5H), 0.96 (s, 3H), 0.93 (s, 3H).

[0676] Step 2 : At room temperature to 6,6-dimethyl-8,11-dioxadispiro[3.2.4 7 .2 4 ] To a mixture of tridecan-2-ol (446 mg, 1.971 mmol) in THF (5 mL) was added HCl (1 M in H2O, 5 mL, 5.00 mmol). The resulting mixture was warmed to 35°C and stirred for 1 h. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate solution (25 mL) and extracted with ethyl acetate (2x30 mL). The combined organic fractions were washed with brine (25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 1-43% ethyl acetate / petroleum ether to provide 2-hydroxy-6,6-dimethylspiro[3.5]nonan-7-one (312 mg, 1.712 mmol, 87% yield) as a light yellow oil. 11 H 18 O2[M+H] + MS ESI calculated value 183.14, found 183.25. 1 H-NMR (300 MHz, CHLOROFORM-d) δ 4.50-4.30 (m, 1H), 2.52-2.36 (m, 4H), 2.04-1.97 (m, 1H), 1.95-1.83 (m, 3H), 1.78 (s, 1H), 1.76 (s, 2H), 1.12 (s, 3H), 1.09 (s, 3H).

[0677] Step 3: To a mixture of 2-hydroxy-6,6-dimethylspiro[3.5]nonane-7-one (312 mg, 1.712 mmol) in toluene (6 mL) was added ethyl formate (1268 mg, 17.12 mmol) and sodium methoxide (30% in MeOH, 3083 mg, 17.12 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 35 ° C for 3 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic fractions were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide (Z)-2-hydroxy-8-(hydroxymethylene)-6,6-dimethylspiro[3.5]nonane-7-one (355 mg, 1.688 mmol, 99% yield) (crude) as a light yellow oil. 12 H 18 O3[M+H] + MS ESI calculated value 211.13, found 211.15.

[0678] Step 4 To (Z)-2-hydroxy-8-(hydroxymethylene)-6,6-dimethyl spiro [3.5] nonyl-7-ketone (355mg, 1.688mmol) in the mixture of EtOH (12mL) at room temperature, add hydroxylamine hydrochloride (1173mg, 16.88mmol) in water (1.2mL).The mixture obtained is stirred at 80 ℃ for 2h.By reaction mixture saturated NaHCO the aqueous solution (40mL) is quenched, and extracted with ethyl acetate (2x50mL).The organic fraction merged is washed with salt water (45mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-39% ethyl acetate / petroleum ether to provide 7,7-dimethyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,1′-cyclobutane]-3′-ol (189 mg, 0.912 mmol, 54.0% yield) as a pale yellow oil. 12 H 17 NO2[M+H] + MS ESI calculated value: 208.13, found: 208.25. 1 H-NMR (300 MHz, chloroform-d) δ 8.03 (d, J = 1.7 Hz, 1H), 4.67-4.25 (m, 1H), 2.65 (s, 1H), 2.52 (s, 1H), 2.51-2.40 (m, 1H), 2.34-2.23 (m, 1H), 2.01-1.88 (m, 1H), 1.89-1.76 (m, 3H), 1.37 (s, 3H), 1.34 (s, 3H).

[0679] Step 5 : Under nitrogen at 0 ° C to a mixture of 7,7-dimethyl-6,7-dihydro-4H-spiro [benzo [d] isoxazole -5,1 '- cyclobutane] -3 '- alcohol (350mg, 1.689mmol) in DCM (4.5mL) was added Dess-Martin periodinane (1432mg, 3.38mmol). The resulting mixture was warmed to room temperature and stirred for 1.5h. The reaction progress was monitored by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate (40mL) and extracted with ethyl acetate (130mL × 3). The combined organic fractions were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1-40% ethyl acetate / petroleum ether to provide 7,7-dimethyl-6,7-dihydro-4H-spiro[benzo[d]isoxazol-5,1′-cyclobutane]-3′-one (312 mg, 1.520 mmol, 90% yield) as a white solid. 12 H 15 NO2[M+H] + MS ESI calculated value 206.11, found value 206.10. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.06 (s, 1H), 3.17-3.03 (m, 2H), 2.84-2.74 (m, 2H), 2.66 (s, 2H), 2.06 (s, 2H), 1.39 (s, 6H).

[0680] Step 6 : To a solution of 7,7-dimethyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,1′-cyclobutane]-3′-one (100 mg, 0.487 mmol) in THF (1 ml) was added aniline (52.2 mg, 0.56 mmol). The resulting mixture was stirred at room temperature for 2 h, to which sodium triacetoxyborohydride (147.8 mg, 0.69 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0-50% ethyl acetate / petroleum ether to provide 7,7-dimethyl-N-phenyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,1′-cyclobutane]-3′-amine (90 mg, 0.319 mmol, 65.4% yield) as a colorless oil. 18 H 22 N2O[M+H] + MS ESI calculated value: 283.17, found: 283.20. 1H NMR (400 MHz, chloroform-d) δ 8.06-7.98 (m, 1H), 7.27-7.20 (m, 2H), 6.98-6.80 (m, 3H), 4.10-3.82 (m, 1H), 2.68-2.59 (m, 2H), 2.52-2.25 (m, 2H), 2.12-2.09 (m, 2H), 1.84 (d, J=5.9 Hz, 2H), 1.35 (s, 4H), 1.28 (s, 2H).

[0681] Option 43:

[0682]

[0683] Intermediate 59: N,7,7-trimethyl-N-phenyl-6 , 7-Dihydro-4H-spiro[benzo[d]isoxazole-5,1′-cyclobutane [alkyl]-3′-amine

[0684] Step 1 : To 7,7-dimethyl-N-phenyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,1′-cyclobutane]-3′-amine (75mg, 0.266mmol) in MeOH (0.5mL) solution of acetic acid (159mg, 2.66mmol), formaldehyde (80mg, 2.66mmol) and sodium cyanoborohydride (134mg, 2.125mmol) in MeOH (0.5mL) was added. The resulting mixture was stirred at room temperature for 1h, then quenched with saturated sodium bicarbonate aqueous solution (10mL). The reaction mixture was extracted with ethyl acetate (30mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate / petroleum ether to provide N,7,7-trimethyl-N-phenyl-6,7-dihydro-4H-spiro[benzo[d]isoxazole-5,1′-cyclobutane]-3′-amine (70 mg, 0.224 mmol, 84% yield) as a colorless oil. 19 H 24 N2O[M+H] + MS ESI calculated value: 297.19, found: 297.25.

[0685] Plan 44 :

[0686]

[0687] Intermediate 60: 9,9-Dimethyl-1,8-dioxo-2-phenyl-2-azaspiro[4.5]decane-7-carbonitrile

[0688] Step 1:To 1-azaspiro [4.5] decane-2,8-diketone (2g, 12mmol) in the solution of MeOH (24mL), add trimethyl orthoformate (1.59mL, 14.4mmol) and CSA (0.139g, 0.598mmol).Mixture is stirred at room temperature for 1h.Reaction is quenched with triethylamine and under reduced pressure concentrated to be provided as 8,8-dimethoxy-1-azaspiro [4.5] decane-2-one of solid.Described material is used in next step with crude former state.

[0689] Step 2: To 8,8-dimethoxy-1-azaspiro [4.5] decane-2-one (2.44g, 11.4mmol) in THF (17mL) and DMF (5.7mL) solution, add NaH (1.33g, 33.2mmol) portion by portion. The mixture is stirred at room temperature for 30 minutes. Iodomethane (1.57ml, 25.2mmol) is added and the reaction is stirred at room temperature overnight. The mixture is diluted with water and DCM, and the aqueous layer is extracted with DCM (3x). The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (0-10% MeOH / DCM) to provide 8,8-dimethoxy-1-methyl-1-azaspiro [4.5] decane-2-one as an oil. MS: 228 (M+1).

[0690] Step 3: To 8,8-dimethoxy-1-methyl-1-azaspiro [4.5] decane-2-one (1.34 g, 5.89 mmol) in acetone (20 mL) was added water (5.31 ml, 295 mmol) and CSA (0.137 g, 0.589 mmol). The mixture was heated at 70 ° C for 30 minutes. The reaction was quenched with a saturated aqueous sodium bicarbonate solution, extracted with DCM (3x), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% MeOH / DCM) to provide 9,9-dimethyl-1,8-dioxo-2-phenyl-2-azaspiro [4.5] decane-7-carbonitrile as a solid. MS: 182 (M+1).

[0691] Option 45:

[0692]

[0693] Intermediate 61: 3,5,5-Trimethyl-3-(methylamino)-6-oxocyclohex-1-ene-1-carbonitrile Salt acid salt

[0694] Step 1:To a solution of tert-butyl (1-methyl-4-oxocyclohexyl)carbamate (2 g, 8.80 mmol) in THF (70 mL) was added lithium aluminum hydride (1 M in THF, 26.4 mL, 26.4 mmol) dropwise at 0 ° C. The resulting mixture was heated to 75 ° C and stirred for 1 h. The mixture was then cooled to 0 ° C and quenched by adding water (1 mL), 10% NaOH aqueous solution (1 mL) and water (3 mL). The mixture was then filtered. The solid was washed with THF (100 mL × 3). The filtrate was concentrated under reduced pressure to produce a crude product, which was used directly in the next step. CH 17 NO[M+H] + MS ESI calculated value 144.13, found 144.25.

[0695] Step 2: To a solution of 4-methyl-4-(methylamino)cyclohexane-1-ol (1.260 g, 8.80 mmol) in DCM (90 mL) was added di-tert-butyl dicarbonate (3.84 g, 17.60 mmol) at 0°C. The resulting mixture was stirred at room temperature for 16 h. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with 0%-55% ethyl acetate / petroleum ether to produce tert-butyl (4-hydroxy-1-methylcyclohexyl)(methyl)carbamate (1.95 g, 8.01 mmol, 91% yield) as a light yellow oil. 13 H 25 NO3[M+H] + MS ESI calculated value 244.18, found 244.25. 1 HNMR (400 MHz, chloroform-d): δ 3.73-3.64 (m, 1H), 2.85 (s, 3H), 1.93-1.69 (m, 4H), 1.47 (s, 9H), 1.44-1.35 (m, 2H), 1.32-1.22 (s, 2H), 1.19 (s, 3H).

[0696] Step 3:To a solution of tert-butyl (4-hydroxy-1-methylcyclohexyl) (methyl) carbamate (1.95 g, 8.01 mmol) in anhydrous DCM (200 mL) was added DMP (6.80 g, 16.03 mmol) at 0 ° C under N2 atmosphere. The resulting mixture was stirred at room temperature for 16 h. The mixture was then quenched with saturated Na2S2O3 aqueous solution (150 mL) and saturated NaHCO3 aqueous solution (150 mL) and extracted with DCM (300 mL×3). The combined organic phases were washed with brine (400 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with 0%-40% ethyl acetate / petroleum ether to produce tert-butyl methyl (1-methyl-4-oxocyclohexyl) carbamate (1.81 g, 7.50 mmol, 94% yield) as a light yellow oil. 13 H 23 NO3[M+H] + MS ESI calculated value 242.17, found 242.25. 1 H NMR (400 MHz, chloroform-d): δ 2.92 (s, 3H), 2.81-2.70 (m, 2H), 2.45-2.23 (m, 4H), 1.78-1.67 (m, 2H), 1.46 (s, 9H), 1.31 (s, 3H).

[0697] Step 4: To a solution of tert-butyl methyl (1-methyl-4-oxocyclohexyl) carbamate (2.81 g, 11.64 mmol) in t-BuOH (110 mL) was added potassium 2-methylpropane-2-olate (1 M in THF, 29.1 mL, 29.1 mmol) at room temperature. The mixture was stirred at 25 ° C for 1 h. A solution of iodomethane (3.47 g, 24.45 mmol) in THF (5 mL) was then added at 0 ° C. The resulting mixture was stirred at 25 ° C for 3 h. The mixture was then quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with 0%-20% ethyl acetate / petroleum ether to yield tert-butyl methyl(1,3,3-trimethyl-4-oxocyclohexyl)carbamate (1.53 g, 5.68 mmol, 48.8% yield) as a yellow oil. 15 H 27 NO3[M+H] + MS ESI calculated value 270.20, found value 270.20. 1HNMR (300 MHz, chloroform-d): δ 3.16 (dd, J = 14.7, 4.2 Hz, 1H), 2.91 (s, 3H), 2.67-2.39 (m, 2H), 2.33-2.21 (m, 1H), 1.87-1.61 (m, 2H), 1.46 (s, 9H), 1.28 (s, 3H), 1.18 (s, 3H), 1.04 (s, 3H).

[0698] Step 5: At -70 ℃ under N2 atmosphere, to a solution of tert-butyl methyl (1,3,3-trimethyl-4-oxocyclohexyl) carbamate (1.2g, 4.45mmol) in THF (25mL), LiHMDS (1M in THF, 9.80mL, 9.80mmol) was added dropwise. The resulting mixture was stirred at -70 ℃ for 1h. A solution of 4-methylbenzenesulfonyl cyanide (1.211g, 6.68mmol) in THF (5mL) was then added. After stirring at -70 ℃ for 30min, the mixture was warmed to room temperature and stirred for 2h. The main desired product was detected on LCMS, and some SM remained. The mixture was then quenched with saturated NH4Cl aqueous solution (100mL) and extracted with ethyl acetate (100mL×3). The combined organic phases were washed with brine (150mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0%-30% ethyl acetate / petroleum ether to yield tert-butyl (5-cyano-1,3,3-trimethyl-4-oxocyclohexyl)(methyl)carbamate (680 mg, 2.31 mmol, 51.9% yield) as a white solid. 16 H 26 N2O3[M+H] + MS ESI calculated value: 295.19, found: 295.30. 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.00 (dd, J = 14.0, 4.0 Hz, 1H), 3.19-3.08 (m, 2H), 3.00 (dd, J = 14.0, 3.2 Hz, 1H), 2.92 (s, 3H), 2.85 (s, 3H), 2.57 (dd, J = 16.4, 3.2 Hz, 1H), 2.30 (d, J = 16.4 Hz, 1H), 2.04-1.94 (m, 1H), 1.54-1.40 (m, 21H), 1.35 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H), 1.11 (s, 3H).

[0699] Step 6: A solution of pyridine (107 mg, 1.359 mmol) in DCM (0.3 mL) was added dropwise to phenylselenyl chloride (260 mg, 1.359 mmol) in DCM (5 mL) at 0 ° C. The mixture was stirred at 0 ° C for 20 min and then treated dropwise with a solution of (5-cyano-1,3,3-trimethyl-4-oxocyclohexyl) (methyl) carbamic acid tert-butyl ester (200 mg, 0.679 mmol) in DCM (2 mL). The resulting mixture was stirred at 0 ° C for 2 h. Hydrogen peroxide (30%, 770 mg, 6.79 mmol) was then added dropwise at 0 ° C, and the mixture was vigorously stirred at 0 ° C for 40 min. The reaction mixture was quenched with saturated Na2S2O3 aqueous solution (20 mL), extracted with DCM (20 mL × 3), washed with brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with 0%-35% ethyl acetate / petroleum ether to yield tert-butyl (3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)(methyl)carbamate (110 mg, 0.376 mmol, 55.4% yield) as a yellow oil. 16 H 24 N2O3[M-56+H] + MS ESI calculated value: 237.18, found: 237.15. 1 H NMR (300 MHz, chloroform-d): δ 7.70 (s, 1H), 2.86 (s, 3H), 2.33 (d, J=14.1 Hz, 1H), 1.92 (d, J=14.1 Hz, 1H), 1.54 (s, 3H), 1.43 (s, 9H), 1.23 (s, 3H), 1.21 (s, 3H).

[0700] Step 7: To a solution of tert-butyl (3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-ene-1-yl)(methyl)carbamate (110 mg, 0.376 mmol) in DCM (2.1 mL) was added hydrogen chloride (4 M solution in dioxane, 0.941 mL, 3.76 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to produce crude 3,5,5-trimethyl-3-(methylamino)-6-oxocyclohex-1-ene-1-carbonitrile hydrochloride (86 mg, 0.376 mmol, 100% yield) as a light yellow solid, which was used directly in the next step. 11 H 16 N2O[M+H] + MS ESI calculated value 193.14, found 193.20. 1H NMR (400MHz, DMSO-d6): δ9.81 (s, 2H), 7.89 (s, 1H), 2.56 (s, 3H), 2.35 (d, J=1 4.4Hz, 1H), 2.13 (dd, J=14.4Hz, 1H), 1.67 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H).

[0701] Plan 46:

[0702]

[0703] Intermediate 62: 3-Amino-3,5,5-trimethyl-6-oxocyclohex-1-ene-1-carbonitrile hydrochloride

[0704] Step 1: Under nitrogen, at room temperature, 6,6-dimethyl-1,4-dioxaspiro [4.5] decane-8-one (2g, 10.86mmol) in a mixture of tetraethyl titanate (IV) (7.43g, 32.6mmol) in THF (80mL) was added. The mixture was stirred for 15min. After this, 2-methylpropane-2-sulfinamide (1.316g, 10.86mmol) was slowly added to THF (80mL) at room temperature. The mixture obtained was warmed to 65°C and stirred for 4h. The reaction process was monitored by LCMS. The reaction mixture was cooled to ambient temperature and quenched with salt water (80mL). The slurry solution obtained was filtered through a diatomaceous earth pad and the filter cake was washed with ethyl acetate (200mL). The filtrate was washed with salt water (80mL). The water layer was extracted with ethyl acetate (200mL). The combined organic fractions were washed with brine (120 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with 0-42% ethyl acetate / petroleum ether to provide N-(6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-ylidene)-2-methylpropane-2-sulfinamide (1.96 g, 6.82 mmol, 62.8% yield) as an off-white solid. 14 H 25 NO3S[M+H] + MS ESI calculated value: 288.16, found: 288.10. 1 H NMR (400MHz, CDCl3) δ4.08-3.93(m, 4H), 3.22-2.74(m, 2H), 2.62-2.44(m, 2H), 2.05-1. 76(m, 2H), 1.25(d, J=2.1Hz, 9H), 1.03(s, 1H), 1.02(s, 2H), 1.01(s, 2H), 1.00(s, 1H),.

[0705] Step 2: To a mixture of methyllithium (1.6M in Et2O, 9.79mL, 15.66mmol) in toluene (21mL) at 0°C under nitrogen was added a solution of N-(6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-ylidene)-2-methylpropane-2-sulfinamide (900mg, 3.13mmol) in toluene (6mL). The mixture was stirred for 15min. The resulting mixture was warmed to 25°C and stirred for 16h. The reaction progress was monitored by LCMS. The reaction mixture was quenched with saturated Na2SO4 aqueous solution (until gas generation stopped) and diluted with ethyl acetate (25mL). Solid Na2SO4 was added and the resulting slurry was stirred for another 10min at 0°C. The slurry was then filtered and washed with ethyl acetate (50mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-56% ethyl acetate / petroleum ether to provide 2-methyl-N-(6,6,8-trimethyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfenamide (326 mg, 1.074 mmol, 34.3% yield) as a pale yellow oil. 15 H 29 NO3S[M+H] + MS ESI calculated value 304.19, found 304.15. 1 H NMR (300MHz, CDCl3) δ4.03-3.88 (s, 4H), 3.41 (s, 1H), 2.10-1.87 (m, 2H), 1.85-1. 63(m, 3H), 1.51-1.40(m, 1H), 1.35(s, 3H), 1.23(s, 9H), 1.14(s, 3H), 0.98(s, 3H).

[0706] Step 3: To a mixture of 2-methyl-N-(6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-yl)propane-2-sulfinamide (3g, 9.89mmol) in MeOH (30mL) and 1,4-dioxane (30mL) was added water (12mL) and HCl (4M in dioxane, 60mL, 240mmol) at room temperature. The resulting mixture was warmed to 55°C and stirred for 16h. The reaction progress was monitored by LCMS. The reaction mixture was cooled to ambient temperature and the pH value of the solution was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was concentrated under reduced pressure to provide 4-amino-2,2,4-trimethylcyclohexane-1-one (4.6g, 9.78mmol, 99% yield) (crude) as a light yellow solid. 17 NO[M+H] +MS ESI calculated value 156.13, found 156.05.

[0707] Step 4: To a mixture of 4-amino-2,2,4-trimethylcyclohexane-1-one (5.37 g, 11.42 mmol) in MeOH (50 mL) was added sodium bicarbonate (2.88 g, 34.2 mmol) and Boc2O (3.98 mL, 17.12 mmol) at room temperature. The resulting mixture was stirred at 25 ° C for 16 h. The reaction progress was monitored by LCMS. The reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (200 mLx2). The combined organic fractions were washed with brine (120 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-15% ethyl acetate / petroleum ether to provide tert-butyl (1,3,3-trimethyl-4-oxocyclohexyl)carbamate (1.54 g, 6.03 mmol, 52.8% yield) as an off-white solid. 14 H 25 NO3[M+H-C4H8] + MS ESI calculated value: 200.13, found: 200.15. 1 HNMR (400MHz, CDCl3) δ4.56 (s, 1H), 2.82-2.66 (m, 1H), 2.57-2.45 (m, 1H), 2.36-2.17 (m, 2H), 1 .89-1.73 (m, 1H), 1.58 (d, J=14.7Hz, 1H), 1.46 (s, 9H), 1.38 (s, 3H), 1.27 (s, 3H), 1.06 (s, 3H).

[0708] Step 5: To a mixture of (1,3,3-trimethyl-4-oxocyclohexyl) tert-butyl carbamate (2.2g, 8.62mmol) in toluene (66mL) was added ethyl formate (6.38g, 86mmol) and sodium methoxide (30% in MeOH, 15.51g, 86mmol) at room temperature under nitrogen. The resulting mixture was stirred at 25°C for 1h. The reaction progress was monitored by LCMS. The reaction mixture was quenched with saturated NH4Cl aqueous solution (100mL) and extracted with DCM (150mL×2). The combined organic fractions were washed with brine (120mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide tert-butyl (5-(hydroxymethylene)-1,3,3-trimethyl-4-oxocyclohexyl) carbamate (2.441g, 8.62mmol, 100% yield) (crude product) as an off-white solid. 15 H 25NO4[M+H-C4H8] + MS ESI calculated value 228.12, found 228.00.

[0709] Step 6: To a mixture of tert-butyl (5-(hydroxymethylene)-1,3,3-trimethyl-4-oxocyclohexyl)carbamate (2.441g, 8.61mmol) in EtOH (120mL) was added a solution of hydroxylamine hydrochloride (5.99g, 86mmol) in water (12mL) at room temperature. The resulting mixture was stirred at 80°C for 1h. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (120mL) and extracted with DCM (120mL×2). The combined organic fractions were washed with brine (100mL), dried over anhydrous sodium sulfate and filtered. The filtrate was dissolved in THF (17mL), and Boc2O (5.00mL, 21.54mmol) was subsequently added at room temperature. The resulting mixture was stirred at room temperature for 1h. The reaction progress was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-19% ethyl acetate / petroleum ether to provide tert-butyl (5,7,7-trimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-5-yl)carbamate (1.84 g, 6.56 mmol, 76% yield) as an off-white solid. 15 H 24 N2O3[M+H] + MS ESI calculated value: 281.19, found: 281.25. 1 H NMR (300MHz, CDCl3) δ 8.05 (s, 1H), 4.37 (s, 1H), 2.69-2.52 (m, 3H), 1.62 (d, J = 14.2Hz, 1H), 1.51 (s, 3H), 1.42 (s, 9H), 1.38 (s, 3H), 1.35 (s, 3H).

[0710] Step 7:To a mixture of (5,7,7-trimethyl-4,5,6,7-tetrahydrobenzo [d] isoxazol-5-yl) tert-butyl carbamate (0.9 g, 3.21 mmol) in Et o (60 mL) was added sodium methoxide (30% in MeOH, 17.34 g, 96 mmol) at 0 ° C under nitrogen. The resulting mixture was stirred for 3 h at 25 ° C. The reaction progress was monitored by LCMS. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic fractions were washed with brine (25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-18% ethyl acetate in petroleum ether to provide tert-butyl (5-cyano-1,3,3-trimethyl-4-oxocyclohexyl)carbamate (833 mg, 2.97 mmol, 93% yield) as an off-white solid. 15 H 24 N2O3[M+H] + MS ESI calculated value: 281.19, found: 281.10. 1 H NMR (300MHz, CDCl3) δ4.47 (s, 1H), 4.12 (dd, J=13.8, 4.8Hz, 1H), 3.11-2.90 (m, 1H), 2.58-2.26 (m, 1 H), 2.16-1.96 (m, 1H), 1.66 (d, J=15.0Hz, 1H), 1.48 (s, 9H), 1.39 (s, 3H), 1.36 (s, 3H), 1.15 (s, 3H).

[0711] Step 8: To a mixture of pyridine (0.854mL, 10.56mmol) in DCM (15mL) was added a solution of phenylselenyl chloride (2.022g, 10.56mmol) in DCM (15mL) at 0°C, and the mixture was stirred for 15min. A solution of tert-butyl (5-cyano-1,3,3-trimethyl-4-oxocyclohexyl)carbamate (1.48g, 5.28mmol) in DCM (15mL) was added to the reaction mixture at 0°C. The resulting mixture was warmed to 25°C and stirred for 16h. The reaction progress was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-24% ethyl acetate / petroleum ether to provide tert-butyl (3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-ene-1-yl)carbamate (1.42g, 5.10mmol, 97% yield) as a colorless oil. 15 H 22 N2O3[M+H-C4H8] +MS ESI calculated value 223.11, found 223.05. 1 H NMR (300MHz, CDCl3) δ7.67 (s, 1H), 4.72 (s, 1H), 2.44 (d, J=14.4Hz, 1H), 1.91 (d, J=14.4, 1H), 1.56 (s, 3H), 1.45 (s, 9H), 1.28 (s, 3H), 1.27 (s, 3H).

[0712] Step 9: To a mixture of tert-butyl (3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-ene-1-yl)carbamate (1.6 g, 5.75 mmol) in DCM (16 mL) was added HCl (4 M in dioxane, 16 mL, 64.0 mmol) at 0 ° C. The resulting mixture was stirred for 1 h at 25 ° C. The reaction progress was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was provided as 3-amino-3,5,5-trimethyl-6-oxocyclohex-1-ene-1-carbonitrile hydrochloride (1.2 g, 5.59 mmol, 97% yield) (crude product) as an off-white solid. 10 H 15 ClN2O[M+H+H2O] + MS ESI calculated value 197.13, found 197.05.

[0713] Plan 47:

[0714]

[0715] Intermediate 63: N-((3-Cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)-N-methylbenzene Formamide

[0716] Step 1:To a solution of 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-one (3 g, 16.28 mmol) in tetrahydrofuran (150 mL) was added 2-methylpropane-2-olate potassium (2.193 g, 19.54 mmol) at 0 ° C, and the mixture was stirred at 30 ° C for 20 min. Then 1-((isocyanatomethyl)sulfonyl)-4-methylbenzene (3.81 g, 19.54 mmol) was added to the reaction at the same temperature. The resulting mixture was stirred for another 4 h. The reaction mixture was quenched with saturated NH4Cl (150 mL) and extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-50% ethyl acetate / petroleum ether to yield 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (2 g, 9.22 mmol, 56.6% yield) as a yellow oil. 11 H 17 NO2[M+H] + MS ESI calculated value 196.13, found 196.20. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.07-3.80 (m, 4H), 2.73-2.53 (m, 1H), 2.08-1.96 (m, 1H), 1.96-1.80 (m, 2H), 1.70-1.62 (m, 3H), 1.03 (s, 3H), 0.95 (s, 3H).

[0717] Step 2: To a solution of 6,6-dimethyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (6 g, 30.7 mmol) in tetrahydrofuran (60 mL) was added bis(trimethylsilyl)amide lithium (1.3 M in THF, 27.2 mL, 35.3 mmol) at 0 ° C, and the mixture was stirred for 1 h. Then iodomethane (4.80 g, 33.8 mmol) was added to the mixture, and the mixture was stirred at the same temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-30% ethyl acetate / petroleum ether to yield 6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (5.5 g, 23.65 mmol, 77% yield) as a yellow oil. 12 H 19 NO2[M+H] +MS ESI calculated value 210.14, found 210.15. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.00-3.89 (m, 4H), 2.08-1.97 (m, 2H), 1.77-1.53 ​​(m, 4H), 1.42-1.29 (m, 6H), 0.96-0.85 (m, 3H).

[0718] Step 3: To a solution of 6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1 g, 4.78 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (2.4 M in THF, 3.98 mL, 9.56 mmol) at 25 ° C, and the mixture was stirred at 70 ° C for 3 h. The reaction mixture was cooled to 0 ° C, diluted with diethyl ether (10 mL), and quenched by adding water (0.3 mL), 15% NaOH aqueous solution (0.3 mL) and water (0.9 mL). The mixture was then filtered. The solid was washed with THF (20 mL × 3). The filtrate was concentrated under reduced pressure to produce (6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methylamine (1 g, 4.22 mmol, 88% yield) as a colorless oil. 12 H 23 NO2[M+H] + MS ESI calculated value 214.17, found 214.25. 1 HNMR (300MHz, chloroform-d) δ4.04-3.84 (m, 4H), 2.52 (d, J=12.9Hz, 1H), 2.43 (d, J =13.0Hz, 1H), 1.75 (ddd, J = 13.6, 10.5, 4.3Hz, 1H), 1.65-1.50 (m, 1H), 1.5 5-1.44 (m, 1H), 1.44 (d, J = 3.8Hz, 1H), 1.36 (dddd, J = 13.0, 8.0, 5.2, 3.0Hz , 1H), 1.24 (dd, J=13.9, 1.8Hz, 1H), 1.07 (s, 3H), 0.98 (s, 3H), 0.94 (s, 3H).

[0719] Step 4:To a solution of (6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methanamine (5.7 g, 26.7 mmol) in tetrahydrofuran (57 mL) was added di-tert-butyl dicarbonate (5.83 g, 26.7 mmol) at 30 ° C, and the mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 0-50% ethyl acetate / petroleum ether to produce tert-butyl ((6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methyl)carbamate (7 g, 20.10 mmol, 75% yield) as a yellow oil. 17 H 31 NO4[M+H] + MS ESI calculated value 314.23, found value 314.30. 1 H NMR (300MHz, chloroform-d) δ3.96-3.90 (m, 4H), 3.05 (dd, J=13.5, 6.6Hz, 1H), 2.92 (dd, J=13.5, 6.0Hz, 1H), 1 .79-1.32 (m, 5H), 1.45 (s, 9H), 1.26 (dd, J=13.9, 1.6Hz, 1H), 1.05 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).

[0720] Step 5: To a solution of tert-butyl ((6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methyl)carbamate (7 g, 22.33 mmol) in tetrahydrofuran (70 mL) was added lithium aluminum hydride (2.4 M in THF, 9.31 mL, 22.33 mmol) at 25 ° C, and the mixture was stirred at 70 ° C for 1 h. The mixture was then cooled to 0 ° C, diluted with diethyl ether (70 mL), and quenched by adding water (0.8 mL), 15% NaOH aqueous solution (0.8 mL) and water (2.4 mL). The mixture was then filtered. The filtrate was washed with THF (70 mL×3). The filtrate was concentrated under reduced pressure to produce N-methyl-1-(6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methanamine (5 g, 19.79 mmol, 89% yield) as a yellow oil. C 13 H 25 NO2[M+H] + The MSESI calculated value is 228.19 and the measured value is 228.30. 1H NMR (300MHz, chloroform-d) δ4.07-3.85 (m, 4H), 2.44 (s, 3H), 2.41 (d, J=11.4Hz, 1H), 2.33 (d, J=11.4Hz, 1H), 1.76 (ddd, J=13.8, 10.7, 4.2Hz, 1H), 1.60 (dq, J=7.4, 3.9Hz, 1H), 1.53 (dd, J=13.8, 3.8Hz, 2H), 1.48-1.35 (m, 1H), 1.31 (dd, J=13.9, 1.7Hz, 1H), 1.07 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H).

[0721] Step 6: To a solution of N-methyl-1-(6,6,8-trimethyl-1,4-dioxaspiro[4.5]decane-8-yl)methanamine (5 g, 21.99 mmol) in tetrahydrofuran (50 mL) was added hydrogen chloride (2M in water, 50.00 mL, 100 mmol) at 25 ° C, and the mixture was stirred for 2 h. The reaction was neutralized with saturated aqueous sodium carbonate. The mixture was concentrated under reduced pressure to produce 2,2,4-trimethyl-4-((methylamino)methyl)cyclohexane-1-one hydrochloride (4 g, 18.2 mmol, 83%) as an off-white solid, which was used in the next step without further purification. 11 H 21 NO[M+H] + MS ESI calculated value 184.16, found 184.30. 1 HNMR (300 MHz, methanol-d4) δ 3.09 (d, J = 12.3 Hz, 1H), 2.89 (d, J = 12.3 Hz, 1H), 2.72 (s, 3H), 2.51-2.26 (m, 2H), 1.92-1.73 (m, 2H), 1.77-1.57 (m, 2H), 1.18 (s, 3H), 1.15 (s, 3H), 1.14 (s, 3H).

[0722] Step 7:To a solution of 2,2,4-trimethyl-4-((methylamino)methyl)cyclohexane-1-one hydrochloride (4 g, 18.20 mmol) in MeOH (40 ml) was added sodium carbonate (5.79 g, 54.6 mmol) and di-tert-butyl dicarbonate (5.96 g, 27.3 mmol) at 0°C, and the mixture was stirred at 30°C for 1 h. The mixture was extracted with ethyl acetate (100 mL×3), washed with brine (50 mL×3), dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 0-30% ethyl acetate / petroleum ether to produce tert-butyl methyl ((1,3,3-trimethyl-4-oxocyclohexyl)methyl)carbamate (5.2 g, 16.51 mmol, 91% yield) as a yellow oil. 16 H 29 NO3[M+H] + MS ESI calculated value 284.21, found 284.30. 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.44-3.15 (m, 1H), 3.04 (d, J = 14.6 Hz, 1H), 2.94 (s, 3H), 2.65-2.48 (m, 1H), 2.50-2.32 (m, 1H), 1.92-1.76 (m, 1H), 1.74-1.62 (m, 2H), 1.56 (dd, J = 14.3, 2.3 Hz, 1H), 1.47 (s, 9H), 1.20 (s, 3H), 1.17 (s, 3H), 1.12 (s, 3H).

[0723] Step 8:To a solution of tert-butyl methyl ((1,3,3-trimethyl-4-oxocyclohexyl)methyl)carbamate (300 mg, 1.059 mmol) in tetrahydrofuran (3 mL) was added dropwise bis(trimethylsilyl)amide lithium (1.3 M in THF, 1.791 mL, 2.329 mmol) at -70 ° C under N2 atmosphere. The resulting mixture was stirred at -70 ° C for 1 h. A solution of 4-methylbenzenesulfonyl cyanide (288 mg, 1.588 mmol) in tetrahydrofuran (1 mL) was then added. After stirring at -70 ° C for 30 min, the mixture was warmed to 25 ° C and stirred for 2 h. The mixture was then quenched with saturated NH4Cl aqueous solution (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0% to 30% ethyl acetate / petroleum ether to yield tert-butyl ((5-cyano-1,3,3-trimethyl-4-oxocyclohexyl)methyl)(methyl)carbamate (300 mg, 0.875 mmol, 83% yield) as a yellow solid. 17 H 28 N2O3[M+H] + MS ESI calculated value 309.21, found 309.25. 1 H NMR (300MHz, chloroform-d) δ4.76-4.63 (m, 0.25H), 4.42-4.29 (m, 0.25H), 3.99-3.85 (m, 0.5H), 3.23-3.04 (m, 1H), 3.04-2.88 (m, 3 H), 2.63-2.50(m, 0.5H), 2.35-2.21(m, 0.5H), 2.23-2.08(m, 1H), 1.97-1.56(m, 3H), 1.56-1.41(m, 9H), 1.41-0.94(m, 9H).

[0724] Step 9:To a solution of phenylselenyl chloride (1118 mg, 5.84 mmol) in DCM (10 mL) was added dropwise a solution of pyridine (462 mg, 5.84 mmol) in DCM (10 mL) at 0 ° C. The mixture was stirred at 0 ° C for 20 min and then treated dropwise with a solution of ((5-cyano-1,3,3-trimethyl-4-oxocyclohexyl)methyl)(methyl)carbamic acid tert-butyl ester (900 mg, 2.92 mmol) in DCM (2 mL). The resulting mixture was stirred at 30 ° C for 2 h. Hydrogen peroxide (30%, 662 mg, 5.84 mmol) was then added dropwise at 0 ° C, and the mixture was vigorously stirred at 0 ° C for 1 h. The reaction mixture was quenched with saturated Na2S2O3 aqueous solution (20 mL), extracted with DCM (50 mL × 3), washed with brine (10 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with 0% to 35% ethyl acetate / petroleum ether to yield tert-butyl ((3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)(methyl)carbamate (800 mg, 2.350 mmol, 81% yield) as a yellow solid. 17 H 26 N2O3[M+H] + MS ESI calculated value 307.19, found value 307.20. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.46-7.43 (m, 1H), 3.65-3.46 (m, 1H), 3.23-3.08 (m, 1H), 3.00-2.90 (m, 3H), 1.95-1.91 (m, 1H), 1.75-1.70 (m, 1H), 1.49 (s, 9H), 1.32 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H).

[0725] Step 10: To a solution of tert-butyl ((3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)(methyl)carbamate (800 mg, 2.61 mmol) in DCM (8 mL) was added hydrogen chloride (4M in 1,4-dioxane, 8 mL, 32.0 mmol) at 0° C., and the mixture was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure to give 3,5,5-trimethyl-3-((methylamino)methyl)-6-oxocyclohex-1-ene-1-carbonitrile hydrochloride (650 mg, 2.410 mmol, 92% yield) as an off-white solid, which was used in the next step without further purification. 12 H 18 N2O[M+H] +MS ESI calculated value: 207.14, found: 207.15. 1 H NMR (400 MHz, methanol-d4) δ 7.60 (s, 1H), 3.18 (s, 2H), 2.77 (s, 3H), 2.12 (d, J = 14.7 Hz, 1H), 1.94 (dd, J = 14.7, 1.6 Hz, 1H), 1.44 (s, 3H), 1.28 (s, 3H), 1.23 (s, 3H).

[0726] Step 11: To a solution of 3,5,5-trimethyl-3-((methylamino)methyl)-6-oxocyclohex-1-ene-1-carbonitrile (50 mg, 0.242 mmol) in DCM (2.3 mL) was added TEA (0.068 mL, 0.485 mmol) and benzoyl chloride (40.9 mg, 0.291 mmol) at room temperature. The resulting mixture was stirred at 30°C for 3 h. Water (20 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC using petroleum ether:ethyl acetate = 1:1 as eluent to yield N-((3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)-N-methylbenzamide (63 mg, 0.203 mmol, 84% yield) as a white oil. 19 H 22 N2O2[M+H] + MS ESI calculated value 311.17, found 311.10.

[0727] Step 12: The product was isolated by preparative chiral HPLC using the following conditions: column: CHIRALPAK 1H, 2×25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: from 30% B to 30% B in 13.6 min; wavelength: 254 / 220 nm; RT1: 7.87 min; RT2: 10.55 min. The first peak containing the product (RT1: 7.87 min) was combined and concentrated under reduced pressure, then freeze-dried to produce N-((3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)-N-methylbenzamide (24.7 mg, 0.080 mmol, 27.4% yield) as a white solid. 19 H 22 N2O2[M+H] + MS ESI calculated value 311.17, found 311.10. 1H NMR (300 MHz, chloroform-d) δ 7.53-7.22 (m, 6H), 3.97 (d, J = 13.5 Hz, 1H), 3.43 (d, J = 14.1 Hz, 1H), 3.07 (s, 3H), 2.10 (d, J = 13.8 Hz, 1H), 1.86 (d, J = 14.7 Hz, 1H), 1.44 (s, 3H), 1.29 (s, 6H). The second peak containing the product (RT2: 10.55 min) was combined and concentrated under reduced pressure, then freeze-dried to produce N-((3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)-N-methylbenzamide (21.8 mg, 0.070 mmol, 24.22% yield) as a white solid. 19 H 22 N2O2[M+H] + MS ESI calculated value 311.17, found 311.10. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.61-7.14 (m, 6H), 3.97 (d, J = 13.5 Hz, 1H), 3.43 (d, J = 13.5 Hz, 1H), 3.05 (s, 3H), 2.10 (d, J = 13.8 Hz, 1H), 1.86 (d, J = 14.7 Hz, 1H), 1.41 (s, 3H), 1.27 (s, 6H).

[0728] Plan 48:

[0729]

[0730] Intermediate 64: tert-Butyl ((3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)carbamate ester

[0731] Step 1: To a solution of (6,6,8-trimethyl-1,4-dioxaspiro[4.5]decan-8-yl)methanamine (300 mg, 1.406 mmol) in tetrahydrofuran (3 mL) was added hydrogen chloride (2M in water, 3 mL, 6.00 mmol) at 25° C., and the mixture was stirred for 2 h. The reaction was concentrated under reduced pressure to produce 4-(aminomethyl)-2,2,4-trimethylcyclohexane-1-one hydrochloride (289 mg, 1.406 mmol) as a white solid, which was used directly in the next step without further purification. 10 H 19 NO[M+H] + The MSESI calculated value was 170.15 and the measured value was 170.15.

[0732] Step 2:To a solution of 4-(aminomethyl)-2,2,4-trimethylcyclohexane-1-one hydrochloride (289 mg, 1.406 mmol) in MeOH (2.5 mL) was added sodium carbonate (464 mg, 4.37 mmol) and di-tert-butyl dicarbonate (477 mg, 2.187 mmol) at 0°C, and the mixture was stirred at 25°C for 1 h. The mixture was diluted with ethyl acetate (50 mL), washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 0-30% ethyl acetate / petroleum ether to produce tert-butyl ((1,3,3-trimethyl-4-oxocyclohexyl)methyl)carbamate (280 mg, 0.935 mmol, 70.0% yield) as a yellow solid. 15 H 27 NO3[M+H] + The MSESI calculated value was 270.20, and the measured value was 270.20. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.66 (brs, 1H), 3.18 (dd, J = 13.9, 7.0 Hz, 1H), 3.00 (dd, J = 13.8, 6.4 Hz, 1H), 2.55-2.40 (m, 2H), 1.80-1.73 (m, 1H), 1.68-1.61 (m, 2H), 1.54 (d, J = 14.4 Hz, 1H), 1.46 (s, 9H), 1.18 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H).

[0733] Step 3: To a solution of tert-butyl ((1,3,3-trimethyl-4-oxocyclohexyl)methyl)carbamate (400 mg, 1.485 mmol) in toluene (4 mL) was added ethyl formate (550 mg, 7.42 mmol) and sodium methoxide (401 mg, 7.42 mmol) at 25 ° C, and the mixture was stirred for 1 h. The mixture was then quenched with saturated aqueous NH4Cl solution (10 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to produce tert-butyl ((5-(hydroxymethylene)-1,3,3-trimethyl-4-oxocyclohexyl)methyl)carbamate (442 mg, 1.485 mmol) as a brown solid, which was used directly in the next step without further purification. 16 H 27 NO4[M+H] + MS ESI calculated value: 298.19, found: 298.20.

[0734] Step 4:To a solution of tert-butyl ((5-(hydroxymethylene)-1,3,3-trimethyl-4-oxocyclohexyl)methyl)carbamate (442 mg, 1.485 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (93 mg, 1.345 mmol) at 25° C., and the mixture was stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified as follows: Column: XBridgePrep C 18 OBD column, 19×150 mm, 5 μm; mobile phase A: water, mobile phase B: MeCN; flow rate: 20 mL / min; gradient: from 0% B to 50% B, 50% B in 30 min; detector: UV 220 / 254 nm to provide tert-butyl ((5,7,7-trimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-5-yl)methyl)carbamate (140 mg, 0.476 mmol, 30.4% yield) as a white solid. 16 H 26 N2O3[M+H] + MS ESI calculated value 295.19, found 295.25. 1 H NMR (400 MHz, CHLOROFORM-d) 68.02 (s, 1H), 4.66 (brs, 1H), 3.14-3.03 (m, 2H), 2.35 (d, J = 15.3 Hz, 1H), 2.20 (d, J = 15.4 Hz, 1H), 1.68 (d, J = 14.0 Hz, 1H), 1.58 (d, J = 14.1 Hz, 1H), 1.47 (s, 9H), 1.38 (s, 3H), 1.34 (s, 3H), 1.01 (s, 3H).

[0735] Step 5: To a solution of tert-butyl ((5,7,7-trimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-5-yl)methyl)carbamate (140 mg, 0.476 mmol) in diethyl ether (2.5 mL) was added sodium methoxide (30% in MeOH, 1.285 g, 7.13 mmol) in MeOH (1 mL) at 0°C, and the mixture was stirred at 25°C for 2 h. The reaction was neutralized with acetic acid. The resulting mixture was diluted with ethyl acetate (20 mL), washed with brine (5 mL×3), dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 0% to 30% ethyl acetate / petroleum ether to produce tert-butyl ((5-cyano-1,3,3-trimethyl-4-oxocyclohexyl)methyl)carbamate (120 mg, 0.408 mmol, 86% yield) as a yellow solid. 16 H 26 N2O3[M+H] +MS ESI calculated value 295.19, found value 295.10

[0736] Step 6: To a solution of phenylselenyl chloride (156 mg, 0.815 mmol) in DCM (1 mL) was added pyridine (64.5 mg, 0.815 mmol) at 0°C. The mixture was stirred at 0°C for 20 min and then treated dropwise with a solution of tert-butyl ((5-cyano-1,3,3-trimethyl-4-oxocyclohexyl)methyl)carbamate (120 mg, 0.408 mmol) in DCM (0.5 mL). The resulting mixture was stirred at 25°C for 2 h. Hydrogen peroxide (30%, 92 mg, 0.815 mmol) was then added dropwise at 0°C, and the mixture was stirred vigorously at 0°C for 1 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 (5 mL), extracted with DCM (10 mL × 3), washed with brine (10 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with 0% to 35% ethyl acetate / petroleum ether to produce tert-butyl ((3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)carbamate (90 mg, 0.277 mmol, 68.0% yield) as a yellow solid. 16 H 24 N2O3[M+H] + MS ESI calculated value: 293.18, found: 293.20. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.37 (s, 1H), 4.72 (brs, 1H), 3.27-3.16 (m, 2H), 1.93 (d, J=14.6 Hz, 1H), 1.70 (d, J=14.6 Hz, 1H), 1.47 (s, 9H), 1.31 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H).

[0737] Step 7: To a solution of tert-butyl ((3-cyano-1,5,5-trimethyl-4-oxocyclohex-2-en-1-yl)methyl)carbamate (100 mg, 0.342 mmol) in DCM (1 mL) was added hydrogen chloride (4M in dioxane, 1 mL, 4.00 mmol) at 25° C., and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give 3-(aminomethyl)-3,5,5-trimethyl-6-oxocyclohex-1-ene-1-carbonitrile hydrochloride (78 mg, 0.341 mmol) as a brown solid, which was used directly in the next step without further purification. 11 H 16 N2O[M+H] +MS ESI calculated value 193.13, found value 193.15. 1 HNMR (400 MHz, methanol-d4) δ 7.62-7.59 (m, 1H), 3.11 (s, 2H), 2.08 (d, J = 14.3 Hz, 1H), 1.92 (dd, J = 14.7, 1.6 Hz, 1H), 1.44 (s, 3H), 1.30 (s, 3H), 1.24 (s, 3H).

[0738] Example

[0739] The following experimental procedures detail the preparation of specific examples of the present disclosure.

[0740] NOTE: Many of the claimed compounds exist in solution as a mixture of rotamers at room temperature, which makes it possible to 1 Analysis by H-NMR spectroscopy is complicated. In these cases, the peak shifts are listed as a multiplet range including signals from both rotamers, rather than describing a single rotamer peak.

[0741] Note: Racemic compounds purified by reverse-phase or normal-phase chromatography were further purified by chiral SFC or chiral HPLC. Where indicated, enantiomer 1 represents the first-eluting peak, and enantiomer 2 represents the second-eluting peak. In cases where more than one chiral center is present, the compounds are reported as the active isomer in the order of elution or preparation, where the absolute stereochemistry has not been determined. Otherwise, the compound is achiral or racemic.

[0742] Example 1 - Enantiomer 1: 9,9-Trimethyl-8-oxo-1-oxaspiro[4.5]dec-6-ene-7-carbonitrile

[0743] Example 2 - Enantiomer 2: 9,9-Trimethyl-8-oxo-1-oxaspiro[4.5]dec-6-ene-7-carbonitrile

[0744]

[0745] Step 1: 1-oxaspiro [4.5] decane-8-one (1g, 6.5mmol) is dissolved in tBuOH (32mL). Potassium tert-butoxide (1.82g, 16.2mmol) is slowly added under a nitrogen atmosphere, and the mixture is stirred at room temperature for 1h. Iodomethane (0.852mL, 13.6mmol) is added dropwise, and the mixture is stirred at room temperature overnight. Water (60mL) is added, and the aqueous phase is extracted with EtOAc (3x). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (0-100% Et2O / hexane) to produce 7,7-dimethyl-1-oxaspiro [4.5] decane-8-one as a liquid. MS: 183 (M+H).

[0746] Examples can be prepared using procedures similar to those described in steps 2-5, where step 1 is not required.

[0747] Step 2 : To a suspension of sodium hydride (239 mg, 5.97 mmol) in THF (8.5 mL) was added 7,7-dimethyl-1-oxaspiro [4.5] decane-8-one (946 mg, 5.19 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 20 minutes. Ethyl formate (1.26 mL, 15.6 mmol) was added, and the reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched with saturated NH4Cl (aqueous solution) and extracted with EtOAc (2x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide (Z) -9- (hydroxymethylene) -7,7-dimethyl -1-oxaspiro [4.5] decane-8-one as a liquid, which was used without further purification. MS: 211 (M+H).

[0748] Step 3To a solution of (Z)-9-(hydroxymethylene)-7,7-dimethyl-1-oxaspiro[4.5]decane-8-one (984 mg, 4.68 mmol) in 10:1 EtOH: H2O (12 mL) was added a solution of hydroxylamine hydrochloride (358 mg, 5.15 mmol) in 10:1 EtOH: H2O (12 mL). The reaction mixture was stirred at 40 ° C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was alkalized with saturated NaHCO3 (aqueous solution) and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% Et2O / hexanes) to give 7,7-dimethyl-4',5',6,7-tetrahydro-3'H,4H-spiro[benzo[d]isoxazole-5,21-furan] as a solid. MS: 208 (M+H). 1 H NMR (600MHz, chloroform-d) δ8.03 (s, 1H), 3.88 (t, J=6.9Hz, 2H), 2.63-2.54 (m, 2H), 2.05-1.99 (m, 2H), 1 .96 (d, J=13.9Hz, 1H), 1.84 (t, J=7.5Hz, 2H), 1.74 (d, J=13.9Hz, 1H), 1.45 (s, 3H), 1.36 (s, 3H).

[0749] Examples can be prepared using procedures similar to those described in steps 3-5, where steps 1-2 are not required.

[0750] Step 4 To a solution of 7,7-dimethyl-4′, 5′, 6,7-tetrahydro-3′H, 4H-spiro[benzo[d]isoxazole-5,2′-furan] (473 mg, 2.28 mmol) in MeOH (11 mL) was added sodium methoxide (30% in MeOH, 1.31 mL, 6.85 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with EtOAc, and neutralized with 1M HCl aqueous solution (1.6 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to produce 9,9-dimethyl-8-oxo-1-oxaspiro[4.5]decane-7-carbonitrile as a solid, which was used without further purification. MS: 208 (M+H).

[0751] Step 5: To a solution of 9,9-dimethyl-8-oxo-1-oxaspiro[4.5]decane-7-carbonitrile (70 mg, 0.34 mmol) in THF (675 μL) was added palladium(II) acetate (15.2 mg, 0.068 mmol) at room temperature. The mixture was stirred at room temperature overnight. Palladium(II) acetate was added until 1 complete equivalent was obtained, and the reaction was stirred at room temperature for 48 h. The mixture was concentrated under reduced pressure and then diluted with DCM (5 mL) and 1:1 water:brine (5 mL). The organic layer was collected through a phase separator and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-70% Et2O / hexanes) to yield 9,9-dimethyl-8-oxo-1-oxaspiro[4.5]dec-6-ene-7-carbonitrile. The racemic mixture was purified by chiral SFC (Lux-2 column, 20% / 80% MeOH / CO2 with 0.1% NH4OH modifier) ​​to afford two products as oils:

[0752] 9,9-Dimethyl-8-oxo-1-oxaspiro[4.5]dec-6-ene-7-carbonitrile (Example 1 - Enantiomer 1). MS: 206 (M+H). 1 H NMR (600MHz, DMSO-d6) δ7.81 (s, 1H), 3.88-3.80 (m, 2H), 2.13-2.04 (m, 4H), 1.98-1.91 (m, 2H), 1.15 (s, 3H), 1.11 (s, 3H).

[0753] 9,9-Dimethyl-8-oxo-1-oxaspiro[4.5]dec-6-ene-7-carbonitrile (Example 2 - Enantiomer 2). MS: 206 (M+H). 1 H NMR (600MHz, DMSO-d6) δ7.81 (s, 1H), 3.88-3.80 (m, 2H), 2.12-2.04 (m, 4H), 1.98-1.91 (m, 2H), 1.15 (s, 3H), 1.11 (s, 3H).

[0754] Alternative Step 5Benzene selenyl chloride (420mg, 2.2mmol) in DCM (3mL) is added to the solution of pyridine (0.18mL, 2.2mmol) in DCM (2mL) at 0 DEG C. The reaction mixture is stirred at 0 DEG C for 20 minutes, then 3,3-dimethyl-4-oxo-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-5-formonitrile (280mg, 1.1mmol) in DCM (3mL) is added. The reaction mixture is stirred at 0 DEG C for 1h, then washed with HCl aqueous solution (1M, 5mL). Separate each phase, and organic phase is treated with hydrogen peroxide (50 % by weight in H2O, 1.3mL, 22mmol) at 0 DEG C. The reaction mixture is stirred for 15 minutes, then separate each phase, and organic phase is concentrated under reduced pressure. The residue was purified by mass-triggered reverse phase HPLC (ACN / H2O with 0.1% TFA modifier) ​​to afford 5,5-dimethyl-4-oxo-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-2-ene-3-carbonitrile. The racemic mixture was purified by chiral SFC (OJ-H column, 15% / 85% MeOH / CO2 with 0.1% NH4OH modifier) ​​to afford two products as solids:

[0755] 5,5-Dimethyl-4-oxo-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-2-ene-3-carbonitrile (Example 8 - Enantiomer 1). MS: 254 (M+H). 1 H NMR (600MHz, CDCl3) δ7.42-7.33 (m, 2H), 7.30 (d, J=7.4Hz, 1H), 7.17 (d, J=2.0Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 5.21 (s, 2H), 2.29 (d, J=15.0Hz, 1H), 2.20 (dd, J=15.0, 2.0Hz, 1H), 1.43 (s, 3H), 1.23 (s, 3H)

[0756] 5,5-Dimethyl-4-oxo-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-2-ene-3-carbonitrile (Example 9 - Enantiomer 2). MS: 254 (M+H). 1 H NMR (600MHz, CDCl3) δ7.42-7.33 (m, 2H), 7.30 (d, J=7.4Hz, 1H), 7.17 (d, J=2.1Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 5.21 (s, 2H), 2.29 (d, J=15.0Hz, 1H), 2.20 (dd, J=15.0, 2.1Hz, 1H), 1.43 (s, 3H), 1.23 (s, 3H).

[0757] Table 7: The following examples were prepared using a procedure similar to that described above for Examples 1, 2, 8, and 9. For oxidation conditions, 1 = palladium(II) acetate and 2 = PhSeCl, pyridine, H2O2

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768] Example 54: 5,5-Dimethyl-4-oxo-1′H-spiro[cyclohexane-1,3′-furo[3,4-c]pyridine]-2-ene-3-carbonitrile

[0769]

[0770] Step 1: To a stirred mixture of 1′H-spiro[cyclohexane-1,31-furo[3,4-c]pyridine]-4-one (350 mg, 1.722 mmol) in toluene (7 mL) was added potassium tert-butoxide (406 mg, 3.62 mmol) and iodomethane (464 mg, 3.27 mmol) at ambient temperature. The mixture was stirred at 110° C. for 3 h. The reaction mixture was then quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by RP-Combi-Flash using the following conditions: column: 18 gel column (80 g), 20-35 μm; mobile phase A: 5 mM NH4HCO3 aqueous solution; mobile phase B: MeCN; gradient: hold at 30% for 2 min, to 35% in 20 min; flow rate: 70 mL / min; detector: UV 254 and 210 nm; RT: 15 min to give 3,3-dimethyl-1′H-spiro[cyclohexane-1,3′-furo[3,4-c]pyridin]-4-one (110 mg, 0.476 mmol, 27% yield) as a white solid. MS: m / z = 232.20 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.57-8.56 (m, 1H), 8.42 (s, 1H), 7.35-7.34 (m, 1H), 5.19 (s, 2H), 3.20-3.11 (m, 1H), 2.37-2.32 (m, 1H), 2.20-2.13 (m, 2H), 2.05 (s, 2H), 1.42 (s, 3H), 1.11 (s, 3H).

[0771] Step 2:To a stirred mixture of 3,3-dimethyl-1′H-spiro[cyclohexane-1,31-furo[3,4-c]pyridine]-4-one (88 mg, 0.380 mmol) in THF (2 mL) was added 1 M lithium bis(trimethylsilyl)amide / THF (0.761 mL, 0.761 mmol) at -78°C. The mixture was stirred at -78°C for 1 h. 4-Methylbenzenesulfonyl cyanide (103 mg, 0.571 mmol) was then added to the mixture at -78°C. The mixture was stirred at -78°C for 30 min and at ambient temperature for 1.5 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by RP-Combi-Flash using the following conditions: column: C18 gel column (40 g), 20-35 μm, 19×150 mm; mobile phase A: 5 mM aqueous NH4HCO3; mobile phase B: MeCN; gradient: hold at 25% for 3 min, to 35% in 20 min; flow rate: 40 mL / min; detector: UV 254 and 210 nm; RT: 15 min to give 3,3-dimethyl-4-oxo-1′H-spiro[cyclohexane-1,3′-furo[3,4-c]pyridine]-5-carbonitrile (86 mg, 0.336 mmol, 88% yield) as a yellow solid. MS: m / z=257.20 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.63-8.59 (m, 1H), 8.43-8.42 (m, 1H), 7.30-7.29 (m, 1H), 5.21 (s, 2H), 4.52-4.47 (m, 1H), 2.60-2.51 (m, 2H), 2.15-2.09 (m, 2H), 1.48 (s, 3H), 1.21 (s, 3H).

[0772] Step 3:To a mixture of phenylselenyl chloride (74.7 mg, 0.390 mmol) in DCM (5 mL) was added pyridine (30.9 mg, 0.390 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 20 min. 3,3-dimethyl-4-oxo-1'H-spiro[cyclohexane-1,3'-furo[3,4-c]pyridine]-5-carbonitrile (50 mg, 0.195 mmol) was then added to the mixture at 0 ° C., and the mixture was stirred at 0 ° C for 2 h. The reaction progress was monitored by LCMS and TLC. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic phases were washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (PE: EA = 1: 1) to provide a crude product as a small amount of yellow solid. The combined crude product (38 mg) was purified by achiral-SFC using the following conditions: column: TriartDiol-NP, 20x250 mm, 5 μm; mobile phase A: CO 2 , mobile phase B: isopropanol; flow rate: 60 mL / min; gradient: 25% B; detector: UV 254 nm; RT: 6.50 min. The fractions containing the product were collected and rotary evaporated in vacuo to yield 5,5-dimethyl-4-oxo-1′H-spiro[cyclohexane-1,3′-furo[3,4-c]pyridine]-2-ene-3-carbonitrile (3.4 mg, 0.013 mmol, 8.95% yield) as a light yellow solid. MS: m / z=255.20 [M+H] + .

[0773] When necessary, Step 4:1′-(3,4-Dimethylbenzyl)-5,5-dimethyl-2′,4-dioxospiro[cyclohexane-1,3′-indoline]-2-ene-3-carbonitrile (150 mg, 0.390 mmol) was dissolved in TFA (3 mL, 0.390 mmol). The reaction solution was then stirred at 90° C. for 3 h. The reaction progress was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated under vacuum and co-evaporated with toluene (3 times, 3 mL each) to remove excess TFA. The residue was purified by RP-Combi-Flash using the following conditions: Column: AQ18 gel column (80 g), 20-35 μm; Mobile phase A: 5 mM NH4HCO3 in water; Mobile phase B: MeCN (Gradient: 0% B for 5 min, 49.2% B in 31 min, 49.2% B for 1.2 min; 95% B in 1 min, 95% B for 5 min); Flow rate: 60 mL / min; Detector: UV 254 and 210 nm; RT: 31.3 min. Fractions containing product were collected and rotary evaporated in vacuo to yield 5,5-dimethyl-2′,4-dioxospiro[cyclohexane-1,3′-indoline]-2-ene-3-carbonitrile (49.2 mg, 0.185 mmol, 47.4% yield) as a white solid. MS: m / z = 265.05 [MH] - . 1 H-NMR (400 MHz, chloroform-d) δ 7.89 (s, 1H), 7.38-7.30 (m, 1H), 7.24-7.12 (m, 2H), 7.09 (s, 1H), 7.02-6.87 (m, 1H), 2.49-2.45 (m, 1H), 2.30-2.26 (m, 1H), 1.62 (s, 3H), 1.36 (s, 3H).

[0774] Table 8: The following examples were prepared using a procedure similar to that described above for Example 54.

[0775]

[0776]

[0777] Example 64, Enantiomer 1: 3′-Methoxy-5,5-dimethyl-4-oxo-5′H-spiro[cyclohexane-1,7′-furo[3,4-b]pyridine]-2-ene-3-carbonitrile

[0778] Example 65, Enantiomer 2: 3′-Methoxy-5,5-dimethyl-4-oxo-5′H-spiro[cyclohexane-1,7′-furo[3,4-b]pyridine]-2-ene-3-carbonitrile

[0779]

[0780] Step 1: Sodium hydride (60% in mineral oil, 1.83 g, 45.7 mmol) was added to a mixture of 6-bromo-5-methylpyridine-3-ol (4.3 g, 22.87 mmol) in dimethylformamide (60 mL) at 0 ° C. The mixture was stirred at 0 ° C for 1 h. Iodomethane (2.15 mL, 34.3 mmol) was then added dropwise. The resulting solution was stirred at ambient temperature for 2 h. The resulting solution was diluted with water (50 mL), and the aqueous layer was extracted with ethyl acetate (400 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: petroleum ether = 0: 1 to 1: 1. The fractions containing the desired product were combined and concentrated under reduced pressure to afford 2-bromo-5-methoxy-3-methylpyridine (2.38 g, 11.78 mmol, 52% yield) as a pale yellow solid. + MS ESI calculated values: 201.98, 203.98, found: 201.95, 203.95. 1 H NMR (300 MHz, chloroform-d): δ 7.91 (d, J = 3.0 Hz, 1H), 7.09 (d, J = 2.9 Hz, 1H), 3.84 (s, 3H), 2.37 (s, 3H).

[0781] Step 2: To a stirred solution of 2-bromo-5-methoxy-3-methylpyridine (2.38 g, 11.78 mmol) in tetrachloromethane (15 mL) was added 1-bromopyrrolidine-2,5-dione (2.20 g, 12.37 mmol) and be...

Claims

1. A compound according to formula (I): or a pharmaceutically acceptable salt thereof, in: R 1 and R 2 are each independently H or C 1-6 alkyl; or R 1 and R 2 Together with the carbon to which they are bonded, they form C 3-6 Cycloalkyl; R 3 and R 4 Together with the carbon to which they are bonded, they form -C 3-8 Cycloalkyl or a 3-8 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, and wherein the -C 3-8 The cycloalkyl group and the 3-8 membered saturated or unsaturated heterocyclic ring are optionally substituted by 1-4 substituents R 12 replace; Each R 12 Independently selected from: (1)-C 1-6 alkyl, (2) Oxo, (3)-(CH2) p C 3-6 Cycloalkyl, (4)-(CH2) p C 6-10 Aryl, (5)-(CH2) p het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-4 heteroatoms independently selected from O, S and N, (6)-(CH2) p -OR 14 , (7)-(CH2) p -NR 15 R 16 , (8)-(CH2) p -C(O)R 19 , (9)-(CH2) p -S(O) n R 19 and (10)-(CH2) p -C(O)OR 20 , wherein the C 3-6 Cycloalkyl, C 6-10 The aryl group and the 3-9 membered heterocyclic ring are each independently substituted by one or more substituents selected from halogen, -OC 1-6 Alkyl and optionally substituted by one or more halogen or one or more hydroxyl groups -C 1-6 alkyl; R 14 Is H or -C 1-6 alkyl; R 15 It is H; R 16 It is C 6-10 aryl; R 19 and R 20 Each independently is -C 1-6 Alkyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 6-12 Aryl or 5-10 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms independently selected from O, S and N, wherein said -C 1-6 Alkyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 6-12 Aryl and 5-10 membered heteroaryl are each optionally independently substituted by one or more substituents R 27 replace; R 27 Is halogen, hydroxyl, nitrile, -C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C(O)NHC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 6-10 Aryl, -OC 6-10 Aryl, -OC 1-2 Alkyl C 6-10 Aryl or 5-8 membered heteroaryl, said heteroaryl containing 1-3 heteroatoms independently selected from O, S and N, wherein said -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 6-10 Each occurrence of aryl and 5-8 membered heteroaryl is independently substituted with one or more substituents selected from halogen, nitrile, -C 1-6 Alkyl and -OC 1-6 Alkyl, wherein the -C 1-6 Alkyl and -OC 1-6 The alkyl groups are each independently substituted with one or more halogens; m is 1; n is 2 and Each p is independently 0, 1, or 2; The premise is that compounds are not included 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2. are independently H or -C 1-6 alkyl.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 It's methyl.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the carbon to which they are bound, they form a cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, said cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups being optionally substituted by 1 to 4 substituents R 12 replace.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the carbon to which they are bound, they form azetidine, piperidine, pyrrolidine, morpholine, tetrahydrofuran or tetrahydropyran, said azetidine, piperidine, pyrrolidine, morpholine, tetrahydrofuran and tetrahydropyran being optionally substituted with 1 to 4 substituents R 12 replace.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Together with the carbon to which they are bound, they form a spirocyclic carbocyclic or heterocyclic ring selected from: wherein the asterisk indicates the point of attachment of the spirocyclic carbocyclic or heterocyclic ring to the cyanoenone, the spirocyclic carbocyclic or heterocyclic ring optionally being substituted by 1 to 4 substituents R 12 replace.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula Ia, Ib, Ic or Id in, R 12 Selected from hydroxyl, -C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-10 Aryl, -S(O)2-C 6-10 Aryl, -C 6-10 Aryl, het, -CH2-C 6-10 Aryl, -CH2-C 3-6 Cycloalkyl and -CH2-het, wherein het represents a 3-9 membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from O, S and N, wherein the C 3-6 Cycloalkyl, C 6-10 Each occurrence of aryl and 3-9 membered heterocyclic is optionally substituted independently by one or more substituents selected from halogen, C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl and -OC 1-6 alkyl.

8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the formula IIa in, X 1 Is O or CHR 12a ; X 2 It is CHR 12a , C(O) or NR 12a ; X 3 、X 4 、X 5 and X 6 Each independently is N or CR 23 , the prerequisite is that X 3 -X 6 No more than 2 of them can be N; Each R 12a is independently H, optionally substituted with hydroxy -C(O)C 1-6 Alkyl, or -C optionally substituted by hydroxy 1-6 alkyl, and Each R 23 are independently H, halogen, -C 1-6 Alkyl or -C 1-6 Halogenated alkyl.

9. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

11. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in therapy.

12. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a neurodegenerative disease in a patient, wherein the neurodegenerative disease is selected from Friedreich's ataxia, amyotrophic lateral sclerosis, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, peripheral neuropathy and hearing loss.

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