USP30 inhibitors and their use

Abstract

The present invention provides compounds, compositions thereof, and methods of use thereof for the inhibition of USP30 and the treatment of USP30-mediated disorders.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 898,820, filed September 11, 2019, and U.S. Provisional Patent Application No. 63 / 022,165, filed May 8, 2020, each of which is incorporated herein by reference in its entirety.

[0002] Technical field of inventions The present invention relates to compounds and methods useful for inhibiting ubiquitin carboxyl-terminal hydrolase 30 ("USP30"), also known as deubiquitinating enzyme 30, ubiquitin thioesterase 30, or ubiquitin-specific processing protease 30. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods for using said compositions in the treatment of various disorders. [Background technology]

[0003] Parkinson's disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer's disease (AD), affecting approximately 1 million Americans, with an estimated economic cost of $15 billion (Marras et al. Parkinson's Foundation PG: Prevalence of Parkinson's disease across North America. NPJ Parkinsons Dis 2018, 4:21. PMC6039505; Gooch et al. The burden of neurological disease in the United States: A summary report and call to action. Ann Neurol 2017, 81:479-484). This number is expected to increase further with the growing elderly population worldwide. Parkinson's disease (PD) is increasingly understood to be a systemic disease affecting many peripheral tissues as well as multiple brain regions and neuronal populations other than dopaminergic neurons (Obeso et al. Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. Mov Disord 2017, 32:1264-1310. PMC5685546.). However, existing treatments for PD primarily aim to enhance dopaminergic neurotransmission to provide symptomatic benefits. Such treatments become less effective as the disease progresses, and a significant proportion of patients develop intolerable motor complications. Furthermore, non-motor symptoms (including cognitive impairment reflecting non-dopaminergic pathology) remain a major cause of impairment. Given the precision of previous studies linking mitochondrial deficiency to PD and AD, targeting the parkin-USP30 pathway to restore mitochondrial homeostasis as a means of slowing disease progression is highly promising in the treatment of PD and AD.

[0004] Converging evidence (specifically, from human pharmacology, genetics, and histopathology, as well as animal model data) suggests that restoring mitochondrial quality control (including mitophagy (clearance of damaged mitochondria) and induction of bioenergy) may slow the progression of both PD (Park et al. Mitochondrial Dysfunction in Parkinson's Disease: New Mechanistic Insights and Therapeutic Perspectives. Curr Neurol Neurosci Rep 2018,18:21.PMC5882770.) and AD (Fang et al. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci 2019,22:401-412.). The first evidence for mitochondrial dysfunction in PD emerged from the finding that exposure to the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) induced rapid Parkinsonian symptoms and dopamine neuron death (Langston et al. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983, 219:979-980.). Genetic studies of monogenic Parkinson's disease have shown that pathogenic mutations in genes encoding proteins involved in mitochondrial quality control, such as PINK1, PRKN, FBXO7, DJ-1, VPS13C, and CHCHD2, cause autosomal recessive early-onset Parkinsonian symptoms (Canet-Aviles et al.).The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.Proc Natl Acad Sci U S A 2004,101:9103-9108.PMC428480、Funayama et al.CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease:a genome-wide linkage and sequencing study.Lancet Neurol 2015,14:274-282、Burchell et al.The Parkinson’s disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy.Nat Neurosci 2013,16:1257-1265.PMC3827746、Lesage et al.French Parkinson’s Disease Genetics S,International Parkinson’s Disease Genomics C:Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1 / Parkin-Dependent Mitophagy.Am J Hum Genet 2016,98:500-513.PMC4800038、Paisan-Ruiz et al.Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2,PLA2G6,FBXO7 and spatacsin mutations.Mov Disord 2010,25:1791-1800.PMC6005705.Importantly, genome-wide association (GWA) studies of sporadic Parkinson's Disease (PD) have shown that genes associated with mitochondrial function are risk factors for sporadic late-onset PD (Billingsley et al. International Parkinson's Disease Genomics C, Ryten M, Koks S: Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset. NPJ Parkinsons Dis 2019, 5:8. PMC6531455.). Furthermore, autopsy brain tissue from sporadic PD cases has shown reduced mitochondrial respiratory capacity (Schapira et al. Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 1990, 54:823-827.). Recent evidence from peripheral blood cells in early / prodromal Parkinson's disease patients also demonstrates mitochondrial dysfunction (Smith et al. Mitochondrial dysfunction and increased glycolysis in prodromal and early Parkinson's blood cells. Mov Disord 2018, 33:1580-1590. PMC6221131). Finally, mitochondrial complex I inhibitors (e.g., MPTP or rotenone) induce retrograde degeneration of substantia nigra dopamine neurons in animal models. This highlights the particular susceptibility of these neurons, which exhibit the most severe and prototypical degeneration in PD, to mitochondrial dysfunction.

[0005] Abnormal mitochondrial accumulation and mitophagy deficiency have been observed in other age-related diseases such as Alzheimer's disease (AD), and also in aging itself (Fang et al. 2019; Ridge and Kauwe, Mitochondria and Alzheimer's Disease: the Role of Mitochondrial Genetic Variation. Curr Genet Med Rep 2018, 6:1-10. PMC5842281). Recent research by Fang et al. has shown that mitophagy is reduced in the hippocampus of AD patients, and that increased mitophagy can alleviate cognitive impairment and prevent both Aβ plaques and tau hyperphosphorylation in induced pluripotent stem cells (iPSCs) and several animal models of AD (Fang et al., 2019). Positron emission tomography (PET) imaging from AD patients suggests a reduction in oxidative phosphorylation and the TCA cycle, and postmortem analysis suggests a reduction in PGC1α, a transcriptional regulator of mitochondrial biosynthesis and an essential component of the mitochondrial quality control cycle (Kapogiannis and Mattson, Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol 2011, 10:187-198. PMC3026092; Katsouri et al. PPARgamma-coactivator-1alpha gene transfer reduces neuronal loss and amyloid-beta generation by reducing beta-secretase in an Alzheimer's disease model. Proc Natl Acad Sci USA 2016, 113:12292-12297. PMC5087021).Postmortem transmission electron microscopy (TEM) analysis of mitochondrial structure in the hippocampus of Alzheimer's disease patients revealed abnormalities in mitochondrial morphology, altered mitophagy, and decreased Parkin levels, which worsened with disease progression (Ye et al., Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains. Hum Mol Genet 2015, 24:2938-2951. PMC4406302).

[0006] Modification of mitochondrial pathways, including increased parkin expression or USP30 depletion, has been shown to be protective in various gene and toxin-based animal models of parkinar (PD) across multiple species. 2,20-27(Bingol et al.,The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy.Nature 2014,510:370-375、Bian et al.,Overexpression of parkin ameliorates dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.PLoS One 2012,7:e39953.PMC3390003、Hou et al.,Parkin represses 6-hydroxydopamine-induced apoptosis via stabilizing scaffold protein p62 in PC12 cells.Acta Pharmacol Sin 2015,36:1300-1307.PMC4635325、Lo Bianco et al.,Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease.Proc Natl Acad Sci U S A 2004,101:17510-17515.PMC536019、Paterna et al.,DJ-1 and Parkin modulate dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron loss in mice.Mol Ther 2007,15:698-704、Vercammen et al.,Parkin protects against neurotoxicity in the 6-hydroxydopamine rat model for Parkinson’s disease.Mol Ther 2006,14:716-723、Yasuda et al.,Parkin-mediated protection of dopaminergic neurons in a chronic MPTP-minipump mouse model of Parkinson disease. J Neuropathol Exp Neurol 2011,70:686-697, Yasuda et al., Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates. Neuroscience 2007,144:743-753, Liang et al., USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death. EMBO Rep 2015,16:618-627. PMC4428036.). PINK1 / Parkin-dependent linear ubiquitination of proteins on the outer mitochondrial membrane (OMM) leads to the removal of damaged proteins and mitochondria through the fission of mitochondrial vesicles (MDVs), or the recruitment of phagophores to initiate the mitophagy process. The deubiquitinating (DUB) enzyme USP30 (unlike other DUBs such as USP8, 15, and 35, which are involved in mitochondrial quality control) is specifically located on the mitochondrial mesoplastic matrix (OMM) and acts to equilibrate this process by specifically removing ubiquitin chains from the Parkin substrate. The involvement of USP30 in mitophagy regulation has been well-established through functional genomic studies in mammalian (including human) cells and flies, and it has been further confirmed as a promising target (Bingol et al., 2014). While we do not wish to be bound by any particular theory, USP30 inhibitors are thought to promote the clearance of damaged mitochondria, restore mitochondrial homeostasis, and attenuate the pathogenic cascade associated with PD pathogenesis. [Overview of the project]

[0007] The compounds of the present invention and their pharmaceutically acceptable compositions have been found to be effective inhibitors of USP30. Such compounds have general formula I: [ka] or a pharmaceutically acceptable salt thereof, each variable element as defined and described herein.

[0008] In some embodiments, such compounds have the general formula I': [ka] or a pharmaceutically acceptable salt thereof, each variable as defined and described herein.

[0009] The compounds of the present invention and their pharmaceutically acceptable compositions are useful for treating a variety of diseases, disorders, or conditions related to USP30, which is involved in mitochondrial homeostasis. Such diseases, disorders, or conditions include those described herein.

[0010] Furthermore, the compounds provided by the present invention are useful for studying USP30 in biological and pathological phenomena, studying mitochondrial homeostasis occurring in living tissues, and for comparative in vitro or in vivo evaluation of novel USP30 inhibitors or other regulators of mitochondrial homeostasis. [Modes for carrying out the invention]

[0011] 1. General description of a specific embodiment of the present invention The compounds and compositions of the present invention are useful as inhibitors of USP30.

[0012] In a particular embodiment, the present invention relates to a compound of formula I: [ka] or to provide a pharmaceutically acceptable salt thereof, in the formula, Ring A is a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. L 1 However, covalent or C 1~3 A divalent hydrocarbon chain, where one or two methylene units of the chain are independently and arbitrarily selected from -C(CF3)H-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, -S(O)N(R)-, -S(O)2N(R)-, or -S(O)(R)=N-. Each R is independently either hydrogen or optionally substituted with C. 1~3 It is an aliphatic group, or Two R groups on the same nitrogen atom, optionally together with their intervening atoms, form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to the nitrogen atom, or R groups and R groups located on the same nitrogen atom 1 However, they can optionally combine with the intervening atoms to form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. R 1 However, is it hydrogen, or C 1~6 A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocyclic rings, 5-8 member saturated or partially unsaturated bridged bicyclic carbocyclic rings, 4-7 member saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or phenyl, or 5-6 member heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 2independently, halogen, -CF3, -CN, -C(O)NHR, -NO2, -NHR, -NHC(O)R, -NHS(O)2R, -N(R)2, or -OR, or optionally substituted C 1~6 is an aliphatic group, or two Rs on the same carbon 2 optionally combine together to form =O, L 2 is selected from the group consisting of -C(O)N(R’)-, -CH2O-, -CH2N(R’)-, and -C(OH)(H)CH2N(R’)-, R’ is hydrogen or C 1~3 is an aliphatic group, L 3 is selected from the group consisting of -C(O)N(R”)-, -OC(O)N(R”)-, and -CH2O-, R” is hydrogen or C 1~3 is an aliphatic group,[[ID=--]] R 3 is hydrogen or C 1~3 is aliphatic, or R 3 and R 4 optionally combine with the intervening atoms therebetween to form a 3- to 5-member saturated carbon ring, or R 3 and R 5 optionally combine with the intervening atoms therebetween to form a 3- to 5-member saturated carbocyclic ring, R 4 is hydrogen or C 1~3 is aliphatic, R 5 is hydrogen or C 1~3 is aliphatic,<00016--8>ring B is a 5- to 6-member heteroaryl ring having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8- to 10-member bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each R 6 independently, halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or optionally substituted C 1~6 is an aliphatic group, or Two Rs located on the same carbon 6 However, they can be chosen to come together and form =O, R 6 The group and the R' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. R 6 Base and R 3 The groups, optionally together with their intervening atoms, form a 5-8 member partially unsaturated spirocondensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R 6 The group and the R'' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. Ring C is a phenyl, a 3-8 member saturated or partially unsaturated carbocyclic ring, a 4-7 member saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 7 C is independently replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 7 However, they can be chosen to come together and form =O, The present invention provides a compound, or a pharmaceutically acceptable salt thereof, in which each of m, n, and p is independently 0, 1, 2, 3, or 4.

[0013] In a particular embodiment, the present invention relates to a compound of formula I': [ka] or to provide a pharmaceutically acceptable salt thereof, in the formula, Ring A is a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. L 1 However, covalent or C 1~3 A divalent hydrocarbon chain, where one or two methylene units of the chain are independently and arbitrarily selected from -C(CF3)H-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, -S(O)N(R)-, -S(O)2N(R)-, or -S(O)(R)=N-. Each R is independently either hydrogen or optionally substituted with C. 1~3 It is an aliphatic group, or Two R groups on the same nitrogen atom, optionally together with their intervening atoms, form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to the nitrogen atom, or R groups and R groups located on the same nitrogen atom 1 However, they can optionally combine with the intervening atoms to form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. R 1 However, is it hydrogen, or C 1~6 A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocyclic rings, 5-8 member saturated or partially unsaturated bridged bicyclic carbocyclic rings, 4-7 member saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or phenyl, or 5-6 member heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 2Independently, C is replaced by halogen, -CF3, -CN, -C(O)NHR, -NO2, -NHR, -NHC(O)R, -NHS(O)2R, -N(R)2, or -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 2 They can be chosen to come together to form =O, or Two R's 2 The groups, optionally together with their intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. L 2 However, selected from the group consisting of -C(O)N(R')-, -CH2O-, -CH2N(R')-, and -C(OH)(H)CH2N(R')-, R' is hydrogen or C 1~3 It is an aliphatic group, L 3 However, selected from the group consisting of -C(O)N(R")-, -OC(O)N(R")-, and -CH2O-, R'' is hydrogen or C 1~3 It is an aliphatic group, R 3 However, hydrogen or C 1~3 It is aliphatic, or R 3 and R 4 However, they can optionally combine with the intervening atoms to form a 3-5 member saturated carbon ring, or R 3 and R 5 However, they can optionally combine with the intervening atoms to form a 3-5 member saturated carbocyclic ring. R 4 However, hydrogen or C 1~3 It is aliphatic, R 5 However, hydrogen or C 1~3 It is aliphatic, Ring B is a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 6 C is independently replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 6 However, they can be chosen to come together and form =O, R 6 The group and the R' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. R 6 Base and R 3 The groups, optionally together with their intervening atoms, form a 5-8 member partially unsaturated spirocondensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R 6 The group and the R'' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. Ring C is a phenyl, a 3-8 member saturated or partially unsaturated carbocyclic ring, a 4-7 member saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 7 C is independently replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 7 They can be chosen to come together to form =O, or R 7 The group and the R'' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. Each of m, n, and p is independently 0, 1, 2, 3, or 4.

[0014] 2. Compounds and Definitions: The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are defined as those in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry are identified according to Ed. Furthermore, the general principles of organic chemistry are found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5 th This is described in Ed.,Smith, MB and March, J., John Wiley & Sons, New York: 2001 (the entire contents of which are incorporated herein by reference).

[0015] As used herein, the terms “aliphatic” or “aliphatic group” mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”) and has a single attachment site on the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to monocyclic C3-C6 hydrocarbons that are either fully saturated or contain one or more unsaturated units but are not aromatic, and have a single attachment site on the rest of the molecule. Preferred aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and their hybrids (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0016] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system having at least one bridge, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring system. As defined by IUPAC, a “bridge” is an unbranched chain of atoms, or an atom or valence bond connecting two bridgeheads (a “bridgehead” being any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen)). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include groups in which each of the groups shown below is bonded to any substitutable carbon or nitrogen atom of the rest of the molecule. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, as is the case with aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic compounds include: [ka]

[0017] The term "lower alkyl" is C 1~4 This refers to linear or branched alkyl groups. Exemplary lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0018] The term "lower haloalkyl" refers to a carbon atom substituted with one or more halogen atoms. 1~4 This refers to linear or branched alkyl groups.

[0019] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituteable nitrogen in a heterocyclic ring, e.g., N (like 3,4-dihydro-2H-pyrrolyl), NH (like pyrrolidinyl), or NR) + (Including N-substituted pyrrolidinyls))

[0020] As used herein, the term “unsaturated” means that a part has one or more unsaturated units.

[0021] When used herein, "divalent C 1~8 (or C 1~6 The term "saturated or unsaturated, linear or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains that are linear or branched as defined herein.

[0022] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents. Preferred substituents include substituted aliphatic groups, which will be described later.

[0023] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Preferred substituents include substituted aliphatic groups, which will be discussed later.

[0024] As used herein, the term "cyclopropyrenyl" refers to a divalent cyclopropyl group having the following structure. [ka]

[0025] The term "halogen" refers to F, Cl, Br, or I.

[0026] The term "aryl" used alone, or as part of a larger term such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, with at least one ring in the system being aromatic, and each ring in the system containing 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system (including, but not limited to, phenyl, biphenyl, naphthyl, anthrathyl, etc.) which may have one or more substituents. The scope of the term "aryl" as used herein also includes groups in which an aromatic ring is fused with one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenanslidinyl, or tetrahydronaphthyl, etc.).

[0027] The terms “heteroaryl” and “heteroara-” are used alone or as part of a larger phrase (e.g., “heteroaralkyl” or “heteroaralkoxy”) to refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, sharing 6, 10, or 14 π electrons within the cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes oxidized forms of nitrogen or sulfur, and any quaternized forms of basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" include groups formed by the condensation of one or more aryl, alicyclic, and heterocyclyl groups with a heteroaromatic ring, where the radical or attachment site is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which include a ring that is optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are optionally substituted independently.

[0028] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are interchangeable and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably 1 to 4, heteroatoms as defined above, in addition to the carbon atoms. When used with respect to the ring atoms of a heterocyclic ring, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + It may also be NR (as in N-substituted pyrrolidinyl).

[0029] The heterocyclic ring may be attached with any heteroatom or carbon atom of its pendant group, resulting in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which a heterocyclic ring is fused with one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanslidinyl, or tetrahydroquinolinyl). The heterocyclyl group may be monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, where the alkyl moiety and the heterocyclyl moiety are independently and optionally substituted.

[0030] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double bond or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0031] As described herein, the compounds of the invention may contain "optionally substituted" moieties. Generally, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens on the indicated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have suitable substituents at each of its substitutable positions, and when two or more positions in any given structure can be substituted with two or more substituents selected from the designated group, the substituents may be the same or different at any position. The combinations of substituents contemplated by the present invention are preferably combinations that are stable or that result in the formation of a chemically realizable compound. As used herein, the term "stable" refers to a compound that is substantially unmodified when subjected to conditions that allow for its generation, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0032] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently, halogen, -(CH2) 0~4 R ○ 、-(CH2) 0~4 OR ○ 、-O(CH2) 0~4 R ○ 、-O-(CH2) 0~4 C(O)OR ○ 、-(CH2) 0~4 CH(OR ○ )2、-(CH2) 0~4 SR ○ 、-(CH2) 0~4 Ph(R ○which may be replaced by), -(CH2) 0~4 O(CH2) 0~1 Ph(R ○ which may be replaced by), -CH=CHPh(R ○ which may be replaced by), -(CH2) 0~4 O(CH2) 0~1 -pyridyl(R ○ which may be replaced by), -NO2, -CN, -N3, -(CH2) 0~4 N(R ○ )2, -(CH2) 0~4 N(R ○ )C(O)R ○ , -N(R ○ )C(S)R ○ , -(CH2) 0~4 N(R ○ )C(O)NR ○ , -N(R ○ )C(S)NR ○ , -(CH2) 0~4 N(R ○ )C(O)OR ○ , -N(R ○ )N(R ○ )C(O)R ○ , -N(R ○ )N(R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​2, -C(S)NR ○ 2, -C(S)SR ○ ,-(CH2) 0~4 OC(O)NR ○ 2, -C(O)N(OR ○ )R ○ ,-C(O)C(O)R ○ -C(O)CH2C(O)R ○ -C(NOR ○ )R ○ ,-(CH2) 0~4 SSR ○ ,-(CH2) 0~4 S(O)2R ○ ,-(CH2) 0~4 S(O)2OR ○ ,-(CH2) 0~4 OS(O)2R ○ -S(O)2NR ○ 2, -(CH2) 0~4 S(O)R ○ , -N(R ○ )S(O)2NR ○ 2, -N(R ○ )S(O)2R ○ , -N(OR ○ )R ○ -C(NH)NR ○ 2, -P(O)2R ○ ,-P(O)R ○ 2. -OP(O)R ○ 2, -OP(O)(OR ○ )2, -SiR ○ 3, -(C 1~4 Linear or branched alkylenes) ON(R ○ )2, or -(C 1~4 Linear or branched alkylene)C(O)ON(R ○ )2, and in the formula, each R ○ These may be substituted as defined below, independently of hydrogen and C. 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5-6 member heteroaryl ring), or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent R○ The presence of these atoms, together with the intervening atom(s), forms a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0033] R ○ (or two independent R ○ Suitable monovalent substituents on the ring formed by using them together with the intervening atoms are, independently, halogens, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2, -O(HaroR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● ,-(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● ,-(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● And in the formula, each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur. ○ Examples of divalent substituents on the saturated carbon atom include =O and =S.

[0034] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include: =O, =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S-(where each independent R * The presence of hydrogen may be substituted as defined below. 1~6 (Selected from aliphatic, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur). Preferred divalent substituents bonded to a substituted carbon near the "optionally substituted" group include -O(CR * 2) 2~3 O- is mentioned, and in the formula, each independent R * The presence of hydrogen may be substituted as defined below. 1~6 Selected from aliphatic, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] R * Suitable substituents on the aliphatic group include halogens and -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR● , -NR ● Examples include 2 or -NO2, and each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0036] A suitable substituent on the substituted nitrogen of the "optionally substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † These are listed, and in the formula, each R † C may be substituted independently with hydrogen, as defined below. 1~6 An aliphatic, unsubstituted-OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent R † The presence of these atoms, together with the intervening atom(s), forms a monocyclic or bicyclic ring of an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl group having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ●), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● It is 2 or -NO2, and each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0038] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within reasonable medical judgment, is suitable for use in contact with human or lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (as incorporated herein by reference). pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed by using inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates.

[0039] Suitable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+ (C 1~4 Examples include alkyl)4 salts. Typical alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions (e.g., halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acid, and aryl sulfonic acid ions) where appropriate.

[0040] Unless otherwise specified, the structures shown herein are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or stereostructural) forms) in the structure, such as R and S configurations at each chiral center, Z and E double bond isomers, and Z and E stereostructural isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomers, diastereomers, and geometric (or stereostructural) mixtures, are within the scope of the present invention. Unless otherwise specified, all tautomer forms of the compounds of the present invention are within the scope of the present invention. In addition, unless otherwise specified, the structures shown herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, substitution of hydrogen with deuterium or tritium, or carbon 13 C or 14 Compounds having the structure of the present invention, including substitution with C-enriched carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. In certain embodiments, the warhead portion of the provided compound is R 1 It contains one or more deuterium atoms. In certain embodiments, ring B of the provided compound may be substituted with one or more deuterium atoms.

[0041] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits USP30 with measurable affinity. In certain embodiments, the IC of the inhibitor50 The and / or binding constants are less than approximately 50 μM, less than approximately 1 μM, less than approximately 500 nM, less than approximately 100 nM, less than approximately 10 nM, or less than approximately 1 nM.

[0042] The compounds of the present invention may be tethered to detectable moieties. It will be understood that such compounds are useful as contrast agents. Those skilled in the art will recognize that detectable moieties can be attached to the provided compounds via suitable substituents. As used herein, the term “suitable substituent” refers to moieties that can be covalently bonded to the detectable moieties. Such moieties are well known to those skilled in the art and include, to name just a few examples, groups comprising carboxylate moieties, amino moieties, thiol moieties, or hydroxyl moieties. It will be understood that such moieties can be attached to the provided compounds directly or via tether groups (e.g., divalent saturated or unsaturated hydrocarbon chains). In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties may be attached by 1,3-addition cycloaddition of azides and alkynes, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described in Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0043] As used herein, the term “detectable portion” is used interchangeably with the term “label” and relates to any detectable portion, e.g., primary and secondary labels. Primary labels include, for example, radioactive isotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), the mass tag, and the fluorescent label are signal-generating reporter groups that can be detected without further modification. The detectable portion also includes the luminescent group and the phosphorescent group.

[0044] As used herein, the term “secondary label” refers to a moiety (e.g., biotin and various protein antigens) that requires the presence of a second intermediate to produce a detectable signal. In the case of biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. In the case of antigen labeling, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups function as secondary labels by transferring energy to another group via non-radioactive fluorescence resonance energy transfer (FRET), where the second group generates a detection signal.

[0045] As used herein, the terms “fluorescent label,” “fluorescent dye,” and “fluorophore” refer to a part that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels, though not limited to them, include: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), Carboxyrhodamine 6G, Carboxy-X-Rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dye (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-Dimethoxyfluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IRDye (IRD40, IRD700, IRD800), JOE, Lissamine Rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-Rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0046] As used herein, the term “mass tag” refers to any portion that can be uniquely detected by mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretic emission tags, such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isopicotic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of these mass tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of various lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of different lengths and monomer compositions. Furthermore, a wide variety of organic molecules within a suitable mass range (100–2000 daltons), whether neutral or charged (both biomolecules and synthetic compounds), can also be used as mass tags.

[0047] As used herein, the terms “measurable affinity” and “measurable inhibition” mean the measurable change in USP30 activity between a sample containing the compound or composition of the present invention and USP30 and an equivalent sample containing USP30 but without the compound or composition.

[0048] 3. Description of exemplary embodiments: As described above, in a particular embodiment, the present invention relates to a compound of formula I: [ka] or to provide a pharmaceutically acceptable salt thereof, in the formula, Ring A is a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. L 1 However, covalent or C 1~3 A divalent hydrocarbon chain, where one or two methylene units of the chain are independently and arbitrarily selected from -C(CF3)H-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, -S(O)N(R)-, -S(O)2N(R)-, or -S(O)(R)=N-. Each R is independently either hydrogen or optionally substituted with C. 1~3 It is an aliphatic group, or Two R groups on the same nitrogen atom, optionally together with their intervening atoms, form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to the nitrogen atom, or R groups and R groups located on the same nitrogen atom 1 However, they can optionally combine with the intervening atoms to form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. R 1 However, is it hydrogen, or C 1~6 A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocyclic rings, 5-8 member saturated or partially unsaturated bridged bicyclic carbocyclic rings, 4-7 member saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or phenyl, or 5-6 member heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 2Independently, C is replaced by halogen, -CF3, -CN, -C(O)NHR, -NO2, -NHR, -NHC(O)R, -NHS(O)2R, -N(R)2, or -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 2 However, they can be chosen to come together and form =O, L 2 However, selected from the group consisting of -C(O)N(R')-, -CH2O-, -CH2N(R')-, and -C(OH)(H)CH2N(R')-, R' is hydrogen or C 1~3 It is an aliphatic group, L 3 However, selected from the group consisting of -C(O)N(R")-, -OC(O)N(R")-, and -CH2O-, R'' is hydrogen or C 1~3 It is an aliphatic group, R 3 However, hydrogen or C 1~3 It is aliphatic, or R 3 and R 4 However, they can optionally combine with the intervening atoms to form a 3-5 member saturated carbon ring, or R 3 and R 5 However, they can optionally combine with the intervening atoms to form a 3-5 member saturated carbocyclic ring. R 4 However, hydrogen or C 1~3 It is aliphatic, R 5 However, hydrogen or C 1~3 It is aliphatic, Ring B is a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 6 C is independently replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 6 However, they can be chosen to come together and form =O, R 6 The group and the R' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. R 6 Base and R 3 The groups, optionally together with their intervening atoms, form a 5-8 member partially unsaturated spirocondensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R 6 The group and the R'' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. Ring C is a phenyl, a 3-8 member saturated or partially unsaturated carbocyclic ring, a 4-7 member saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 7 C is independently replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 7 However, they can be chosen to come together and form =O, Each of m, n, and p is independently 0, 1, 2, 3, or 4.

[0049] In a particular embodiment, the present invention relates to a compound of formula I': [ka] or to provide a pharmaceutically acceptable salt thereof, in the formula, Ring A is a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. L 1 However, covalent or C 1~3 A divalent hydrocarbon chain, where one or two methylene units of the chain are independently and arbitrarily selected from -C(CF3)H-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, -S(O)N(R)-, -S(O)2N(R)-, or -S(O)(R)=N-. Each R is independently either hydrogen or optionally substituted with C. 1~3 It is an aliphatic group, or Two R groups on the same nitrogen atom, optionally together with their intervening atoms, form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to the nitrogen atom, or R groups and R groups located on the same nitrogen atom 1 However, they can optionally combine with the intervening atoms to form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. R 1 However, is it hydrogen, or C 1~6 A optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocyclic rings, 5-8 member saturated or partially unsaturated bridged bicyclic carbocyclic rings, 4-7 member saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or phenyl, or 5-6 member heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 2Independently, C is replaced by halogen, -CF3, -CN, -C(O)NHR, -NO2, -NHR, -NHC(O)R, -NHS(O)2R, -N(R)2, or -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 2 They can be chosen to come together to form =O, or Two R's 2 The groups, optionally together with their intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. L 2 However, selected from the group consisting of -C(O)N(R')-, -CH2O-, -CH2N(R')-, and -C(OH)(H)CH2N(R')-, R' is hydrogen or C 1~3 It is an aliphatic group, L 3 However, selected from the group consisting of -C(O)N(R")-, -OC(O)N(R")-, and -CH2O-, R'' is hydrogen or C 1~3 It is an aliphatic group, R 3 However, hydrogen or C 1~3 It is aliphatic, or R 3 and R 4 However, they can optionally combine with the intervening atoms to form a 3-5 member saturated carbon ring, or R 3 and R 5 However, they can optionally combine with the intervening atoms to form a 3-5 member saturated carbocyclic ring. R 4 However, hydrogen or C 1~3 It is aliphatic, R 5 However, hydrogen or C 1~3 It is aliphatic, Ring B is a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 6 C is independently replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 6 However, they can be chosen to come together and form =O, R 6 The group and the R' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. R 6 Base and R 3 The groups, optionally together with their intervening atoms, form a 5-8 member partially unsaturated spirocondensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R 6 The group and the R'' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. Ring C is a phenyl, a 3-8 member saturated or partially unsaturated carbocyclic ring, a 4-7 member saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R 7 C is independently replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group, or Two Rs located on the same carbon 7 They can be chosen to come together to form =O, or R 7 The group and the R'' group, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. The present invention provides a compound, or a pharmaceutically acceptable salt thereof, in which each of m, n, and p is independently 0, 1, 2, 3, or 4.

[0050] As generally defined above, ring A is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] In some embodiments, ring A is phenyl. In some embodiments, ring A is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is an 8-10 membered bicyclic aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] That is the case.

[0053] In some embodiments, ring A is selected from those shown in Table 1 below.

[0054] As generally defined above, L 1 is a covalent bond or C 1~3 A divalent hydrocarbon chain, where one or two methylene units of the chain are arbitrarily and independently selected from -C(CF3)H-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, -S(O)N(R)-, -S(O)2N(R)-, or -S(O)(R)=N-.

[0055] In some embodiments, L 1 L is a covalent bond. In some embodiments, L 1 is a covalent bond or C 1~3 A divalent hydrocarbon chain, where one or two methylene units of the chain are arbitrarily and independently selected from -C(CF3)H-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O)2-, -S(O)N(R)-, -S(O)2N(R)-, or -S(O)(R)=N-.

[0056] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] That is the case.

[0057] In some embodiments, L 1 If R is -S(O)2N(R)-,1 This is any compound other than hydrogen, isopropyl, t-butyl, 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 1-trifluoromethylcyclopropyl, or 3-methyl-3-oxetanyl.

[0058] In some embodiments, L 1 The following selection is made from the options shown in Table 1.

[0059] As generally defined above, each R is independently a hydrogen or optionally substituted C 1~3 Aliphatic groups, where two R groups on the same nitrogen atom optionally combine with their intervening atoms to form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or where two R groups on the same nitrogen atom 1 These atoms, optionally together with the intervening atoms, form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen.

[0060] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted with C 1~3 It is an aliphatic group. In some embodiments, two R groups on the same nitrogen atom, together with their intervening atoms, form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. In some embodiments, two R groups on the same nitrogen atom and R 1 These intervening atoms, together with the nitrogen atom, form a 4-7 member saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen.

[0061] In some embodiments, R is selected from those shown in Table 1 below.

[0062] As generally defined above, R 1 is either hydrogen or C 1~6 The group is optionally substituted from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocyclic rings, 5-8 member saturated or partially unsaturated bridged bicyclic carbocyclic rings, 4-7 member saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or phenyl, or 5-6 member heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 C 1~6 The group is optionally substituted from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocyclic rings, 5-8 member saturated or partially unsaturated bridged bicyclic carbocyclic rings, 4-7 member saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or phenyl, or 5-6 member heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0064] In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] That is the case.

[0065] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] That is the case.

[0066] In some embodiments, R 1 teeth [ka] That is the case.

[0067] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] That is the case.

[0068] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] That is the case.

[0069] In some embodiments, L 1 If R is -S(O)2N(R)-,1 This is any compound other than hydrogen, isopropyl, t-butyl, 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 1-trifluoromethylcyclopropyl, or 3-methyl-3-oxetanyl.

[0070] In some embodiments, L 1 If is -S(O)2N(R)- and ring A is naphthyl, then R 1 It is anything other than hydrogen or ethyl.

[0071] In some embodiments, R 1 The following selection is made from the options shown in Table 1.

[0072] As generally defined above, each R 2 C is independently substituted with halogen, -CF3, -CN, -C(O)NHR, -NO2, -NHR, -NHC(O)R, -NHS(O)2R, -N(R)2, or -OR, or optionally. 1~6 It is an aliphatic group, or two R groups located on the same carbon. 2 They can be chosen to come together to form =O, or two Rs 2 These atoms, optionally together with the intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0073] In some embodiments, R 2 is a halogen, -CF3, -CN, -C(O)NHR, -NO2, -NHR, -NHC(O)R, -NHS(O)2R, -N(R)2, or -OR. In some embodiments, R 2 This is C, which has been replaced by an optional substitution. 1~6 It is an aliphatic group. In some embodiments, two R groups are located on the same carbon. 2 These can optionally come together to form = O. In some embodiments, two R 2The groups, optionally together with their intervening atoms, form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0074] In some embodiments, R 2 It is methyl.

[0075] In some embodiments, R 2 is methoxy. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 It is cyano.

[0076] In some embodiments, two R 2 The groups, together with their intervening atoms, form a six-membered, partially unsaturated condensed ring having one nitrogen atom. In some embodiments, two R1 groups, together with their intervening atoms, [ka] It forms.

[0077] In some embodiments, R 2 The following selection is made from the options shown in Table 1.

[0078] As generally defined above, L 2 The group is selected from the group consisting of -C(O)N(R')-, -CH2O-, -CH2N(R')-, and -C(OH)(H)CH2N(R')-.

[0079] In some embodiments, L 2 is -C(O)N(R')-. In some embodiments, L 2 is -CH2O-. In some embodiments, L 2 is -CH2N(R')-. In some embodiments, L 2It is -C(OH)(H)CH2N(R')-.

[0080] In some embodiments, L 2 teeth [ka] In some embodiments, L 2 teeth [ka] In some embodiments, L 2 teeth [ka] In some embodiments, L 2 teeth [ka] In some embodiments, L 2 teeth [ka] In some embodiments, L 2 teeth [ka] That is the case.

[0081] In some embodiments, L 2 The following selection is made from the options shown in Table 1.

[0082] As generally defined above, R' is either hydrogen or C 1~3 It is an aliphatic group.

[0083] In some embodiments, R' is hydrogen. In some embodiments, R' is C 1~3It is an aliphatic group. In some embodiments, R' is methyl. In some embodiments, R' is ethyl. In some embodiments, R' is n-propyl.

[0084] In some embodiments, R' is selected from those shown in Table 1 below.

[0085] As generally defined above, L 3 The group is selected from the group consisting of -C(O)N(R)-, -OC(O)N(R)-, and -CH2O-.

[0086] In some embodiments, L 3 is -C(O)N(R)-. In some embodiments, L 3 is -OC(O)N(R)-. In some embodiments, L 3 is -CH2O-. In some embodiments, L 3 is -C(O)NH-. In some embodiments, L 3 It is -OC(O)NH-.

[0087] In some embodiments, L 3 teeth [ka] In some embodiments, L 3 teeth [ka] In some embodiments, L 3 teeth [ka] In some embodiments, L 3 teeth [ka] In some embodiments, L 3 teeth [ka] In some embodiments, L 3 teeth [ka] That is the case.

[0088] In some embodiments, L 3 The following selection is made from the options shown in Table 1.

[0089] As generally defined above, R'' is either hydrogen or C 1~3 It is an aliphatic group.

[0090] In some embodiments, R'' is hydrogen. In some embodiments, R'' is C 1~3 It is an aliphatic group. In some embodiments, R'' is methyl. In some embodiments, R'' is ethyl. In some embodiments, R'' is n-propyl.

[0091] In some embodiments, R'' is selected from those shown in Table 1 below.

[0092] As generally defined above, R 3 is hydrogen or C 1~3 It is aliphatic, or R 3 and R 4 They optionally combine with the intervening atoms to form a 3-5 member saturated carbocyclic ring, or R 3 and R 5 These atoms can optionally combine with the intervening atoms to form a 3- to 5-membered saturated carbocyclic ring.

[0093] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1~3 It is aliphatic. In some embodiments, R 3and R 4 These, together with the intervening atoms, form a 3-5 membered saturated carbon ring. In some embodiments, R 3 and R 5 These atoms, together with the intervening atoms, form a 3- to 5-membered saturated carbon ring.

[0094] In some embodiments, R 3 and R 4 together [ka] Forms R 3 and R 4 together [ka] Forms R 3 and R 4 together [ka] Forms R 3 and R 4 together [ka] It forms.

[0095] In some embodiments, R 3 and R 5 together [ka] Forms R 3 and R 5 together [ka] Forms R 3 and R 5together [ka] Forms R 3 and R 5 together [ka] It forms.

[0096] In some embodiments, R 3 The following selection is made from the options shown in Table 1.

[0097] As generally defined above, R 4 is hydrogen or C 1~3 It is an aliphatic.

[0098] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1~3 It is an aliphatic.

[0099] In some embodiments, R 4 The following selection is made from the options shown in Table 1.

[0100] As generally defined above, R 5 is hydrogen or C 1~3 It is an aliphatic.

[0101] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C 1~3 It is an aliphatic.

[0102] In some embodiments, R 5 The following selection is made from the options shown in Table 1.

[0103] As generally defined above, ring B is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0104] In some embodiments, ring B is phenyl. In some embodiments, ring B is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring B is an 8-10 membered bicyclic aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0105] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] That is the case.

[0106] In some embodiments, ring B is selected from those shown in Table 1 below.

[0107] As generally defined above, each R 6C is independently replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group, or two R groups located on the same carbon. 6 They can be chosen to come together to form =O, R 6 The R' group and the R' group optionally combine with the intervening atoms to form a 5-8 member partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen, R 6 Base and R 3 The groups, optionally together with their intervening atoms, form a 5-8 member partially unsaturated spirocondensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R 6 The group and the R'' group optionally combine with the intervening atom to form a 5-8 membered partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen.

[0108] In some embodiments, R 6 C is replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group. In some embodiments, two R groups are located on the same carbon. 6 These combine to form =O. In some embodiments, R 6 The R' group and the R' group, together with the intervening atoms, form a 5-8 membered partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen. In some embodiments, R 6 Base and R 3 The groups, together with the intervening atoms, form a 5-8 membered partially unsaturated spirocondensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R 6 The R'' group and the intervening atom together form a 5-8 membered partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen.

[0109] In some embodiments, R 6 is methyl. In some embodiments, R 6 is methoxy. In some embodiments, R 6 It is fluoro.

[0110] In some embodiments, R 6 The group and the R' group together [ka] Forms R 6 The group and the R' group together [ka] It forms.

[0111] In some embodiments, R 6 The group and the R'' group together [ka] Forms R 6 The group and the R'' group together [ka] Forms R 6 The group and the R'' group together [ka] Forms R 6 The group and the R'' group together [ka] Forms R 6 The group and the R'' group together [ka] Forms R 6 The group and the R'' group together [ka] Forms R 6 The group and the R'' group together [ka] Forms R 6 The group and the R'' group together [ka] Forms R 6 The group and the R'' group together [ka] It forms.

[0112] In some embodiments, R 6 Base and R 3 The base is together [ka] Forms R 6 Base and R 3 The base is together [ka] It forms.

[0113] In some embodiments, R 6 The following selection is made from the options shown in Table 1.

[0114] As generally defined above, ring C is a phenyl ring, a 3-8 member saturated or partially unsaturated carbocyclic ring, a 4-7 member saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0115] In some embodiments, ring C is phenyl. In some embodiments, ring C is a 3- to 8-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, ring C is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring C is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring C is an 8- to 10-membered bicyclic aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0116] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] That is the case.

[0117] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] That is the case.

[0118] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] That is the case.

[0119] In some embodiments, ring C is selected from those shown in Table 1 below.

[0120] As generally defined above, R 7 C is independently replaced by -CN, -NO2, -NHR, -N(R)2, -OR, or any other of the above. 1~6 It is an aliphatic group, or two R groups 7 These elements can be chosen to combine to form =O.

[0121] As generally defined above, R 7 The group and the R'' group optionally combine with the intervening atom to form a 5-8 membered partially unsaturated condensed ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in addition to nitrogen.

[0122] In some embodiments, R 7 C is replaced by halogen, -CN, -NO2, -NHR, -N(R)2, -OR, or of any choice. 1~6 It is an aliphatic group. In some embodiments, two R groups are located on the same carbon. 7 These elements can be chosen to combine to form =O.

[0123] In some embodiments, R 7 It is fluoro.

[0124] In some embodiments, R 7 The group and the R'' group, together with the intervening atom, [ka] Forms R 7 The group and the R'' group, together with the intervening atom, [ka] It forms.

[0125] In some embodiments, R 7 The following selection is made from the options shown in Table 1.

[0126] As generally defined above, each of m, n, and p is independently 0, 1, 2, 3, or 4.

[0127] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0128] In some embodiments, m is selected from those shown in Table 1 below.

[0129] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0130] In some embodiments, n is selected from those shown in Table 1 below.

[0131] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0132] In some embodiments, p is selected from those shown in Table 1 below.

[0133] In a particular embodiment, the present invention provides a compound of formula I, where L 2 is -C(O)N(R')- and L 3 is -C(O)N(R)-, and R 3 , R 4 , and R 5 Each of these is hydrogen, and thereafter the compound of formula II, [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, ring A, ring B, ring C, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0134] In certain embodiments, the present invention provides compounds of formula II, wherein ring A is phenyl, ring B is phenyl, and ring C is phenyl; or ring A is naphthyl, ring B is phenyl, and ring C is phenyl; or ring A is phenyl, ring B is phenyl, and ring C is cyclohexyl; or ring A is naphthyl, ring B is phenyl, and ring C is cyclohexyl, thereby forming compounds of formula III-a, III-b, III-c, or III-d, respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0135] In certain embodiments, the present invention provides compounds of formula III-a, III-b, III-c, or III-d, wherein L 1 Each of these is -S(O)2N(R)-, where R is hydrogen, and thus the compounds of formulas IV-a, IV-b, IV-c, and IV-d are respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0136] In certain embodiments, the present invention provides compounds of formula III-a, III-b, III-c, or III-d, wherein L 1 Each of these is -S(O)2-, and thereafter compounds of formulas Va, Vb, Vc, and Vd, respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0137] In certain embodiments, the present invention provides compounds of formula III-a, III-b, III-c, or III-d, wherein L 1 Each of these is -S(O)N(R)-, where R is hydrogen, and thus the compounds of formulas VI-a, VI-b, VI-c, and VI-d are formed. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0138] In a particular embodiment, the present invention provides a compound of formula III-a, where R 6 The R' group and the R' group, together with their intervening atoms, form a 6-membered partially unsaturated condensed ring, or R 6 The group and the R'' group, together with their intervening atoms, form a 5-membered partially unsaturated condensed ring, thereby forming compounds of formula VII-a and formula VII-b, respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0139] In a particular embodiment, the present invention provides a compound of formula I, where L 2 is -C(O)N(R')- and L 3 is -C(O)N(R”)-, ring B is phenyl, and R 4 is hydrogen, R 5 is hydrogen, R 6 Base and R 3 The groups, together with the intervening atoms, form a five-membered partially unsaturated condensed ring, thereby forming the compound of formula VIII. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, ring A, ring C, L 1 , R 1 , R 2 , R 6 , R 7Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0140] In a particular embodiment, the present invention provides a compound of formula I, where L 2 is -C(O)N(R')- and L 3 is -C(O)N(R”)-, ring B is phenyl, and R 4 is hydrogen, R 5 is hydrogen, R 6 Base and R 3 The groups, together with the intervening atoms, form a six-membered partially unsaturated condensed ring, thereby forming the compound of formula IX. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, ring A, ring C, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0141] In a particular embodiment, the present invention provides a compound of formula I, where L 2 is -C(O)N(R')- and L 3 is -C(O)N(R”)-, ring B is phenyl, and R 3 is hydrogen, R 4 is hydrogen, R 5 The base is hydrogen, R 6 The R' group and the R' group, together with the intervening atoms, form a 6-membered partially unsaturated condensed ring, thereby forming the compound of formula X. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, ring A, ring C, L 1 , R 1 , R 2 , R 6 , R 7Each of R'', m, n, and p, either individually or in combination, is as defined above and in the embodiments herein.

[0142] In a particular embodiment, the present invention provides a compound of formula I, where L 2 is -C(O)N(R')- and L 3 is -C(O)N(R”)-, ring B is phenyl, and R 3 is hydrogen, R 4 is hydrogen, R 5 The base is hydrogen, R 6 The R' group and the R' group, together with the intervening atoms, form a 7-membered partially unsaturated condensed ring, thereby forming the compound of formula XI. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, ring A, ring C, L 1 , R 1 , R 2 , R 6 , R 7 Each of R'', m, n, and p, either individually or in combination, is as defined above and in the embodiments herein.

[0143] In a particular embodiment, the present invention provides a compound of formula I, where L2 is -C(O)N(R')- and L 3 is -C(O)N(R”)-, ring B is phenyl, and R 3 is hydrogen, R 4 is hydrogen, R 5 The base is hydrogen, R 6 The R'' group and the intervening atom together form a 5-membered partially unsaturated condensed ring, thereby forming the compound of formula XII. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, ring A, ring C, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', m, n, and p, either individually or in combination, is as defined above and in the embodiments herein.

[0144] In a particular embodiment, the present invention provides a compound of formula I, where L 2 is -C(O)N(R')- and L 3 is -C(O)N(R”)-, ring B is phenyl, and R 3 is hydrogen, R 4 is hydrogen, R 5 The base is hydrogen, R 6 The group and the R'' group, together with the intervening atoms, form a 6-membered partially unsaturated condensed ring, thereby forming the compound of formula XIII. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, ring A, ring C, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', m, n, and p, either individually or in combination, is as defined above and in the embodiments herein.

[0145] In a particular embodiment, the present invention provides a compound of formula I, where L 2 is -C(O)N(R')- and L 3 is -C(O)N(R”)-, where the ring C is phenyl, and R 3 , R 4 , and R 5 Each of them is hydrogen, and R 7 The R'' group and the R'' group, together with the intervening atoms, form a 5-membered or 6-membered partially unsaturated fused ring, thereby forming the compound of formula XIV-a or XIV-b. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, ring A, ring B, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', m, n, and p, either individually or in combination, is as defined above and in the embodiments herein.

[0146] In certain embodiments, the present invention provides compounds of formula II, wherein ring A is phenyl, ring B is phenyl and ring C is 2-pyridyl, or ring A is phenyl, ring B is phenyl and ring C is 3-pyridyl, or ring A is phenyl, ring B is phenyl and ring C is 3-oxetanyl, or ring A is phenyl, ring B is 3-pyridyl and ring C is phenyl, thereby forming compounds of formula XV-a, XV-b, XV-c, or XV-d, respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0147] In certain embodiments, the present invention provides compounds of formula XV-a, XV-b, XV-c, or XV-d, wherein L 1 Each of these is -S(O)2N(R)-, where R is hydrogen, and thus the compounds of formula XVI-a, XVI-b, XVI-c, and XVI-d are respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0148] In certain embodiments, the present invention provides compounds of formula II, wherein ring A is 3-pyridyl, ring B is phenyl, and ring C is phenyl; or ring A is 2-pyridyl, ring B is phenyl, and ring C is phenyl; ring A is tetrahydroquinolyl, ring B is phenyl, and ring C is cyclohexyl; or ring A is tetrahydroquinolyl, ring B is phenyl, and ring C is phenyl, thereby providing compounds of formula XVII-a, XVII-b, XVII-c, or XVII-d, respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0149] In a particular embodiment, the present invention provides compounds of formula XVII-a, XVII-b, XVII-c, or XVII-d, wherein L 1Each of these is -S(O)2N(R)-, where R is hydrogen, and thus the compounds of formula XVIII-a, XVIII-b, XVIII-c, and XVIII-d are respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0150] In a particular embodiment, the present invention provides a compound of formula II, wherein ring A is phenyl, ring B is phenyl, ring C is phenyl, and R 2 is methoxy, m is 1, or ring A is phenyl, ring B is phenyl, ring C is phenyl, R 2 is methoxy, m is 1, or ring A is phenyl, ring B is phenyl, ring C is phenyl, R 2 is fluoro, m is 1, or ring A is phenyl, ring B is phenyl, ring C is phenyl, R 2 is fluoro, m is 1, and thereby compounds of formula XIX-a, XIX-b, XIX-c, or XIX-d, respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, L 1 , R 1 , R 6 , R 7 Each of R', R'', n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0151] In a particular embodiment, the present invention provides compounds of formula XIX-a, XIX-b, XIX-c, or XIX-d, wherein L 1Each of these is -S(O)2N(R)-, where R is hydrogen, and thus the compounds of formulas XX-a, XX-b, XX-c, and XX-d are respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R 1 , R 6 , R 7 Each of R', R'', n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0152] In certain embodiments, the present invention provides a compound of formula II, where ring A is phenyl, ring B is 2-pyridyl, and ring C is phenyl, thereby providing a compound of formula XXI. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, L 1 , R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0153] In a particular embodiment, the present invention provides a compound of formula XXI, wherein L 1 is -S(O)2N(R)-, where R is hydrogen, and thus the compound of formula XXII, [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 6 , R 7 Each of R', R'', m, n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0154] In a particular embodiment, the present invention provides a compound of formula II, wherein ring A is phenyl, ring B is phenyl, ring C is phenyl, and R 2 is methyl, m is 1, or ring A is phenyl, ring B is phenyl, ring C is phenyl, R 2 is methyl, m is 1, and thereby the compounds of formula XXIII-a or XXIII-b, respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, L 1 , R 1 , R 6 , R 7 Each of R', R'', n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0155] In certain embodiments, the present invention provides a compound of formula XXIII-a or formula XXIII-b, wherein L 1 Each of these is -S(O)2N(R)-, where R is hydrogen, and thus each is a compound of formula XXIV-a or formula XXIV-b. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R 1 , R 6 , R 7 Each of R', R'', n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0156] In a particular embodiment, the present invention provides a compound of formula II, wherein ring A is phenyl, ring B is phenyl, ring C is phenyl, and R 2 is cyano, m is 1, or ring A is phenyl, ring B is phenyl, ring C is phenyl, R 2 is cyano, m is 1, or ring A is phenyl, ring B is phenyl, ring C is phenyl, R2 is chloro, m is 1, or ring A is phenyl, ring B is phenyl, ring C is phenyl, R 2 is chloro, m is 1, and thereafter compounds of formula XXV-a, XXV-b, XXV-c, or XXV-d, respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula, L 1 , R 1 , R 6 , R 7 Each of R', R'', n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0157] In certain embodiments, the present invention provides compounds of formula XXV-a, XXV-b, XXV-c, or XXV-d, wherein L 1 Each of these is -S(O)2N(R)-, where R is hydrogen, and thus the compounds of formula XXVI-a, XXVI-b, XXVI-c, and XXVI-d are respectively. [ka] or to form a pharmaceutically acceptable salt thereof, in the formula R 1 , R 6 , R 7 Each of R', R'', n, and p, individually or in combination, is as defined above and as described in the embodiments herein.

[0158] Exemplary compounds of the present invention are listed in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36

[0159] In some embodiments, the method uses the compounds listed in Table 1 above, or pharmaceutically acceptable salts thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0160] In certain embodiments, the present invention provides compounds other than those selected from Table 1-1 above, or pharmaceutically acceptable salts thereof.

[0161] 5. Use, formulation, and administration Medicinally acceptable compositions According to another embodiment, the present invention provides a composition comprising the compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is such that it is effective in measurably inhibiting USP30 in a biological sample or patient. In a particular embodiment, the amount of the compound in the composition of the present invention is such that it is effective in measurably inhibiting USP30 in a biological sample or patient. In a particular embodiment, the composition of the present invention is formulated for administration to a patient requiring such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0162] As used herein, the term “patient” means an animal, preferably a mammal, most preferably a human.

[0163] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compounds formulated together. Examples of pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, sodium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0164] "Medically acceptable derivative" means any non-toxic salt, ester, ester salt, or other derivative of the compound of the present invention that, when administered to a recipient, can directly or indirectly provide the compound of the present invention or an inhibitory active metabolite or residue thereof.

[0165] As used herein, the term “its inhibitory active metabolite or residue” means that the metabolite or residue is also an inhibitor of USP30.

[0166] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term “parenterally” includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intrafocal, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile infusion forms of the compositions of the present invention may be aqueous or oily suspensions. Such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Alternatively, the sterile infusion preparation may be a sterile infusion solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (e.g., as a solution in 1,3-butanediol). Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixative oils have traditionally been used as solvents or suspension media.

[0167] For this purpose, any non-irritating fixative oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injections, as are naturally pharmaceutically acceptable oils (e.g., olive oil or castor oil), particularly their polyoxyethylene versions. Solutions or suspensions of these oils may also contain long-chain alcohol diluents or dispersants (e.g., carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions). Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used for formulation purposes.

[0168] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral administration, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners, flavorings, or colorants may also be added as desired.

[0169] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for transrectal administration. Such suppositories can be prepared by mixing with a suitable non-irritating excipient that is solid at room temperature but becomes liquid at rectal temperature, thus melting in the rectum and releasing the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0170] The pharmaceutically acceptable compositions of the present invention can also be administered topically, particularly when the target of treatment includes a site or organ that is easily accessible by topical application (including diseases of the eyes, skin, or lower intestines). Suitable topical formulations can be readily prepared for each of these sites or organs.

[0171] Topical application for the lower intestinal tract can be achieved with transrectal suppositories (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0172] For topical application, the pharmaceutically acceptable compositions provided can be formulated into suitable ointments containing the active components suspended or dissolved in one or more carriers. Suitable carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated into suitable lotions or creams containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0173] For ophthalmic use, the pharmaceutically acceptable compositions provided can be formulated as a finely powdered suspension in isotonic pH-adjusted sterile saline, or, preferably, as a solution in isotonic pH-adjusted sterile saline with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as an ointment (e.g., petrolatum).

[0174] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0175] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0176] The amount of the compound of this disclosure that can be combined with a carrier material to produce a composition in a single dosage form varies depending on the host being treated and the specific mode of administration. Preferably, the composition provided should be formulated so that a drug dose of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving such a composition.

[0177] Furthermore, it should be understood that specific drug dosages and treatment regimens for any particular patient depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, elimination rate, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the present invention in a composition also depends on the specific compound in the composition.

[0178] Use of compounds and pharmaceutically acceptable compositions The compounds and compositions described herein are generally useful for inhibiting USP30.

[0179] USP30, a duubiquitinase (DUB) localized in mitochondria and peroxisomes, is an antagonist of parkin-mediated mitophagy and PEX2-mediated pexophagy. Through its duubiquitinase activity, USP30 counteracts ubiquitination and degradation of damaged mitochondria, and inhibition of USP30 rescues mitophagy deficiencies caused by mutant parkin. Furthermore, inhibiting USP30 reduces oxidative stress and provides protection against the mitochondrial toxin rotenone. Since damaged mitochondria are prone to parkin accumulation, inhibiting USP30 should preferentially remove unhealthy mitochondria. USP30 inhibition may beneficially increase the rate of basic mitophagy, increase mitochondrial vesicle production, halt mitochondrial fission and transport, and generally improve mitochondrial quality control mechanisms. In addition to nerve cells (e.g., substantia nigra neurons, which are particularly susceptible to mitochondrial dysfunction in Parkinson's disease), long-lived metabolically active cells (e.g., cardiomyocytes) also depend on an efficient mitochondrial quality control system. In this regard, Parkin has been shown to protect cardiomyocytes from ischemia-reperfusion injury by activating mitophagy in response to ischemic stress and removing damaged mitochondria. Therefore, USP30 inhibitors are offered for use in the treatment of conditions involving mitochondrial deficiencies (including neurological, cardiac, and systemic conditions). Deubiquitinating enzymes have the function of counteracting the action of ubiquitinating enzymes in post-translational modification of cellular proteins. These conditions collectively represent age-related disorders and symptoms of spontaneous aging, suggesting further utility of USP30 inhibition for slowing the aging process and the onset of age-related diseases. USP30 is a mitochondrial-localized ubiquitinase, and expression studies have shown that it counteracts parkin-mediated ubiquitination and the clearance of damaged mitochondria, as well as basic ubiquitination mediated by ligases such as MUL1 and MARCH5.USP30, which is localized to peroxisomes, has been shown to counteract ubiquitination and selective autophagy induction by PEX E3 ligase.

[0180] More specifically, this specification discloses methods for modulating the activity of USP30 for the treatment of diseases, developmental delays, and symptoms associated with mitochondrial dysfunction. For example, the compounds and compositions of this disclosure are useful in the treatment of mitochondrial diseases, such as Alpers disease, CPEO (chronic progressive extraocular palsy), Kearns-Sayer syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonus epilepsy and red ragged fibers), NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa), and Pearson syndrome.In addition, the compounds and compositions of this disclosure are also useful in the treatment of other USP30-related diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) (Tsubouchi K, Araya J, Kuwano K. PINK1-PARK2-mediated mitophagy in COPD and IPF pathogeneses. Inflamm Regen. 2018;38:18. Published 2018 Oct 24. doi:10.1186 / s41232-018-0077-6, Kobayashi K, Araya J, Minagawa S, et al. Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis. J Immunol. 2016;197(2):504-516. doi:10.4049 / jimmunol.1600265, Ryter SW, Rosas IO, Owen CA, et al. Mitochondrial Dysfunction as a Pathogenic Mediator of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc.2018;15(Suppl 4):S266-S272.doi:10.1513 / AnnalsATS.201808-585MG, and Ito S, Araya J, Kurita Y, et al.PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis.Autophagy.2015;11(3):547-559.doi:10.1080 / 15548627.2015.1017190).Alternatively, the compounds and compositions of this disclosure are useful in treating other USP30-related diseases, such as cardiovascular disease, renal disease, pulmonary fibrosis, ophthalmic conditions, cancer, cognitive disorders, and other related conditions (Lin Q, Li S, Jiang N, et al. PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol. 2019;26:101254.doi:10.1016 / j.redox.2019.101254, Wang Y, Cai J, Tang C, Dong Z. Mitophagy in Acute Kidney Injury and Kidney Repair. Cells. 2020;9(2):338.Published 2020 Feb 1.doi:10.3390 / cells9020338, Wang Y, Tang C,Cai J,et al.PINK1 / Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury.Cell Death Dis.2018;9(11):1113.Published 2018 Nov 1.doi:10.1038 / s41419-018-1152-2, and Tang C,Han H,Yan M,et al.PINK1-PRKN / PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury.Autophagy.2018;14(5):880-897.doi:10.1080 / 15548627.2017.1405880).The compounds disclosed herein are useful in the treatment of peroxisome-related disorders (e.g., ataxia vasodilator mutation, Heimler syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy, radicular chondrodysplasia punctata, leukodementia, Zellweger syndrome, and Zellweger spectrum disorders) (Riccio et al. Deubiquitinating enzyme USP30 maintains basal peroxisome abundance by regulating pexophagy. J Cell Biol. 2019;218(3):798-807.doi:10.1083 / jcb.201804172, Marcassa et al. Dual role of USP30 in controlling basal pexophagy and mitophagy. EMBO Rep. 2018;19(7):e45595.doi:10.15252 / embr.201745595, and Nazarko TY. Pexophagy is responsible for 65% of cases of peroxisome biogenesis disorders.Autophagy.2017;13(5):991-994.doi:10.1080 / 15548627.2017.1291480).

[0181] This invention discloses a method for treating a USP30-related disease or condition in a subject. The method may involve administering an effective amount of one or more compounds or compositions provided herein to the subject. In one embodiment, the USP30-related disease is a mitochondrial disease. Examples of mitochondrial diseases include, but are not limited to, Alpers disease, CPEO (chronic progressive extraocular palsy), Kearns-Sayer syndrome (KSS), Leber's hereditary optic neuropathy (LHON), MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonus epilepsy / red ragged fibers), NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa), and Pearson syndrome. In other embodiments, the USP30-related disease is a vascular disease (e.g., cardiovascular disease, or any disease that benefits from increased angiogenesis in tissues exhibiting abnormal or insufficient blood flow). In other embodiments, the USP30-related disease is a muscle disease (e.g., muscular dystrophy). Examples of muscular dystrophy include, but are not limited to, Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifus muscular dystrophy. In other embodiments, USP30-related disease is a form of pulmonary fibrosis.In other embodiments, the USP30-associated disease is a natural aging or age-related disease (Sun N, Youle RJ, Finkel T. The Mitochondrial Basis of Aging. Mol Cell.2016;61(5):654-666.doi:10.1016 / j.molcel.2016.01.028, Cornelissen T, Vilain S, Vints K, Gounko N,Verstreken P,Vandenberghe W.Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila.Elife.2018;7:e35878.Published 2018 May 29.doi:10.7554 / eLife.35878, Ryu D,Mouchiroud L,Andreux PA,et al.Urolithin A induces mitophagy and prolongs lifespan in C.elegans and muscle increases function in rodents.Nat Med.2016;22(8):879-888.doi:10.1038 / nm.4132, Brown EE,Lewin AS,Ash JD.Mitochondria: Potential Targets for Protection in Age-Related Macular Degeneration.Adv Exp Med Biol.2018;1074:11-17.doi:10.1007 / 978-3-319-75402-4_2, and Ito et al.2015).

[0182] In some embodiments, the USP30-related disease or condition is a demyelinating disease, such as multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbach disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, or Guillain-Barré syndrome.

[0183] In other embodiments, USP30-related diseases are metabolic diseases. Examples of metabolic diseases include, but are not limited to, obesity, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, hypercholesterolemia, dyslipidemia, syndrome X, and type II diabetes.

[0184] In other embodiments, USP30-related disorders are muscular structural disorders. Examples of muscular structural disorders include, but are not limited to, Bethlem myopathy, central core disease, congenital fibrous disequilibrium, distal muscular dystrophy (MD), Duchenne & Becker type MD, Emery-Dreifus type MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle type MD, muscle sodium channel dysfunction, myotonic chondrodysplasia, myotonic dystrophy, myotonic tubular myopathy, nemaline body disease, oculopharyngeal MD, and stress-induced urinary incontinence.

[0185] In further embodiments, USP30-related disorders are neuronal activation disorders, and examples of neuronal activation disorders include, but are not limited to, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barré syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, neurological lesions, peripheral neuropathy, spinal muscular atrophy, delayed ulnar nerve palsy, and toxic myoneuropathy. In other embodiments, USP30-related disorders are muscle fatigue disorders.

[0186] Examples of muscle fatigue disorders, though not limited to these, include chronic fatigue syndrome, diabetes mellitus (type 1 or type 2), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, and thyroid toxic myopathy.

[0187] In some embodiments, the USP30-related disorder is muscle mass impairment.

[0188] Examples of muscle mass impairment, though not limited to these, include cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, severe disease myopathy, inclusion body myositis, disuse atrophy, sarcopenia, steroid myopathy, and systemic lupus erythematosus.

[0189] In other embodiments, USP30-related diseases are beta-oxidation diseases.

[0190] Examples of beta-oxidation disorders include, but are not limited to, systemic carnitine transporter deficiency, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, and riboflavin-responsive beta-oxidation disorder (RR-MADD).

[0191] In some embodiments, USP30-related diseases are vascular diseases. Examples of vascular diseases include, but are not limited to, peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral artery disease (PAD), peripheral artery occlusive disease (PAOD), and peripheral artery occlusive disease.

[0192] In other embodiments, USP30-related diseases are ophthalmic vascular diseases.

[0193] Examples of ocular vascular diseases include, but are not limited to, age-related macular degeneration (AMD), Stargard disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal hemorrhage, and glaucoma.

[0194] In another embodiment, the USP30-related disease is an ocular muscle disease.

[0195] Examples of ocular muscle diseases include, but are not limited to, strabismus (esotropia / migratory eye / exotropia ophthalmoplegia), progressive extraocular muscle paralysis, esotropia, exotropia, refractive and accommodation disorders, hyperopia, myopia, astigmatism, anisometropia, presbyopia, accommodation disorders, or intrinsic ophthalmoplegia. In other embodiments, USP30-related diseases are metabolic disorders.

[0196] Examples of metabolic disorders include, but are not limited to, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia, and / or HDL noncholesterolemia, VLDL hyperproteinemia, abnormal lipoproteinemia, apolipoprotein AI hypoproteinemia, atherosclerosis, arteriosclerotic disease, cardiovascular disease, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, diabetes mellitus (type I or type II), hyperglycemia, and insulin resistance. These include impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, myocardial infarction, cardiomyopathy, hypertension, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), thrombosis, Parkinson's disease, Alzheimer's disease, neurodegenerative diseases, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, ectopic hair growth, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, and pancreatitis.

[0197] In yet another embodiment, the USP30-related disease is cancer. Examples of cancer include, but are not limited to, cancers of the colon, colorectal gland, skin, breast, prostate, ovaries, and / or lung.

[0198] In other embodiments, USP30-related diseases are ischemic injuries. Examples of ischemic injuries include, but are not limited to, myocardial infarction (e.g., myocardial infarction), cerebral ischemia (e.g., acute ischemic stroke, chronic cerebral ischemia such as vascular dementia, and transient ischemic attacks (TIAs)), intestinal ischemia (e.g., ischemic colitis), limb ischemia (e.g., acute upper or lower limb ischemia), subcutaneous ischemia (e.g., cyanosis or gangrene), and ischemic organ injury (e.g., ischemic kidney injury (IRI)).

[0199] In yet another embodiment, the USP30-related disease is a kidney disease. Examples of kidney diseases include, but are not limited to, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute kidney injury (also known as acute renal failure), chronic renal failure, diabetic nephropathy, or Bartter syndrome.

[0200] While USP30 inhibitors are known in the art, there is a continuing need to provide novel inhibitors that are more effective or advantageous and pharmaceutically significant. These include compounds exhibiting increased activity, selectivity compared to other deubiquitinating enzymes (DUBs) (e.g., USP8, USP15, and USP16), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Therefore, in some embodiments, the present invention provides USP30 inhibitors exhibiting selectivity over other DUBs.

[0201] USP8 is a DUB in the same phylogenetic tree as USP30, localized in mitochondria, and mediates K6-binding deubiquitination (Kemp M: Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors. Prog Med Chem 2016, 55:149-192). USP8 can also deubiquitinate parkin, potentially affecting the mitophagy pathway. Furthermore, embryonic lethality resulting from USP8 knockout (Niendorf et al., Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo. Mol Cell Biol 2007, 27:5029-5039. PMC1951504.) suggests that USP8 inhibition may have harmful toxicity. USP15 also localizes to mitochondria and may alter parkin-mediated mitophagy (Coyne and Wing, The business of deubiquitination - location, location, location. F1000Res 2016, 5. PMC4755399.).USP16 is similar to USP30 in that it lacks aspartic acid as part of its three catalytic residues (Gersch et al, Mechanism and regulation of Lys6-selective deubiquitinase USP30. Nat Struct Mol Biol 2017, 24:920-930. PMC5757785; Nijman et al., A genomic and functional inventory of the deubiquitinating enzymes. Cell 2005, 123:773-786; Mevissen and Komander, Mechanisms of Deubiquitinase Specificity and Regulation. Annu Rev Biochem 2017, 86:159-192.), and knockout of this gene results in embryonic lethality.

[0202] As used herein, the terms “treatment,” “to treat,” and “to treat” refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more of its symptoms described herein. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible subject before the onset of symptoms (e.g., based on symptom history and / or genetic factors or other susceptibility factors). Treatment may also be continued after the resolution of symptoms, for example, to prevent or delay the recurrence of symptoms.

[0203] Since the compounds provided are inhibitors of USP30, they are useful for treating one or more disorders associated with USP30 activity. Accordingly, in certain embodiments, the present invention provides a method for treating a USP30-mediated disorder, comprising the step of administering the compounds of the present invention or a pharmaceutically acceptable composition thereof to a subject in need thereof.

[0204] As used herein, “USP30-mediated” disorders, diseases, and / or conditions means any disease or other adverse condition in which USP30 is known to play a role. Accordingly, another embodiment of the present invention relates to the treatment or reduction of the severity of one or more diseases in which USP30 is known to play a role.

[0205] Furthermore, the present invention provides for the use of compounds as defined herein, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, for the preparation of pharmaceuticals for the treatment of USP30-mediated disorders.

[0206] Concomitant medications Depending on the specific condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as “appropriate for the disease or condition to be treated.”

[0207] In a particular embodiment, the combination or composition provided is administered in combination with another therapeutic agent.

[0208] Furthermore, examples of drugs that can be used in combination with the present invention, though not limited to these, include: drugs for treating Alzheimer's disease (e.g., Aricept® and Excelon®), drugs for treating HIV (e.g., ritonavir), drugs for treating Parkinson's disease (e.g., L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexyfenny, and amantadine), drugs for treating multiple sclerosis (MS) (e.g., beta-interferon (e.g., Avorex® and Rebif®), Copaxone®, and mitoxantrone), drugs for treating asthma (e.g., albuterol and Singulair®), drugs for treating schizophrenia (e.g., Zyprexa, Risperdal, Seroquel, and haloperidol), and anti-inflammatory drugs (e.g., corticosteroids, TNF blockers, IL-1). RA, azathioprine, cyclophosphamide, and sulfasalazine), immunomodulators and immunosuppressants (e.g., cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine), neurotrophic factors (e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents), drugs for treating cardiovascular disease (e.g., beta-blockers, ACE inhibitors) Drugs for treating liver disease (e.g., corticosteroids, diuretics, nitrates, calcium channel blockers, and statins), drugs for treating hematological disorders (e.g., corticosteroids, cholestyramine, interferons, and antivirals), drugs for treating hematological disorders (e.g., corticosteroids, antileukemia agents, and growth factors), drugs for sustaining or improving pharmacokinetics (e.g., cytochrome P450 inhibitors (i.e., metabolic degradation inhibitors) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir)), and drugs for treating immunodeficiency disorders (e.g., gamma globulin).

[0209] In certain embodiments, the combination therapeutic agent of the present invention, or a pharmaceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0210] Such additional agents may be administered separately from the concomitant therapeutic agent provided as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form, which is a mixture of the compounds of the present invention into a single composition. When administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially, or within a certain time interval (usually within 5 hours) from each other.

[0211] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combinations of the present invention may be administered simultaneously or sequentially with other therapeutic agents, in separate unit dosage forms or together in a single unit dosage form.

[0212] The amount of additional therapeutic agent present in the composition of the present invention will not exceed the amount that would normally be administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition of the present disclosure will be in the range of about 50% to about 100% of the amount that would normally be present in a composition containing that therapeutic agent as the sole therapeutic active agent.

[0213] In one embodiment, the present invention provides a composition comprising a compound of formula I or formula I' and one or more additional therapeutic agents. The therapeutic agents may be administered together with the compound of formula I or formula I', or before or after the administration of the compound of formula I or formula I'. Preferred therapeutic agents are described in more detail below. In certain embodiments, the compound of formula I or formula I' may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, compounds of formula I or formula I' can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0214] In another embodiment, the present invention provides a method for administering a compound of formula I or formula I' and one or more additional therapeutic agents to a patient who requires treatment for an inflammatory disease, disorder, or condition. Such additional therapeutic agents may be small molecules or recombinant biological agents and include, for example: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), probenecid, allopurinol, Febuxostat. Xostat (Uloric®), sulfasalazine (Azulfidine®), antimalarial agents (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalic acid (Myochrysine®), and auranofin (Ridaura®)), D-penicillin Cillamin (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simpo)). ni(registered trademark), certolizumab pegol (Cimzia(registered trademark)) and adalimumab (Humira(registered trademark))), "anti-IL-1" agents (e.g., anakinra (Kineret(registered trademark)) and lilonacept (Arcalyst(registered trademark))), canakinumab (Ilaris(registered trademark)), anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan(registered trademark))), "anti-T cell" agents (e.g., abatacept (Orencia(registered trademark))),"Anti-IL-6" agents (e.g., tocilizumab (Actemra®)), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®), and warfarin (Coumadin®)), antidiarrheal agents (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile duct. Acid binders (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (e.g., magnesia milk, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®), Singulair®), beta-2 agonists (e.g., albuterol (Ventolin® HFA)) Proventil® (HFA), revalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), formoterol (Foradil®), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (For example, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®)), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®, and flunisolide (Aerobid®)), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthine (for example,Theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®, and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), zida Nosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stabudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors (e.g., delavirudine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Inte lence(registered trademark), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread(registered trademark))), protease inhibitors (e.g., amprenavir (Agenerase(registered trademark)), atazanavir (Reyataz(registered trademark)), darunavir (Prezista(registered trademark)), hosanprenavir (Lexiva(registered trademark)), indinavir (Crixivan(registered trademark)), lopinavir / ritonavir (Kaletra(registered trademark)), nelfinavir (Viracept(registered trademark)), ritonavir (Norvir (Registered Trademark), Saquinavir (Fortovase® or Invirase®), Tipranavir (Aptivus®), Invasion inhibitors (e.g., Enfuvirtide (Fuzeon®) and Maraviloc (Selzentry®)), Integrase inhibitors (e.g., Raltegravir (Isentress®)), Doxorubicin (Hydrodaunorubicin®), Vincristine (Oncovin®), Bortezomib (Velcade®),Furthermore, combinations of dexamethasone (Decadron®) and lenalidomide (Revlimid®), or any combination(s) of these.

[0215] In another embodiment, the present invention relates to a method for treating rheumatoid arthritis, comprising, to a patient in need, a compound of formula I or formula I', a nonsteroidal anti-inflammatory drug (NSAID) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), sulfasalazine (Azufidine®), and an antimalarial agent. (For example, hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (for example, gold thioglucose (Solganal®), gold thiomalic acid (Myochrysine®), and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imura) n(registered trademark), cyclophosphamide (Cytoxan(registered trademark)), chlorambucil (Leukeran(registered trademark)), cyclosporine (Sandimmune(registered trademark)), leflunomide (Arava(registered trademark)), and "anti-TNF" agents (e.g., etanercept (Embrel(registered trademark)), infliximab (Remicade(registered trademark)), golimumab (Simponi(registered trademark)), certolizumab pegol (Cimzia(registered trademark)), and ada The present invention provides a method comprising administering one or more additional therapeutic agents selected from limumab (Humira®), anti-IL-1 agents (e.g., anakinra (Kineret®) and lilonacept (Arcalyst®)), antibodies (e.g., antibodies such as rituximab (Rituxan®)), anti-T cell agents (e.g., abatacept (Orencia®)), and anti-IL-6 agents (e.g., tocilizumab (Actemra®)).

[0216] In some embodiments, the present invention provides a method for treating osteoarthritis, comprising administering to a patient in need a compound of formula I or formula I' and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies (e.g., tanezumab).

[0217] In some embodiments, the present invention relates to a method for treating systemic lupus erythematosus, comprising, to a patient in need, a compound of formula I or formula I', and acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), and antimalarial agents (e.g., hydroxychloroquine (Pl). The present invention provides a method comprising administering aquenil® and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and one or more additional therapeutic agents selected from anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®), and warfarin (Coomadin®)).

[0218] In some embodiments, the present invention relates to a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising, to a patient in need, a compound of formula I or formula I', mesalamine (Asacol®), sulfasalazine (Azulfidine®), an antidiarrheal agent (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), a bile acid binder (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone) The present invention provides a method comprising administering Amitiza®), laxatives (e.g., magnesia milk, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), and one or more additional therapeutic agents selected from anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®)), anti-TNF therapy, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin).

[0219] In some embodiments, the present invention relates to a method for treating asthma, comprising to a patient in need of the treatment a compound of formula I or formula I', and Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), revalbuterol (Xopenex®), metaproterenol (Alupent®), pyrbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergic agents (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., prednisone, prednisolone, dipropionate) The present invention provides a method comprising administering one or more additional therapeutic agents selected from clometasone (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®), cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®), and aminophylline), and IgE antibodies (e.g., omalizumab (Xolair®)).

[0220] In some embodiments, the present invention relates to a method for treating COPD, comprising to a patient in need of the treatment a compound of formula I or formula I', a beta-2 agonist (e.g., albuterol (Ventolin® HFA, Proventil® HFA), revalbuterol (Xopenex®), metaproterenol (Alupent®), pyrbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic agent (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), a methylxanthine (e.g., theophilic The present invention provides a method comprising administering one or more additional therapeutic agents selected from (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®, and aminophylline), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®)).

[0221] In another embodiment, the present invention provides a method for treating hematological malignancies, comprising administering to a patient in need a compound of formula I or formula I' and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0222] In another embodiment, the present invention provides a method for treating a solid tumor, comprising administering to a patient in need a compound of formula I or formula I' and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0223] In another embodiment, the present invention provides a method for treating a hematological malignancy, comprising administering to a patient in need a compound of formula I or formula I' and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al. “Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk.Res. (2012) (published online July 17; the entire article is incorporated herein by reference).

[0224] In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need a compound of formula I or formula I' and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisolone, hedgehog signaling inhibitors, and combinations thereof.

[0225] In another embodiment, the present invention provides a method for treating multiple myeloma, comprising administering to a patient in need a compound of formula I or formula I', and one or more additional therapeutic agents selected from a combination of bortezomib (Velcade®) and dexamethasone (Decadron®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors and lenalidomide (Revlimid®).

[0226] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, comprising administering a compound of formula I or formula I' and a BTK inhibitor to a patient in need thereof, wherein the disease is inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes mellitus, myasthenia gravis, Hashimoto's disease, Audrey thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, thermogenic autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia generalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerulonephropathy, endometriosis, interstitial cystitis , pemphigus vulgaris, bullous pemphigoid, neurogenic myotonia, scleroderma, vulvar pain, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect toxins, animal hair, animal scales, dust mites, or cockroach calyx), type 1 hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies Ghee, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, panentotitis, maxillitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, interstitial pneumonia, pneumonia, polymyositis,Proctitis, prostatitis, pyelonephritis, rhinitis, sialadenitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders, e.g., diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasmacytoma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, large mediastinal (thymic) B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatous granulomatosis, breast cancer, prostate cancer, or mast cell carcinoma (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mast cell disease), bone cancer, colorectal cancer, pancreatic cancer, diseases of bone and joints (including, but not limited to, rheumatoid arthritis), seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behçet's disease, Sjögren's disease Syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases, thromboembolic disorders (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass, restenosis after coronary artery bypass, stroke, transient ischemia, peripheral artery occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, interstitial pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitus), agammaglobulinemia, psoriasis, allergies, etc. Loan's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), polyglandular autoimmune disease (also known as polyglandular autoimmune syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis / thrombocytopenia, Goodpasture syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes mellitus, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,The following conditions are selected: psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute dyspnea syndrome, ischemia-reperfusion injury, and / or ischemia / reperfusion injury), and Graves' disease.

[0227] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, comprising administering a compound of formula I or formula I' and a PI3K inhibitor to a patient in need thereof, wherein the disease is selected from cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related disorders, organ transplant-related conditions, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune conditions with T-cell activation, cardiovascular disorders, and CNS disorders.

[0228] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, comprising administering a compound of formula I or formula I' and a PI3K inhibitor to a patient in need thereof, wherein the disease is a benign or malignant tumor, cancer, or solid tumor of the following organs: brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitals, esophagus, larynx, skin, bone, or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or stomach Diseases including intestinal cancer, especially colon cancer or adenoma of the large intestine, or tumors of the head and neck, epidermal hyperplasia, psoriasis, prostate hyperplasia, neoplasms, epithelial neoplasms, adenoma, adenocarcinoma, keratoacanthoma, epidermal carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (e.g., non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, testicular cancer, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dudos disease, and Banayan-Zonana syndrome, or diseases involving a different PI3K / PKB pathway. Constantly active diseases, asthma of all types and origins (including endogenous (non-allergic) asthma and exogenous asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection), acute lung injury (ALI), adult-onset / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway, or lung disease (COPD, COAD, or COLD) (including chronic bronchitis or associated dyspnea), emphysema, and other drug therapies (in particular, including exacerbation of airway hyperactivity caused by other inhaled drug therapies), all Bronchitis of any type or origin (including, but not limited to, acute, arachidic, catarrhal, croup, chronic, or tuberculous bronchitis), pneumoconiosis of any type or origin (inflammatory, generally occupational lung diseases, often accompanied by airway obstruction (chronic or acute), caused by repeated inhalation of dust) (e.g., aluminum pneumonitis, anthrax pneumonia, asbestos pneumonia, lithiasis, ostrich pneumonia, iron pneumonitis, silicosis, tobacco pneumonia, and cotomatosis), Refler's syndrome, eosinophilic, pneumonia, parasitic (in particular,Parasitic diseases of metazoans (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), drug-induced eosinophilic granulomas and eosinophil-associated airway disorders, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermolysis bullosa, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis), and inflammatory diseases involving autoimmune reactions or having autoimmune components or etiologies (autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, erythropoiesis)). (including cystic anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma (sclerodoma), Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (nephrotic syndrome (e.g., idiopathic nephrotic syndrome or minimal change syndrome (minal) The following are selected from neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia: restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia.

[0229] In some embodiments, the present invention provides a method for treating a disease or reducing the severity of a disease, comprising administering to a patient in need a compound of formula I or formula I' and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0230] In some embodiments, the present invention provides a method for treating a disease or reducing the severity of a disease, comprising administering to a patient in need a compound of formula I or formula I' and a parkin activator, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a neurological disorder. In some embodiments, the disorder is Parkinson's disease. In some embodiments, the disorder is Alzheimer's disease.

[0231] Compounds and compositions according to the methods of the present invention can be administered in any amount and via any route of administration that is effective in treating or alleviating the severity of autoimmune diseases, inflammatory diseases, proliferative disorders, endocrine disorders, neurological disorders, or transplant-related disorders. The exact amount required will vary from subject to subject depending on the subject's race, age, and general condition, the severity of the infection, the specific drug, and its mode of administration. The compounds of the present invention are preferably formulated into unit dosage forms to facilitate administration and ensure uniformity of the drug dose. As used herein, the term "unit dosage form" refers to a physically separate unit of drug appropriate for the patient being treated. However, it should be understood that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician within reasonable medical judgment. The specific effective dose level for any particular patient or organism depends on a variety of factors, including the disorder being treated, the severity of the disorder, the activity of the specific compound used, the specific composition used, the patient's age, weight, overall health, sex, and diet, the timing of administration, route of administration, and excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field. In this specification, the term “patient” means an animal, preferably a mammal, most preferably a human.

[0232] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, vaginally, intraperitoneally, topically (as powder, ointment, or drops), buccally, or as an oral or nasal spray, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at a drug dose level of about 0.01 mg / kg to about 50 mg / kg of the target body weight per day, preferably about 1 mg / kg to about 25 mg / kg, once or more per day to obtain the desired therapeutic effect.

[0233] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, as well as mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0234] Injectable preparations, such as aqueous or oily sterile injection suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injection preparations may be sterile injection solutions, suspensions, or emulsions (e.g., as a solution in 1,3-butanediol) in non-toxic, parenterally acceptable diluents or solvents. Acceptable vehicles and solvents include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixatives have traditionally been used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, can be used. Furthermore, fatty acids such as oleic acid are used in the preparation of injections.

[0235] Injectable formulations can be sterilized, for example, by filtering with a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0236] To extend the effects of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with low water solubility. In this case, the absorption rate of the compound depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, parenterally administered forms of the compounds delay absorption by dissolving or suspending the compound in an oily vehicle. Depot formulations for injection are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the compound:polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injection formulations can also be prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0237] Compositions for transrectal or transvaginal administration are preferably suppositories, which can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax. Such excipients or carriers are solid at ambient temperature but liquid at body temperature, and thus melt in the rectal or vaginal cavity, releasing the active compound.

[0238] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is provided with at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) water-retaining agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, dichloride. It is mixed with potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) a dissolution retarder, e.g., paraffin, f) an absorption enhancer, e.g., a quaternary ammonium compound, g) a wetting agent, e.g., cetyl alcohol and glycerol monostearate, h) an absorbent, e.g., kaolin and bentonite clay, and i) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0239] Furthermore, similar types of solid compositions can be used as fillers in soft and rigid gelatin capsules with excipients such as lactose and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical field. These dosage forms may optionally contain opacifiers and may be composed to release the active ingredient(s) only in or preferentially in a specific part of the intestinal tract, in an optionally delayed manner. Examples of implantable compositions include polymers and waxes. Furthermore, similar types of solid compositions can be used as fillers in soft and rigid gelatin capsules with excipients such as lactose and high molecular weight polyethylene glycol.

[0240] The active compound can also be microencapsulated with one or more of the excipients described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical field. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, e.g., sucrose, lactose, or starch. Such dosage forms may also include, as is common practice, further substances other than the inert diluent, e.g., tableting lubricants and other tableting aids, e.g., magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may include a buffer. These dosage forms may optionally include an opacifier, and may also be composed to release the active ingredient(s) only in, or preferentially in, a specific portion of the intestinal tract, in an optionally delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0241] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active components are mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of the present invention. In addition, the present invention also intends to utilize transdermal patches, which have the further advantage of controlling the delivery of the compounds to the body. Such dosage forms can be prepared by dissolving or distributing the compounds in a suitable medium. Absorption enhancers can also be used to increase the inflow of the compounds through the skin. The rate can be controlled by providing a rate control membrane or by dispersing the compounds in a polymer matrix or gel.

[0242] According to one embodiment, the present invention relates to a method for inhibiting USP30 activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition containing the compound.

[0243] In another embodiment, the present invention relates to a method for inhibiting USP30 activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition containing the compound. In a particular embodiment, the present invention relates to a method for irreversibly inhibiting the activity of USP30 or a variant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition containing the compound.

[0244] In another embodiment, the present invention provides a method for selectively inhibiting USP30 compared to one or more DUBs. In some embodiments, the compounds of the present invention have more than 2 times selectivity compared to USP8, USP15, and / or USP16. In some embodiments, the compounds of the present invention have more than 5 times selectivity compared to USP8, USP15, and / or USP16. In some embodiments, the compounds of the present invention have more than 10 times selectivity compared to USP8, USP15, and / or USP16. In some embodiments, the compounds of the present invention have more than 50 times selectivity compared to USP8, USP15, and / or USP16. In some embodiments, the compounds of the present invention have more than 100 times selectivity compared to USP8, USP15, and / or USP16.

[0245] As used herein, the term “biological sample” includes, but is not limited to, cell cultures or their extracts, biopsy materials obtained from mammals or their extracts, and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or their extracts.

[0246] Inhibition of USP30 activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological assays.

[0247] Another embodiment of the present invention relates to a method for inhibiting USP30 activity in a patient, comprising the step of administering to the patient a compound of the present invention or a composition containing the compound.

[0248] In another embodiment, the present invention relates to a method for inhibiting the activity of USP30 in a patient, comprising the step of administering to the patient a compound of the present invention or a composition containing said compound. In a particular embodiment, the present invention relates to a method for reversibly or irreversibly inhibiting the activity of USP30 in a patient, comprising the step of administering to the patient a compound of the present invention or a composition containing said compound. In another embodiment, the present invention provides a method for treating a patient who requires treatment for a USP30-mediated disorder, comprising the step of administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0249] Depending on the specific condition or disease to be treated, additional therapeutic agents that are typically administered to treat that condition may be present in the composition of the present invention. As used herein, additional therapeutic agents that are typically administered to treat a particular disease or condition are known as “appropriate for the disease or condition to be treated.”

[0250] Furthermore, the compounds of the present invention can be advantageously used in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activating compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-cancer antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity; and further anti-angiogenic compounds; compounds that target, reduce, or inhibit protein or lipid phosphatase activity; gonadrelin agonists; anti-androgens; and methionine amine peptidases. Inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce, or inhibit Flt-3 activity; Hsp90 inhibitors, e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Examples of therapeutics include temozolomide (Temodal®); kinesin spindle protein inhibitors, e.g., SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx); MEK inhibitors, e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer), and leucovorin. As used herein, the term "aromatase inhibitor" refers to compounds that inhibit estrogen production (e.g., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively).The term includes, but is not limited to, steroids, particularly atamestan, exemestane, and formestan, and more specifically, nonsteroids, particularly aminoglutethimide, logrethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, volozol, fadrozol, anastrozole, and letrozole. Exemestane is marketed under the trade name Aromasin®. Formestan is marketed under the trade name Lentaron®. Fadrozol is marketed under the trade name Afema®. Anastrozole is marketed under the trade name Arimidex®. Letrozole is marketed under the trade names Femara® or Femar®. Aminoglutethimide is marketed under the trade name Orimeten®. The combination of the present invention, including chemotherapeutic agents that are aromatase inhibitors, is particularly useful for the treatment of hormone receptor-positive tumors (e.g., breast tumors).

[0251] As used herein, the term “anti-estrogen” refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. Examples of such compounds include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex®. Raloxifene hydrochloride is marketed under the trade name Evista®. Fulvestrant may be administered under the trade name Faslodex®. Combinations of the present invention, including anti-estrogen chemotherapeutic agents, are particularly useful for the treatment of estrogen receptor-positive tumors (e.g., breast tumors).

[0252] As used herein, the term “anti-androgen” includes, but is not limited to, any substance capable of inhibiting the biological effects of androgenic hormones, including bicalutamide (Casodex®). As used herein, the term “gonadrelin agonist” includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name “Zoladex®”.

[0253] As used herein, the term “topoisomerase I inhibitor” includes, but is not limited to, topotecan, gimatecan, irinotecan, camptotecan and their analogues, 9-nitrocamptotecan and the high molecular weight camptotecan conjugate PNU-166148. Irinotecan may be administered in forms marketed, for example, under the trademark Camptosar®. Topotecan is marketed under the trade name Hycamptin®.

[0254] As used herein, the term “topoisomerase II inhibitor” includes, but is not limited to, anthracyclines (e.g., doxorubicin (including liposomal formulations such as Caelyx®), daunorubicin, epirubicin, idarubicin, and nemorubicin), the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos®. Teniposide is marketed under the trade name VM 26-Bristol. Doxorubicin is marketed under the trade names Acriblastin® or Adriamycin®. Epirubicin is marketed under the trade name Farmorubicin®. Idarubicin is marketed under the trade name Zavedos®. Mitoxantrone is marketed under the trade name Novantron.

[0255] The term "microtubule activators" is not limited to microtubule stabilizing, microtubule destabilizing, and microtubule phosphate polymerization inhibitors, but includes taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine), discodermolide, colchicine, and epothirone, as well as their derivatives. Paclitaxel is marketed under the trade name Taxol®. Docetaxel is marketed under the trade name Taxotere®. Vinblastine sulfate is marketed under the trade name Vinblastin RP®. Vincristine sulfate is marketed under the trade name Farmistin®.

[0256] As used herein, the term “alkylating agent” includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin®. Ifosfamide is marketed under the trade name Holoxan®.

[0257] The terms "histone deacetylase inhibitor" or "HDAC inhibitor" refer to compounds that inhibit histone deacetylase and have antiproliferative activity. This term includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0258] The term “antitemoid antimetabolites” includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation compounds (e.g., 5-azacitidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (e.g., pemetrexed). Capecitabine is marketed under the brand name Xeloda®. Gemcitabine is marketed under the brand name Gemzar®.

[0259] As used herein, the term “platin compounds” includes, but is not limited to, carboplatin, cisplatin, cisplatin, and oxaliplatin. Carboplatin may be administered, for example, in the form marketed under the trademark Carboplat®. Oxaliplatin may be administered, for example, in the form marketed under the trademark Eloxatin®.

[0260] As used herein, the term “compounds that target / reduce protein or lipid kinase activity, or protein or lipid phosphatase activity, or further anti-angiogenic compounds” includes, but is not limited to, the following: protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, for example, a) compounds that target, reduce, or inhibit the activity of platelet-derived growth factor receptor (PDGFR), for example, compounds that target, reduce, or inhibit the activity of PDGFR, in particular those that inhibit the PDGF receptor. a) Compounds that target, reduce, or inhibit the activity of fibroblast growth factor receptor (FGFR); c) Compounds that target, reduce, or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce, or inhibit IGF-IR activity, particularly compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d (a) Compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; (b) Compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; (c) Compounds that target, reduce, or inhibit the activity of the Ret receptor tyrosine kinase; (g) Compounds that target, reduce, or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, e.g., imatinib; (h) Compounds that target, reduce, or inhibit the activity of the C-kit receptor tyrosine kinase (part of the PDGFR family), e.g., c - Compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, particularly compounds that inhibit the c-Kit receptor, e.g., imatinib; i) Compounds that target, reduce, or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinase), and mutants, e.g., compounds that target, reduce, or inhibit the activity of c-Abl family members and their gene fusion products, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107);PD180970;AG957;NSC 680410;PD173955 (manufactured by Parke Davis); or dasatinib (BMS-354825);j) Compounds that target, reduce, or inhibit the activity of members of protein kinase C (PKC), serine / threonine kinases, the Raf family, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK, and TEC families, and / or cyclin-dependent kinase families (CDKs) (including staurosporine derivatives, e.g., midostaurin; further compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosin; llmofosine; RO 318220 and RO 320432;GO 6976;lsis 3521;LY333531 / LY379196;Isoquinoline compounds;FTI;PD184352 or QAN697 (P13K inhibitor), or AT7519 (CDK inhibitor);k)Compounds that target, reduce, or inhibit the activity of protein tyrosine kinase inhibitors, for example, imatinib mesylate (Gleevec®) or tilhostin, for example, tilhostin A23 / RG-50810;AG 99;tilhostin AG 213;tilhostin AG 1748;tilhostin AG 490;tilhostin B44;tilhostin B44(+) enantiomer;tilhostin AG 555;AG 494;tilhostin AG 556, AG957, and adafostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, adafostin);l) Compounds that target, reduce, or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 (as homodimers or heterodimers) and their variants, for example, compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family, in particular proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family (e.g., EGF receptor, ErbB2, ErbB3, and ErbB4), or proteins or antibodies that bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; Trastuzumab (Herceptin®), cetuximab (Erbitux®), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) Compounds that target, reduce, or inhibit the activity of the c-Met receptor, e.g., compounds that target, reduce, or inhibit the activity of c-Met, in particular compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) One or more JAK family members (JAK1 / JAK2 / JA Compounds that target, reduce, or inhibit the kinase activity of K3 / TYK2 and / or pan-JAK (including, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momerotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib); o) Compounds that target, reduce, or inhibit the kinase activity of PI3 kinase (PI3K) (including, but not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelicib, PF-4691502, BYL-719, dactricib, XL-147, XL-765, and idelalisib);Furthermore, q) compounds that target, reduce, or inhibit the signaling activity of the Hedgehog protein (Hh) or Smoothund receptor (SMO) pathway (including, but not limited to, cyclopamine, bismodegib, itraconazole, erythmodegib, and IPI-926 (thalidegib)).

[0261] As used herein, the term “PI3K inhibitor” includes, but is not limited to, compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family (including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87). Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactricib, XL-147, XL-765, and idelalisib.

[0262] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), and includes, but is not limited to, AVL-292 and ibrutinib.

[0263] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), and includes, but is not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0264] As used herein, the term “Bcl-2 inhibitor” includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma protein 2 (Bcl-2), including, but is not limited to, ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitors Ascenta, curcumin (and its analogues), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), genasense (G3139), HA14-1 (and its analogues; see WO2008118802), navitoclax (and its analogues; see US7390799), NH-1 (Shenayng Pharmaceutical University), ovatoclax (and its analogues; see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, Bcl-2 inhibitors are small molecule therapeutics. In some embodiments, Bcl-2 inhibitors are peptomimetic.

[0265] Further examples of BTK inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, both of which are incorporated herein by reference.

[0266] Further examples of SYK inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the present invention can be found in WO2003063794, WO2005007623, and WO2006078846, all of which are incorporated herein by reference.

[0267] Further examples of PI3K inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, all of which are incorporated herein by reference.

[0268] Further examples of JAK inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, all of which are incorporated herein by reference.

[0269] Further anti-angiogenic compounds include those with alternative mechanisms of activity (e.g., unrelated to protein or lipid kinase inhibition), such as thalidomide (Thalomid®) and TNP-470.

[0270] Examples of proteasome inhibitors useful for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0271] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases include, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0272] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0273] As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and its derivatives, such as celecoxib (Celebrex®), rofecoxib (Vioxx®), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0274] As used herein, the term "bisphosphonate" includes, but is not limited to, etidronic acid, clodronic acid, dydronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is sold under the trade name Didronel®. Clodronic acid is sold under the trade name Bonefos®. Dydronic acid is sold under the trade name Skelid®. Pamidronic acid is sold under the trade name Aredia®. Alendronic acid is sold under the trade name Fosamax®. Ibandronic acid is sold under the trade name Bondranat®. Risedronic acid is sold under the trade name Actonel®. Zoledronic acid is sold under the trade name Zometa®. The term "mTOR inhibitor" refers to compounds that inhibit mTOR (mammalian rapamycin target) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican®), CCI-779, and ABT578.

[0275] As used herein, the term “heparanase inhibitor” refers to a compound that targets, reduces, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. As used herein, the term “biological response modifier” refers to a lymphokine or interferon.

[0276] The term “inhibitor of Ras oncogenerative isoforms” (e.g., inhibitors of H-Ras, K-Ras, or N-Ras) is used herein to refer to compounds that target, reduce, or inhibit the oncogenerative activity of Ras, such as “farnesyltransferase inhibitors” (e.g., L-744832, DK8G557, or R115777 (Zarnestra®)). The term “telomerase inhibitor” is used herein to refer to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase include, in particular, compounds that inhibit telomerase receptors, such as telomestatin.

[0277] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Examples of compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamides or their derivatives.

[0278] As used herein, the term “proteasome inhibitor” refers to a compound that targets, reduces, or inhibits the activity of the proteasome. Examples of compounds that target, reduce, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade®) and MLN 341.

[0279] As used herein, the term “matrix metalloproteinase inhibitor” (or “MMP” inhibitor) includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor bacistat and its orally bioavailable biological analogs maristat (BB-2516), prinostat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[0280] As used herein, the term “compounds used in the treatment of hematological malignancies” includes, but is not limited to, FMS-like tyrosine kinase inhibitors (compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R)), interferons, 1-β-D-arabinofrancilcytosine (ara-c) and bisulfan, ALK inhibitors (compounds that target, reduce, or inhibit anaplastic lymphoma kinase), and Bcl-2 inhibitors.

[0281] Compounds that target, reduce, or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are, in particular, compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase (e.g., PKC412, the staurosporine derivative midostaurin, SU11248, and MLN518).

[0282] As used herein, the term “HSP90 inhibitor” includes, but is not limited to, compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin-proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, the geldanamyne derivative 17-demethoxygeldanamyne (17AAG), other geldanamyne-related compounds, radicicol, and HDAC inhibitors.

[0283] As used herein, the term “anti-proliferative antibody” includes, but is not limited to, trastuzumab (Herceptin®), trastuzumab-DM1, erbitux, bevacizumab (Avastin®), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. Antibody means an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and an antibody fragment (as long as it exhibits the desired biological activity).

[0284] With regard to the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly those used to treat AML. More specifically, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other agents useful in the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412. In some embodiments, the present invention provides a method for treating AML associated with ITD and / or the D835Y mutation, comprising administering the compounds of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or restaurtinib), sorafenib, tanzutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozacertib, and sunitinib.

[0285] Other anti-leukemia compounds include, for example, the pyrimidine analog Ara-C, which is a 2-component deoxycytidine compound. ’- These are alpha-hydroxyribose (arabinoside) derivatives. Other examples include the purine analog of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC), such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of the enzyme known as histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US6,552,065 (including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indole-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salts, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indole-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salts), particularly lactates. As used herein, somatostatin receptor antagonist refers to a compound that targets, treats, or inhibits the somatostatin receptor (e.g., octreotide and SOM230). Tumor cell damage approach refers to approaches such as ionizing radiation. The term "ionizing radiation" as used above refers, in the following context, to ionizing radiation that occurs as electromagnetic waves (e.g., X-rays and gamma rays) or particle beams (e.g., alpha and beta particles). Ionizing radiation is provided in radiotherapy, though not limited to this, and is known in the art. (Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4) th See Edition, Vol.1, pp.248-275 (1993).

[0286] The term also includes EDG conjugates and ribonucleotide reductase inhibitors. As used herein, the term “EDG conjugate” refers to a class of immunosuppressants that modulate lymphocyte recirculation (e.g., FTY720). The term “ribonucleotide reductase inhibitor” refers to, but is not limited to, pyrimidine or purine nucleoside analogs, but includes fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatins. Ribonucleotide reductase inhibitors are particularly hydroxyureas or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0287] In addition, the following are also included in particular: VEGF compounds, proteins, or monoclonal antibodies, e.g., 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salts, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin®; Endostatin®; anthranilamide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g., rhuMAb and RHUFab, VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin®).

[0288] Photodynamic therapy refers to the treatment or prevention of cancer using certain chemical substances known as photosensitizing compounds. Examples of photodynamic therapy include treatments using compounds such as Visudyne® or porfimer sodium.

[0289] As used herein, angiogenic steroids refer to compounds that block or inhibit angiogenesis, such as anecoltab, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0290] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0291] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological response modulogenators, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or various other compounds or compounds with unknown mechanisms of action.

[0292] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances (e.g., anti-inflammatory, bronchodilated, or antihistamine drug substances), and are particularly useful in the treatment of obstructive or inflammatory airway diseases as described herein, for example, as enhancers of the therapeutic activity of such drugs, or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be used in pharmaceutical compositions that are mixed and immobilized with other drug substances, or they may be administered separately before, simultaneously with, or after other drug substances. Accordingly, the present invention comprises combinations of the compounds of the present invention as described herein with anti-inflammatory, bronchodilated, antihistamine, or antitussive drug substances, and the compounds and drug substances of the present invention may be included in the same or different pharmaceutical compositions.

[0293] Suitable anti-inflammatory agents include steroids, especially glucocorticosteroids (e.g., budesonide, beclametasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate); nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g., montelukast and zafirlukast); PDE4 inhibitors (e.g., siromirist (Ariflo® (GlaxoSmithKline)), roflumirist (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allophylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID (trademark) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo)); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol-fenoterol, procaterol, and especially formoterol, as well as their pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxytropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolates.

[0294] Suitable antihistamine drugs include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefnadine.

[0295] Other useful combinations of the compounds of the present invention with anti-inflammatory drugs include combinations with antagonists of chemokine receptors (e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9, and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5), particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700, and SCH-D, as well as Takeda antagonists, such as N-[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]aminophenyl]methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0296] The structure of an active compound, identified by its code number, generic name, or trade name, may be cited from the standard abstract "The Merck Index" or database (e.g., international patents (e.g., IMS World Publications)).

[0297] Furthermore, the compounds of the present invention can also be used in combination with known therapeutic processes, such as hormone administration or radiation therapy. In certain embodiments, the provided compounds are used as radiosensitizers, particularly for the treatment of tumors that show low sensitivity to radiotherapy.

[0298] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies include fixed combination forms, or forms in which the compounds of the present invention and one or more other therapeutic compounds are administered at staggered times or independently of each other, or combination administration of a fixed combination and one or more other therapeutic compounds. The compounds of the present invention can also be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for the treatment of tumors. Long-term treatment is possible, as with adjuvant therapy, in the context of the other therapeutic strategies described above. Other possible therapies include therapies to maintain the patient's condition after tumor regression, or, for example, prophylactic chemotherapy in patients at risk.

[0299] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form, which is a mixture of the compound of the present invention and a single composition. When administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially, or within a certain time interval (usually within 5 hours) from each other.

[0300] As used herein, the terms “combined,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent, in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising the compounds of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0301] The amounts of the compound of the present invention and additional therapeutic agents (in the case of a composition containing additional therapeutic agents as described above), which can be combined with a carrier material to produce a single dosage form, vary depending on the host being treated and the specific mode of administration. Preferably, the composition of the present invention should be formulated to allow the compound of the present invention to be administered at a drug dose of 0.01 to 100 mg / kg body weight / day.

[0302] In the case of these compositions containing additional therapeutic agents, the additional therapeutic agent and the compound of the present invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions is less than the amount required in monotherapy using only that therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a drug dose of 0.01 to 1,000 μg / kg body weight / day.

[0303] The amount of additional therapeutic agent present in the composition of the present invention will not exceed the amount that would normally be administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition of the present disclosure will be in the range of about 50% to about 100% of the amount that would normally be present in a composition containing that therapeutic agent as the sole therapeutic active agent. [Examples]

[0304] As shown in the following examples, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. While this general method illustrates the synthesis of a particular compound of the present invention, it will be understood that the following general method, and other methods known to those skilled in the art, may be applied to all the compounds described herein, as well as each of their subclasses and species. Example 1: (S)-4-fluoro-N-(1-(4-(2,2-dimethylpropylsulfonyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide(I-2). [ka]

[0305] Preparation of 1-(2,2-dimethylpropylsulfanyl)-4-nitrobenzene. [ka]

[0306] 1.5 g of 4-nitrobenzenethiol (9.67 mmol, 1.00 equivalent) and 1.89 g of 1-bromo-2,2-dimethylpropane (12.58 mmol, 1.30 equivalent) were dissolved in 30 mL of anhydrous N,N-dimethylformamide at room temperature. To this solution, 1.16 g of sodium hydride (60 wt.% dispersion in mineral oil; 29.0 mmol, 3.00 equivalent) was added all at once. The reaction mixture was stirred at 70°C for 5 hours. Then, it was poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layer was washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (silica gel, petroleum ether:ethyl acetate (1:3, v:v)) yielded 1.6 g of 1-(2,2-dimethylpropylsulfanyl)-4-nitrobenzene as a yellow solid (yield 73%). MS (ESI + ) m / z 226 [M+H] + .

[0307] Preparation of 1-(2,2-dimethylpropylsulfinyl)-4-nitrobenzene. [ka]

[0308] To a solution of 0.75 g of 1-(2,2-dimethyl-propylsulfinyl)-4-nitrobenzene (3.30 mmol, 1.00 equivalent) dissolved in 30 mL of acetonitrile:water (5:1), 1.02 g of Oxon (1.65 mmol, 0.50 equivalent) was added all at once. The reaction mixture was stirred at room temperature for 1 hour, then poured into 50 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layer was washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (silica gel, dichloromethane:methanol (20:1, v:v)) yielded 0.70 g of 1-(2,2-dimethyl-propylsulfinyl)-4-nitrobenzene as a yellow solid (yield 87%). MS (ESI + ) m / z 242 [M+H] + .

[0309] Preparation of 4-(2,2-dimethylpropylsulfinyl)aniline. [ka]

[0310] To a solution of 0.30 g of 1-(2,2-dimethyl-propylsulfinyl)-4-nitrobenzene (1.24 mmol, 1.00 equivalent) in methanol, palladium-activated carbon (50 mg wet catalyst, 10 wt.% palladium dry base) was added. The mixture was placed under hydrogen gas via a balloon and stirred at 40°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (silica gel, petroleum ether:ethyl acetate (3:1, v:v)) yielded 187 mg of 4-(2,2-dimethyl-propylsulfinyl)aniline as a white solid (yield 71%). MS (ESI + ) m / z 212 [M+H] + .

[0311] Preparation of 4-fluoro-N-((2S)-1-(4-(2,2-dimethyl-propylsulfinyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide. [ka]

[0312] To a solution prepared by dissolving 187 mg of 4-(2,2-dimethylpropylsulfinyl)aniline (0.88 mmol, 1.00 equivalent) and 254 mg of (4-fluorobenzoyl)-L-phenylalanine (0.88 mmol, 1.00 equivalent) in 5 mL of anhydrous N,N-dimethylformamide at room temperature, 185 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.96 mmol, 1.10 equivalent), 131 mg of 1-hydroxybenzotriazole (0.96 mmol, 1.10 equivalent), and 227 mg of N,N-diisopropylethylamine (1.76 mmol, 2.00 equivalent) were sequentially added. The reaction mixture was then stirred at room temperature for 16 hours and poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (silica gel, dichloromethane:ethyl acetate (2:1, v:v)) yielded 150 mg of 4-fluoro-N-((2S)-1-(4-(2,2-dimethyl-propylsulfinyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide as a white solid (yield 35%). MS (ESI + ) m / z 481 [M+H] + .

[0313] Preparation of (S)-4-fluoro-N-(1-(4-(2,2-dimethylpropylsulfonyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-2). [ka]

[0314] 100 mg of 4-fluoro-N-((2S)-1-(4-(2,2-dimethyl-propylsulfinyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (0.20 mmol, 1.00 equivalent) was dissolved in 15 mL of acetonitrile:water (5:1), to which 128 mg of oxone (0.20 mmol, 1.00 equivalent) was added all at once. The reaction mixture was stirred at 60°C for 1 hour, and then poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. Purification by preparative scale HPLC yielded 70 mg of (S)-4-fluoro-N-(1-(4-2,2-dimethylpropylsulfonyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-2) as a white solid (yield 68%). MS (ESI + ) m / z 497 [M+H] + , 1 H NMR (400 MHz, d6-DMSO) δ 10.69 (s, 1H), 8.90 (d, J = 7.9 Hz, 1H), 7.89 (dd, J = 8.8, 5.5 Hz, 2H), 7.83 (s, 4H), 7.39 (d, J = 7.4 Hz, 2H), 7.33 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.91 - 4.70 (m, 1H), 3.20 (s, 2H), 3.18 - 3.04 (m, 2H), 1.03 (s, 9H).

[0315] Example 2a: (S)-N-(1-(4-(N-ethylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-5). [ka] Preparation of (S)-tert-butyl 1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropane-2-ylcarbamate. [ka]

[0316] A mixture of 2.65 g of (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (10.0 mmol, 1.0 equivalent), 2.15 g of 4-(benzylthio)aniline (10.0 mmol, 1.00 equivalent), 2.88 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (15.0 mmol, 1.50 equivalent), 1.62 g of 1-hydroxybenzotriazole (12.0 mmol, 1.2 equivalent), and 2.58 g of N,N-diisopropylethylamine (20.0 mmol, 2.00 equivalent) in 20 mL of N,N-dimethylformamide was stirred overnight at room temperature. The mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (5:1, v:v)) to obtain 3.70 g of (S)-tert-butyl 1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropane-2-ylcarbamate as a pale yellow solid (yield 80%). MS (ESI + ) m / z 463.1 [M+H] + .

[0317] Preparation of (S)-2-amino-N-(4-(benzylthio)phenyl)-3-phenylpropanamide, hydrochloride salt. [ka]

[0318] 2.31 g of (S)-tert-butyl 1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropane-2-ylcarbamate (5.00 mmol, 1.00 equivalent) was dissolved in 20 mL of hydrochloric acid (4.0 M HCl) in dioxane and stirred at room temperature for 3 hours. The mixture was concentrated to obtain 1.81 g of (S)-2-amino-N-(4-(benzylthio)phenyl)-3-phenylpropanamide hydrochloride as a pale yellow solid (100% yield). MS (ESI + ) m / z 363.1 [M+H] + .

[0319] Preparation of (S)-N-(1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide [ka]

[0320] A mixture of 3.62 g of (S)-2-amino-N-(4-(benzylthio)phenyl)-3-phenylpropanamide hydrochloride (10.0 mmol, 1.00 equivalent), 1.40 g of 4-fluorobenzoic acid (10.0 mmol, 1.0 equivalent), 2.88 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (15.0 mmol, 1.50 equivalent), 1.62 g of 1-hydroxybenzotriazole (12.0 mmol, 1.2 equivalent), and 2.58 g of N,N-diisopropylethylamine (20.0 mmol, 2.00 equivalent) in 30 mL of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (5:1, v:v)) to obtain 3.87 g of (S)-N-(1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide as a pale yellow solid (yield 80%). MS (ESI + ) m / z 363.1 [M+H] + .

[0321] Preparation of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride [ka]

[0322] To a solution of 2.42 g of (S)-N-(1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (5.00 mmol, 1.00 equivalent), 60 mg of acetic acid (1.0 mmol, 0.2 equivalent), and 18 mg of water (1.0 mmol, 0.2 equivalent) in 30 mL of dichloromethane, 2.66 g of N-chlorosuccinimide (20.0 mmol, 4.00 equivalent) was added at 0°C. The mixture was stirred at room temperature for 1 hour and washed with 3 × 20 mL of water. The organic phase was concentrated to obtain 1.61 g of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride as a white solid (yield 70%). MS (ESI + ) m / z 461.1 [M+H] + .

[0323] Preparation of (S)-N-(1-(4-(N-ethylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-5). [ka]

[0324] To a mixture of 50 mg of ethanolamine (1.1 mmol, 5.0 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was purified by preparative scale HPLC to obtain 25.0 mg of (S)-N-(1-(4-(N-ethylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-5) as a white solid (yield 24%). MS (ESI + ) m / z 470.1 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.85 (d, J = 7.8 Hz, 1H), 7.87 (dt, J = 17.6, 8.8 Hz, 2H), 7.83 - 7.66 (m, 4H), 7.41 (dd, J = 12.7, 6.7 Hz, 3H), 7.31 - 7.20 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.91 - 4.70 (m, 1H), 3.19 - 2.99 (m, 2H), 2.80 - 2.66 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0325] Example 2b: (S)-4-fluoro-N-(1-(4-(N-(1-fluoro-2-methylpropan-2-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide(I-10). [ka] Preparation of (S)-4-fluoro-N-(1-(4-(N-(1-fluoro-2-methylpropan-2-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-10).

[0326] To a mixture of 100 mg of 1-fluoro-2-methylpropan-2-amine (1.10 mmol, 5.00 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was purified by preparative scale HPLC to obtain 25.0 mg of (S)-4-fluoro-N-(1-(4-(N-(1-fluoro-2-methylpropan-2-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-10) as a white solid (yield 22%). MS (ESI + ) m / z 516.1 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.59 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.96 - 7.80 (m, 2H), 7.76 (s, 4H), 7.66 (s, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.33 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 5.00 - 4.62 (m, 1H), 4.21 (s, 1H), 4.09 (s, 1H), 3.11 (qd, J = 13.7, 7.6 Hz, 2H), 1.04 (d, J = 1.8 Hz, 6H).

[0327] Example 2c: (S)-N-(1-(4-(N-bicyclo[1.1.1]pentan-1-ylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-11). [ka] Preparation of (S)-N-(1-(4-(N-bicyclo[1.1.1]pentan-1-ylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-11).

[0328] To a mixture of 91.3 mg of bicyclo[1.1.1]pentan-1-amine (1.10 mmol, 5.00 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was purified by preparative scale HPLC to obtain 25.0 mg of (S)-N-(1-(4-(N-bicyclo[1.1.1]pentan-1-sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-11) as a white solid (yield 22%). MS (ESI + ) m / z 508.1 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.46 (s, 1H), 7.95 - 7.83 (m, 2H), 7.76 (dd, J = 22.1, 8.9 Hz, 2H), 7.42 (dd, J = 21.9, 10.1 Hz, 2H), 7.34 - 7.20 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.92 - 4.70 (m, 1H), 3.11 (qd, J = 13.7, 7.7 Hz, 2H), 2.24 (s, 1H), 1.68 (s, 6H).

[0329] Example 2d: (S)-4-fluoro-N-(1-(4-(N-oxetane-3-ylsulfamoyl)phenylamino)-1-oxo-3-phenylpropane-2-yl)benzamide (I-64). Preparation of (S)-4-fluoro-N-(1-(4-(N-oxetan-3-ylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-64). [ka]

[0330] To a mixture of 198 mg of oxetane-3-amine (2.71 mmol, 5.0 equivalents) and 350 mg of N,N-diisopropylethylamine (2.71 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 250 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.54 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. An 800 μL concentrated solution of the crude product dissolved in DMSO was injected into a 10 μm C18 reverse-phase XBridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 45-95% acetonitrile in water containing 10 mmol / L of ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 1 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 80 mg of (S)-4-fluoro-N-(1-(4-(N-oxetan-3-ylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-64) as a white solid (yield 30%). MS (ESI + ) m / z 498 [M+H] + . 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H), 7.94 - 7.87 (m, 2H), 7.81 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.7 Hz, 2H), 7.29 (dd, J = 14.3, 7.4 Hz, 4H), 7.18 (t, J = 7.3 Hz, 1H), 4.82 (d, J = 13.7 Hz, 1H), 4.49 (t, J = 6.7 Hz, 2H), 4.36 (s, 1H), 4.24 (t, J = 6.2 Hz, 2H), 3.21 - 3.02 (m, 2H)

[0331] Example 2e: (S)-N-(1-(4-(N-cyclopropylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-6). Preparation of (S)-N-(1-(4-(N-cyclopropylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide [ka]

[0332] To a mixture of 63 mg of cyclopropanamine (1.1 mmol, 5.0 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A 500 μL concentrated solution of the crude product dissolved in DMSO was injected into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 2 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 50.0 mg of (S)-N-(1-(4-(N-cyclopropylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-6) as a white solid (yield 48%). MS (ESI + ) m / z 482 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 8.8, 5.6 Hz, 2H), 7.84 - 7.66 (m, 5H), 7.46 - 7.33 (m, 2H), 7.33 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.82 (td, J = 9.9, 5.0 Hz, 1H), 3.20 - 2.97 (m, 2H), 2.06 (d, J = 4.0 Hz, 1H), 0.48 - 0.39 (m, 2H), 0.36 - 0.24 (m, 2H).

[0333] Example 2f: (S)-N-(1-(4-(N-cyclobutylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-7). Preparation of (S)-N-(1-(4-(N-cyclobutylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide [ka]

[0334] To a mixture of 78 mg of cyclobutanamine (1.1 mmol, 5.0 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. 850 μL of the concentrated crude product dissolved in DMSO was injected into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 6 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 35.0 mg of (S)-N-(1-(4-(N-cyclobutylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-7) as a white solid (yield 32%). MS (ESI + ) m / z 496 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.59 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 8.8, 5.6 Hz, 2H), 7.82 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 8.9 Hz, 2H), 7.70 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 7.3 Hz, 2H), 7.31 - 7.20 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.86 - 4.76 (m, 1H), 3.64 - 3.49 (m, 1H), 3.19 - 3.00 (m, 2H), 1.86 (m, 2H), 1.75 - 1.56 (m, 2H), 1.55 - 1.33 (m, 2H).

[0335] Example 2g: (S)-N-(1-(4-(N-cyclopentylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-8). Preparation of (S)-N-(1-(4-(N-cyclopentylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide [ka]

[0336] To a mixture of 94 mg of cyclopentanamine (1.1 mmol, 5.0 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 950 μL volume into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 53-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 4 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 30.0 mg of (S)-N-(1-(4-(N-cyclopentylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-8) as a white solid (yield 27%). MS (ESI + ) m / z 510 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.89 (dd, J = 8.8, 5.5 Hz, 2H), 7.75 (dd, J = 20.3, 8.9 Hz, 4H), 7.49 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 7.3 Hz, 2H), 7.32 - 7.22 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.87 - 4.76 (m, 1H), 3.40 - 3.32 (m, 1H), 3.20 - 2.99 (m, 2H), 1.51 (m, 4H), 1.40 - 1.15 (m, 4H).

[0337] Example 2h: (S)-4-fluoro-N-(1-(4-(N-(1-methylazetidine-3-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropane-2-yl)benzamide(I-65). Preparation of (S)-4-fluoro-N-(1-(4-(N-(1-methylazetidine-3-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-65). [ka]

[0338] To a mixture of 233 mg of 1-methylazetidine-3-amine (2.71 mmol, 5.0 equivalents) and 350 mg of N,N-diisopropylethylamine (2.71 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 250 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.54 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 500 μL volume into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 38-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 30 mg of (S)-4-fluoro-N-(1-(4-(N-(1-methylazetidine-3-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropane-2-yl)benzamide (I-65) as a white solid (yield 11%). MS (ESI + ) m / z 511 [M+H] + . 1H NMR (400 MHz, d6-DMSO) δ 10.64 (s, 1H), 8.90 (d, J = 7.7 Hz, 1H), 8.03 (s, 1H), 7.94 - 7.87 (m, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.4 Hz, 2H), 7.29 (dd, J = 14.2, 7.4 Hz, 4H), 7.18 (t, J = 7.1 Hz, 1H), 4.84 (s, 1H), 3.65 (s, 1H), 3.25 (s, 2H), 3.17 - 3.09 (m, 2H), 2.55 (t, J = 6.9 Hz, 2H), 2.08 (s, 3H).

[0339] Example 2i: (S)-N-(1-(4-(N-(cyclopropylmethyl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-9). Preparation of (S)-N-(1-(4-(N-(cyclopropylmethyl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide [ka]

[0340] To a mixture of 78 mg of cyclopropylmethane (1.1 mmol, 5.0 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. An 800 μL concentrated solution of the crude product dissolved in DMSO was injected into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 4 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 30.0 mg of (S)-N-(1-(4-(N-(cyclopropylmethyl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-9) as a white solid (yield 28%). MS (ESI + ) m / z 496 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.59 (s, 1H), 8.85 (d, J = 7.8 Hz, 1H), 7.88 (dd, J = 8.8, 5.5 Hz, 2H), 7.75 (dd, J = 21.2, 8.9 Hz, 4H), 7.59 (t, J = 5.9 Hz, 1H), 7.39 (d, J = 7.3 Hz, 2H), 7.33 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.82 (td, J = 10.0, 5.2 Hz, 1H), 3.20 - 2.96 (m, 2H), 2.61 (dd, J = 16.2, 9.8 Hz, 2H), 0.90 - 0.67 (m, 1H), 0.42 - 0.18 (m, 2H), 0.04 (q, J = 4.5 Hz, 2H).

[0341] Example 2j: N-((S)-1-((4-(N-((R)-sec-butyl)sulfamoyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-12). Preparation of N-((S)-1-((4-(N((R)-sec-butyl)sulfamoyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-12) [ka]

[0342] To a mixture of 80 mg of (R)-butane-2-amine (1.10 mmol, 5.00 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 700 μL into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 5 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 40.0 mg of N-((S)-1-((4-(N-((R)-sec-butyl)sulfamoyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-12) as a white solid (yield 37%). MS (ESI + ) m / z 498 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.58 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.93 - 7.84 (m, 2H), 7.75 (q, J = 8.9 Hz, 4H), 7.39 (d, J = 7.5 Hz, 3H), 7.32 - 7.22 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.86 - 4.76 (m, 1H), 3.22 - 2.90 (m, 3H), 1.27 (p, J = 7.3 Hz, 2H), 0.84 (d, J = 6.6 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H).

[0343] Example 2k: 4-Fluoro-N-((S)-1-oxo-3-phenyl-1-(4-(N-((S)-1,1,1-trifluoropropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide(I-13). Preparation of 4-fluoro-N-((S)-1-oxo-3-phenyl-1-(4-(N-((S)-1,1,1-trifluoropropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-13). [ka]

[0344] To a mixture of 124 mg of (S)-1,1,1-trifluoropropan-2-amine (1.10 mmol, 5.00 equivalents) in 10 mL of pyridine, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred overnight at room temperature and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 700 μL into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 20.0 mg of 4-fluoro-N-((S)-1-oxo-3-phenyl-1-(4-(N-((S)-1,1,1-trifluoropropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-13) as a white solid (yield 17%). MS (ESI+) m / z 538 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.63 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.36 (s, 1H), 7.95 - 7.84 (m, 2H), 7.84 - 7.72 (m, 4H), 7.39 (d, J = 7.2 Hz, 2H), 7.33 - 7.20 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.87 - 4.75 (m, 1H), 4.26 - 3.69 (m, 1H), 3.11 (qd, J = 13.6, 7.5 Hz, 2H), 0.95 (d, J = 6.9 Hz, 3H).

[0345] Example 2l: N-((S)-1-(4-(N-((R)-1-cyclopropylethyl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-67). Preparation of N-((S)-1-(4-N-((R)-1-cyclopropylethyl)sulfamoyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-67). [ka]

[0346] To a mixture of 94 mg of (R)-1-cyclopropylethanamine (1.10 mmol, 5.00 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 700 μL into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 55-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 50.0 mg of N-((S)-1-(4-(N-((R)-1-cyclopropylethyl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-67) as a white solid (yield 44%). MS (ESI + ) m / z 510 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.57 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.93 - 7.82 (m, 2H), 7.74 (q, J = 9.0 Hz, 4H), 7.54 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.33 - 7.19 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.87 - 4.75 (m, 1H), 3.10 (qd, J = 13.7, 7.6 Hz, 2H), 2.55 (dd, J = 14.3, 7.4 Hz, 1H), 0.92 (d, J = 6.6 Hz, 3H), 0.80 - 0.60 (m, 1H), 0.38 - 0.24 (m, 1H), 0.24 - 0.13 (m, 1H), 0.09 (td, J = 9.4, 5.0 Hz, 1H), -0.08 (td, J = 9.5, 5.0 Hz, 1H).

[0347] Example 2m: (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)phenylamino)propan-2-yl)benzamide(I-23). Preparation of (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-23). [ka]

[0348] To a mixture of 109 mg of 2,2,2-trifluoroethaneamine (1.10 mmol, 5.00 equivalents) in 10 mL of pyridine, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC on a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 500 μL into a 10 μm C18 reverse-phase XBridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 1 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and freeze-dried to obtain 60.0 mg of (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-2,2,2-trifluoroethyl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-23) as a white solid (yield 53%). MS (ESI + ) m / z 524 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.86 (d, J = 7.8 Hz, 1H), 8.49 (t, J = 6.8 Hz, 1H), 7.88 (dd, J = 8.7, 5.6 Hz, 2H), 7.83 - 7.72 (m, 4H), 7.39 (d, J = 7.3 Hz, 2H), 7.32 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.82 (td, J = 9.9, 5.1 Hz, 1H), 3.72 - 3.52 (m, 2H), 3.18 - 2.97 (m, 2H).

[0349] Example 2n: (S)-4-fluoro-N-(1-oxo-1-(4-(N-tert-pentylsulfamoyl)phenylamino)-3-phenylpropan-2-yl)benzamide(I-24). Preparation of (S)-4-fluoro-N-(1-oxo-1-(4-(N-tert-pentylsulfamoyl)phenylamino)-3-phenylpropan-2-yl)benzamide (I-24). [ka]

[0350] To a mixture of 96 mg of 2-methylbutan-2-amine (1.10 mmol, 5.00 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 700 μL into a 10 μm C18 reverse-phase XBridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 45-95% acetonitrile in water containing 10 mmol / L of ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 40.0 mg of (S)-4-fluoro-N-(1-oxo-1-(4-(N-tert-pentylsulfamoyl)phenylamino)-3-phenylpropan-2-yl)benzamide (I-24) as a white solid (yield 35%). MS (ESI + ) m / z 512 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.57 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 8.7, 5.6 Hz, 2H), 7.75 (s, 4H), 7.39 (d, J = 7.3 Hz, 2H), 7.32 - 7.20 (m, 5H), 7.16 (t, J = 7.3 Hz, 1H), 4.81 (td, J = 9.9, 4.9 Hz, 1H), 3.21 - 2.99 (m, 2H), 1.40 (q, J = 7.4 Hz, 2H), 0.99 (s, 6H), 0.72 (t, J = 7.4 Hz, 3H).

[0351] Example 2o: (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-(1,1,1-trifluoro-2-methylpropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide(I-25). Preparation of (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-(1,1,1-2-trifluoro-2-methylpropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-25). [ka]

[0352] To a mixture of 140 mg of 1,1,1-trifluoro-2-methylpropan-2-amine (1.10 mmol, 5.00 equivalents) in 10 mL of pyridine, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred overnight at room temperature and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC on a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 500 μL into a 10 μm C18 reverse-phase XBridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L of ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 20.0 mg of (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-1,1,1-trifluoro-2-methylpropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-25) as a white solid (yield 17%). MS (ESI+) m / z 552 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.63 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H), 7.88 (dd, J = 8.8, 5.5 Hz, 2H), 7.78 (q, J = 9.0 Hz, 4H), 7.39 (d, J = 7.3 Hz, 2H), 7.32 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.87 - 4.76 (m, 1H), 3.20 - 3.00 (m, 2H), 1.23 (s, 6H).

[0353] Example 2p: 4-Fluoro-N-((S)-1-oxo-3-phenyl-1-(4-(N-((R)-1,1,1-trifluoropropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide(I-26). Preparation of 4-fluoro-N-((S)-1-oxo-3-phenyl-1-(4-(N-((R)-1,1,1-trifluoropropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-26). [ka]

[0354] To a mixture of 124 mg of (R)-1,1,1-trifluoropropan-2-amine (1.10 mmol, 5.00 equivalents) in 10 mL of pyridine, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred overnight at room temperature and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 300 μL into a 10 μm C18 reverse-phase XBridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 43-95% acetonitrile in water containing 10 mmol / liter ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 6 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 15.0 mg of 4-fluoro-N-((S)-1-oxo-3-phenyl-1-(4-(N-((R)-1,1,1-trifluoropropan-2-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-26) as a white solid (yield 13%). MS (ESI+) m / z 538 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.63 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.35 (s, 1H), 7.93 - 7.84 (m, 2H), 7.84 - 7.78 (m, 4H), 7.39 (d, J = 7.2 Hz, 2H), 7.32 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.87 - 4.75 (m, 1H), 3.98 (dt, J = 14.5, 7.2 Hz, 1H), 3.20 - 2.98 (m, 2H), 0.95 (d, J = 6.9 Hz, 3H).

[0355] Example 2q: N-((S)-1-(4-(N-((S)-1-cyclopropylethyl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-27). Preparation of N-((S)-1-(4-N-((S)-1-cyclopropylethyl)sulfamoyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-27). [ka]

[0356] To a mixture of 94 mg of (S)-1-cyclopropylethaneamine (1.10 mmol, 5.00 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 700 μL into a 10 μm C18 reverse-phase XBridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L of ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 25.0 mg of N-((S)-1-(4-(N-((S)-1-cyclopropylethyl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-27) as a white solid (yield 22%). MS (ESI + ) m / z 510 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.57 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.93 - 7.84 (m, 2H), 7.74 (q, J = 9.0 Hz, 4H), 7.55 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.34 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.82 (td, J = 10.1, 5.1 Hz, 1H), 3.22 - 2.99 (m, 2H), 2.54 (dt, J = 13.6, 6.8 Hz, 1H), 0.93 (d, J = 6.6 Hz, 3H), 0.81 - 0.61 (m, 1H), 0.36 - 0.24 (m, 1H), 0.24 - 0.13 (m, 1H), 0.09 (td, J = 9.3, 5.0 Hz, 1H), -0.05 - -0.19 (m, 1H).

[0357] Example 2r: N-((S)-1-((4-(N-((S)-sec-butyl)sulfamoyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-28). Preparation of N-((S)-1-((4-(N-((S)-sec-butyl)sulfamoyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-28). [ka]

[0358] To a mixture of 80 mg of (S)-butane-2-amine (1.10 mmol, 5.00 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.0 equivalent) was added. The mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 900 μL into a 10 μm C18 reverse-phase XBridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 50-95% acetonitrile in water containing 10 mmol / L of ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 25.0 mg of N-((S)-1-((4-(N-((S)-sec-butyl)sulfamoyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-28) as a white solid (yield 23%). MS (ESI + ) m / z 498 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.88 (d, J = 7.8 Hz, 1H), 7.91 (dd, J = 8.8, 5.5 Hz, 2H), 7.77 (q, J = 8.9 Hz, 4H), 7.41 (d, J = 7.6 Hz, 3H), 7.35 - 7.22 (m, 4H), 7.18 (t, J = 7.4 Hz, 1H), 4.88 - 4.79 (m, 1H), 3.09 (dtd, J = 20.6, 13.8, 5.8 Hz, 3H), 1.29 (p, J = 7.3 Hz, 2H), 0.86 (d, J = 6.6 Hz, 3H), 0.71 (t, J = 7.4 Hz, 3H).

[0359] Example 2s: (S)-4-fluoro-N-(1-(4-(N-methylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide(I-30). Preparation of (S)-4-fluoro-N-(1-(4-(N-methylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-30). [ka]

[0360] To a mixture of 34 mg of methaneamine (1.08 mmol, 5.0 equivalents) and 139 mg of N,N-diisopropylethylamine (1.08 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 600 μL into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 44-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 5 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 40 mg of (S)-4-fluoro-N-(1-(4-(N-methylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-30) as a white solid (40% yield). MS (ESI + ) m / z 456[M+H] + . 1H NMR (400 MHz, d6-DMSO) δ 10.61 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 8.9, 5.5 Hz, 2H), 7.80 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 7.1 Hz, 2H), 7.28 (ddd, J = 11.5, 9.2, 3.7 Hz, 5H), 7.17 (t, J = 7.3 Hz, 1H), 4.82 (dd, J = 15.3, 7.6 Hz, 1H), 3.17 - 3.02 (m, 2H), 2.37 (d, J = 5.0 Hz, 3H).

[0361] Example 2t: (S)-N-(1-(4-(N-cyclohexylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-31). Preparation of (S)-N-(1-(4-(N-cyclohexylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-31). [ka]

[0362] To a mixture of 108 mg of cyclohexaneamine (1.08 mmol, 5.0 equivalents) and 139 mg of N,N-diisopropylethylamine (1.08 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. An 800 μL concentrated solution of the crude product dissolved in DMSO was injected into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 58-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 6 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 44 mg of (S)-N-(1-(4-(N-cyclohexylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-31) as a white solid (yield 39%). MS (ESI + ) m / z 524 [M+H] + . 1 H NMR (400 MHz, d6-DMSO) δ 10.59 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 8.9, 5.5 Hz, 2H), 7.75 (q, J = 9.1 Hz, 4H), 7.50 (d, J = 7.4 Hz, 1H), 7.39 (d, J = 7.1 Hz, 2H), 7.34 - 7.21 (m, 4H), 7.16 (t, J = 7.4 Hz, 1H), 4.81 (m, 1H), 3.19 - 3.00 (m, 2H), 2.87 (s, 1H), 1.66 - 1.33 (m, 5H), 1.04 (m, 5H).

[0363] Example 2u: (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-phenylsulfamoyl)phenylamino)propan-2-yl)benzamide(I-32). Preparation of (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-phenylsulfamoyl)phenylamino)propan-2-yl)benzamide (I-32). [ka]

[0364] To a mixture of 100 mg of aniline (1.08 mmol, 5.0 equivalents) and 139 mg of N,N-diisopropylethylamine (1.08 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 775 μL into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 53-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 6 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 20 mg of (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-2-phenylsulfamoyl)phenylamino)propan-2-yl)benzamide (I-32) as a white solid (yield 18%). MS (ESI + ) m / z 518 [M+H] + . 1H NMR (400 MHz, d6-DMSO) δ 10.58 (s, 1H), 10.14 (s, 1H), 8.84 (d, J = 7.9 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.69 (q, J = 9.1 Hz, 4H), 7.37 (d, J = 7.2 Hz, 2H), 7.31 - 7.09 (m, 7H), 7.08 - 7.00 (m, 2H), 6.98 (t, J = 7.3 Hz, 1H), 4.84 - 4.73 (m, 1H), 3.16 - 2.98 (m, 2H).

[0365] Example 2v: (S)-4-fluoro-N-(1-(4-(N-(1-methylpiperidine-4-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-33). Preparation of (S)-4-fluoro-N-(1-(4-(N-(1-methylpiperidine-4-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-33). [ka]

[0366] To a mixture of 123 mg of 1-methylpiperidine-4-amine (1.08 mmol, 5.0 equivalents) and 139 mg of N,N-diisopropylethylamine (1.08 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 1000 μL volume into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 40-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 5 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 28 mg of (S)-4-fluoro-N-(1-(4-(N-(1-methylpiperidine-4-yl)sulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-33) as a white solid (yield 24%). MS (ESI + ) m / z 539 [M+H] + . 1H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 8.9, 5.5 Hz, 2H), 7.76 (q, J = 9.0 Hz, 4H), 7.57 (d, J = 7.1 Hz, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.32 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.81 (m, 1H), 3.17 - 3.02 (m, 2H), 2.83 (s, 1H), 2.58 (s, 2H), 2.06 (s, 3H), 1.80 (s, 2H), 1.48 (d, J = 11.3 Hz, 2H), 1.33 (dd, J = 20.4, 10.7 Hz, 2H).

[0367] Example 2w: (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-(tetrahydro-2H-pyran-4-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide(I-34). Preparation of (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-(tetrahydro-2H-pyran-4-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-34). [ka]

[0368] To a mixture of 109 mg of tetrahydro-2H-pyran-4-amine (1.08 mmol, 5.0 equivalents) and 139 mg of N,N-diisopropylethylamine (1.08 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.22 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 700 μL into a 10 μm C18 reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 43-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 5 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 38 mg of (S)-4-fluoro-N-(1-oxo-3-phenyl-1-(4-(N-tetrahydro-2H-pyran-4-yl)sulfamoyl)phenylamino)propan-2-yl)benzamide (I-34) as a white solid (yield 33%). MS (ESI + ) m / z 526 [M+H] + . 1 H NMR (400 MHz, d6-DMSO) δ 10.60 (s, 1H), 8.86 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 8.9, 5.5 Hz, 2H), 7.82 - 7.72 (m, 4H), 7.66 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 7.1 Hz, 2H), 7.34 - 7.23 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.81 (m, 1H), 3.69 (d, J = 11.2 Hz, 2H), 3.23 - 3.06 (m, 5H), 1.47 (d, J = 12.4 Hz, 2H), 1.36 - 1.23 (m, 2H).

[0369] Example 2x: (R)-N-(1-(4-(N-bicyclo[1.1.1]pentan-1-ylsulfamoyl)phenylamino)-1-oxo-3-phenylpropane-2-yl)-4-fluorobenzamide(I-99). Preparation of (R)-N-(1-(4-(N-bicyclo[1.1.1]pentan-1-ylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-99). [ka]

[0370] A mixture of 126 mg of bicyclo[1.1.1]pentane-1-amine hydrochloride (1.05 mmol, 5.0 equivalents) and 135.45 mg of N,N-diisopropylethylamine (1.05 mmol, 5.00 equivalents) in 10 mL of dichloromethane was mixed with 96.6 mg of (R)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.21 mmol, 1.00 equivalent). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with 10 mL of water and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: YMC-Actus Triart C18, 30*250 mm, 5 μm; Mobile phase: Water (10% NH4HCO3 + 0.1% NH3-H2O) and ACN (from 33% ACN to 55% for 7 minutes); UV detection 254 / 220 nm. The fractions containing the product were combined, partially evaporated under vacuum, and freeze-dried overnight to obtain 33.3 mg of (R)-N-(1-(4-(N-bicyclo[1.1.1]pentan-1-ylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-99) as a white solid (yield 31%). MS (ESI + ) m / z 508 [M+H] + ; 1H NMR (300 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.88 (d, 1H), 8.48 (s, 1H), 7.93-7.88 (m, 2H), 7.83-7.74 (m, 4H), 7.41 (d, 2H), 7.33-7.26 (m, 4H), 7.21-7.16 (m, 1H), 4.86-4.82 (m, 1H), 3.15-3.11 (m, 2H), 2.27 (s, 1H), 1.70 (s, 6H).

[0371] Example 3: N-((2S)-1-(4-(N-tert-butylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-15). [ka] Preparation of N-((2S)-1-(4-(N-tert-butylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-15).

[0372] To a solution of 200 mg of (S)-4-(2-(4-fluorobenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.43 mmol, 1.00 equivalent) and 434 mg of triethylamine (4.30 mmol, 10.0 equivalent) in 5.0 mL of dichloromethane at 0°C, 112 mg of triphenylphosphine (0.43 mmol, 1.00 equivalent) and 31.4 mg of 2-methylpropan-2-amine (0.43 mmol, 1.00 equivalent) in 5.0 mL of dichloromethane were added. After 2 hours, the mixture was concentrated and the residue was purified by preparative scale HPLC to obtain 8.0 mg of N-((2S)-1-(4-(N-tert-butylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-15) as a white solid (yield 3.8%). MS (ESI + ) m / z 408.1 [M-73] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.45 (d, J = 3.2 Hz, 1H), 8.82 (d, J = 7.8 Hz, 1H), 7.89 (dd, J = 8.7, 5.6 Hz, 2H), 7.74 (dd, J = 8.8, 3.0 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 7.33 - 7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 6.19 (d, J = 1.3 Hz, 1H), 4.83 (td, J = 9.9, 5.0 Hz, 1H), 3.20 - 2.98 (m, 2H), 1.27 (s, 9H).

[0373] Example 4: N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(4-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-22). [ka] Preparation of methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate. [ka]

[0374] To a solution of 1.77 g of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (10.0 mmol, 1.00 equivalent) in 50 mL of methanol, 5.95 g of thionyl chloride (50.0 mmol, 5.00 equivalent) was added at 0°C. The mixture was refluxed for 2 hours and concentrated to obtain 1.72 g of methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate as a pale yellow solid (yield 90%). MS (ESI + ) m / z 192.1 [M+H] + .

[0375] Preparation of 2-tert-butyl 3-methyl 3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate. [ka]

[0376] To a mixture of 1.91 g of methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (10.0 mmol, 1.00 equivalent) and 2.58 g of N,N-diisopropylethylamine (20.0 mmol, 2.00 equivalent), 2.18 g of di-tert-butyl dicarbonate (10.0 mmol, 1.00 equivalent) was added. The mixture was stirred overnight and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (3:1, v:v)) to obtain 2.32 g of 2-tert-butyl 3-methyl 3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate as a white solid (yield 80%). MS (ESI + ) m / z 292.1 [M+H] + .

[0377] Preparation of tert-butyl 3-(4-(N-tert-butylsulfamoyl)phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. [ka]

[0378] To a mixture of 1.45 g of 2-tert-butyl3-methyl3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (5.00 mmol, 1.00 equivalent) and 1.14 g of 4-amino-N-tert-butylbenzenesulfonamide (5.00 mmol, 1.00 equivalent) in 20.0 mL of dichloromethane, 10.0 mL of trimethylaluminum (2.0 M, 20.0 mmol, 4.00 equivalent) was added. The mixture was stirred overnight and poured into 30 mL of ice water. The mixture was extracted with 3 × 50 mL of ethyl acetate. The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (3:1, v:v)) to obtain 1.2 g of tert-butyl 3-(4-(N-tert-butylsulfamoyl)phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a pale yellow solid (yield 50%). MS (ESI + ) m / z 488.1 [M+H] + .

[0379] Preparation of N-(4-(N-tert-butylsulfamoyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide. [ka]

[0380] A mixture of 1.22 g of tert-butyl 3-(4-(N-tert-butylsulfamoyl)phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.50 mmol, 1.00 equivalent) in 20 mL of dioxane hydrochloric acid (4.0 M HCl) was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum to obtain 967 mg of N-(4-(N-tert-butylsulfamoyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide as a white solid (100% yield). MS (ESI + ) m / z 388.1 [M+H] + .

[0381] Preparation of N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(4-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-22). [ka]

[0382] A mixture of 194 mg of (S)-2-amino-N-(4-(benzylthio)phenyl)-3-phenylpropanamide (0.50 mmol, 1.00 equivalent), 70 mg of 4-fluorobenzoic acid (0.50 mmol, 1.00 equivalent), 144 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.75 mmol, 1.50 equivalent), 81 mg of 1-hydroxybenzotriazole (0.60 mmol, 1.2 equivalent), and 129 mg of N,N-diisopropylethylamine (1.00 mmol, 2.00 equivalent) in 10 mL of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 50 mL of ethyl acetate and washed with 3 × 40 mL of water. The organic phase was concentrated, and the residue was purified by preparative scale HPLC to obtain 25.0 mg of N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(4-fluorobenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-22) as a white solid (yield 10%). MS (ESI + ) m / z 388.1 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.58-7.81 (m, 5H), 7.03-7.49 (m, 7H), 4.62-4.74 (m, 2H), 3.75-3.42 (m, 1H), 3.20-3.26 (m, 2H), 1.15 (s, 9H).

[0383] Example 5: (S)-N-1-(4-(N-tert-butylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluoro-N-methylbenzamide (I-35). [ka] Preparation of (S)-2-(tert-butoxycarbonyl(methyl)amino)-3-phenylpropanoic acid. [ka]

[0384] To a solution of 2.65 g of (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (prepared in the same manner as in Example 1, 10.0 mmol, 1.00 equivalent) in 20 mL of tetrahydrofuran, 0.80 g of sodium hydride (60 wt.% dispersion in mineral oil, 20.0 mmol, 2.0 equivalent) was added at 0°C, and the mixture was stirred for 30 minutes. Then, 2.84 g of iodomethane (20.0 mmol, 2.00 equivalent) was added, and the reaction was stirred overnight at room temperature. The mixture was poured into 30 mL of saturated ammonium chloride aqueous solution and extracted with 3 × 50 mL of ethyl acetate. The combined organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (5:1, v:v)) to obtain 2.23 g of (S)-2-(tert-butoxycarbonyl(methyl)amino)-3-phenylpropanoic acid as a pale yellow solid (yield 80%). MS (ESI + ) m / z 280.1 [M+H] + .

[0385] Preparation of (S)-tert-butyl 1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropan-2-yl(methyl)carbamate. [ka]

[0386] A mixture of 2.79 g of (S)-2-(tert-butoxycarbonyl(methyl)amino)-3-phenylpropanoic acid (10.0 mmol, 1.00 equivalent), 2.15 g of 4-(benzylthio)aniline (10.0 mmol, 1.00 equivalent), 2.88 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (15.0 mmol, 1.50 equivalent), 1.62 g of 1-hydroxybenzotriazole (12.0 mmol, 1.20 equivalent), and 2.58 g of N,N-diisopropylethylamine (20.0 mmol, 2.00 equivalent) in 20 mL of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (5:1, v:v)) to obtain 3.80 g of (S)-tert-butyl 1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropane-2-ylcarbamate as a pale yellow solid (yield 80%). MS (ESI + ) m / z 477.1 [M+H] + .

[0387] Preparation of (S)-N-(4-(benzylthio)phenyl)-2-(methylamino)-3-phenylpropanamide. [ka]

[0388] A mixture of 2.38 g of (S)-tert-butyl 1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropane-2-ylcarbamate (5.0 mmol, 1.0 equivalent) in 20 mL of dioxane hydrochloric acid (4.0 M HCl) was stirred at room temperature for 3 hours. The mixture was concentrated to obtain 1.88 g of (S)-N-(4-(benzylthio)phenyl)-2-(methylamino)-3-phenylpropanamide as a pale yellow solid (100% yield). MS (ESI + ) m / z 377.1 [M+H] + .

[0389] Preparation of (S)-N-(1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluoro-N-methylbenzamide. [ka]

[0390] A mixture of 3.76 g of (S)-N-(4-(benzylthio)phenyl)-2-(methylamino)-3-phenylpropanamide (10.0 mmol, 1.00 equivalent), 1.40 g of 4-fluorobenzoic acid (10.0 mmol, 1.00 equivalent), 2.88 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (15.0 mmol, 1.50 equivalent), 1.62 g of 1-hydroxybenzotriazole (12.0 mmol, 1.20 equivalent), and 2.58 g of N,N-diisopropylethylamine (20.0 mmol, 2.00 equivalent) in 30 mL of N,N-dimethylformamide was stirred overnight at room temperature. 100 mL of ethyl acetate was added to the mixture, and it was washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (5:1, v:v)) to obtain 3.98 g of (S)-N-(1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluoro-N-methylbenzamide as a pale yellow solid (yield 80%). MS (ESI + ) m / z 499.1 [M+H] + .

[0391] Preparation of (S)-4-(2-(4-fluoro-N-methylbenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride. [ka]

[0392] To a solution of 2.49 g of (S)-N-(1-(4-(benzylthio)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluoro-N-methylbenzamide (5.00 mmol, 1.00 equivalent), 60 mg of acetic acid (1.0 mmol, 0.2 equivalent), and 18 mg of water (1.0 mmol, 0.2 equivalent) in 30 mL of dichloromethane, 2.66 g of N-chlorosuccinimide (20.0 mmol, 4.00 equivalent) was added at 0°C. The mixture was stirred at room temperature for 1 hour and washed with 3 × 20 mL of water. The organic phase was concentrated to obtain 1.65 g of (S)-4-(2-(4-fluoro-N-methylbenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride as a white solid (yield 70%). MS (ESI + ) m / z 475.1 [M+H] + .

[0393] Preparation of (S)-N-1-(4-(N-tert-butylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluoro-N-methylbenzamide (I-35). [ka]

[0394] To a mixture of 50 mg of 2-methylpropan-2-amine (1.1 mmol, 5.0 equivalents) and 142 mg of N,N-diisopropylethylamine (1.10 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 100 mg of (S)-4-(2-(4-fluoro-N-methylbenzamide)-3-phenylpropanamide)benzene-1-sulfonyl chloride (0.21 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative scale HPLC to obtain 25.0 mg of (S)-N-(1-(4-(N-tert-butylsulfamoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluoro-N-methylbenzamide (I-35) as a white solid (yield 23%). MS (ESI + ) m / z 512.1 [M+H] +; 1 H NMR (400 MHz, d6-DMSO) δ 10.2 (brs, 1H), 7.78 (s, 4H), 7.16-7.34 (m, 10H), 5.16-5.46 (m, 1H), 3.35-3.37 (m, 1H), 3.13-3.17 (m, 1H), 2.93 (s, 3H), 1.12 (s, 9H).

[0395] Example 6: Preparation of 4-fluoro-N-((2S)-1-(4-(neopentylsulfinyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-4). Preparation of 4-fluoro-N-((2S)-1-(4-(neopentylsulfinyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide. [ka]

[0396] To a solution prepared by dissolving 200 mg of 4-(neopentylsulfinyl)aniline (0.95 mmol, 1.00 equivalent) and 272 mg of (S)-2-(4-fluorobenzamide)-3-phenylpropanoic acid (0.95 mmol, 1.00 equivalent) in 5 mL of anhydrous N,N-dimethylformamide at room temperature, 201 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.05 mmol, 1.10 equivalent), 142 mg of 1-hydroxybenzotriazole (1.05 mmol, 1.10 equivalent), and 245 mg of N,N-diisopropylethylamine (1.90 mmol, 2.00 equivalent) were added sequentially. The reaction mixture was then stirred at room temperature for 16 hours and poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC on a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 500 μL into a 10 μm C18 reverse-phase X-Bridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 48–95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 1 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and freeze-dried to obtain 150 mg of 4-fluoro-N-((2S)-1-(4-(neopentylsulfinyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)benzamide (I-4) as a white solid (yield 33%). MS (ESI + ) m / z 481 [M+H] + . 1H NMR (400 MHz, d6-DMSO) δ 10.59 (s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 7.89 (dd, J = 8.8, 5.6 Hz, 2H), 7.80 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 7.3 Hz, 2H), 7.31 - 7.20 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 4.82 (td, J = 9.8, 5.1 Hz, 1H), 3.19 - 3.02 (m, 2H), 2.71 - 2.56 (m, 2H), 1.10 (s, 9H).

[0397] Example 7: (S)-N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanamide (I-84). [ka] Preparation of (S)-methyl 2-(2-(1-methoxy-1-oxo-3-phenylpropane-2-ylamino)ethyl)benzoate. [ka]

[0398] A solution of 600 mg of methyl 2-(2-bromoethyl)benzoate (2.5 mmol, 1.0 equivalent), 531 mg of (S)-methyl 2-amino-3-phenylpropanoate hydrochloride (2.5 mmol, 1.0 equivalent), and 645 mg of ethyl diisopropylamine (5.0 mmol, 2.0 equivalent) in N,N-dimethylformamide (20 mL) was heated overnight at 80°C. The reaction mixture was diluted with 50 mL of ethyl acetate and washed with 3 × 40 mL of water. The organic phase was concentrated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate (15:1, v:v)) to obtain 250 mg of (S)-methyl 2-(2-(1-methoxy-1-oxo-3-phenylpropane-2-ylamino)ethyl)benzoate as a colorless oil (yield 29%). MS (ESI+) m / z 342 [M+H]+.

[0399] Preparation of (S)-methyl 2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanoate. [ka]

[0400] A solution of 250 mg of (S)-methyl 2-(2-(1-methoxy-1-oxo-3-phenylpropane-2-ylamino)ethyl)benzoate (0.73 mmol, 1.00 equivalent) and 18 mg of 4-dimethylaminopyridine (0.15 mmol, 0.2 equivalent) in 50 mL of ethanol was refluxed for 3 days. The mixture was concentrated, and the compound was purified by column chromatography (silica gel, petroleum ether:ethyl acetate (15:1, v:v)) to obtain 75 mg of (S)-methyl 2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanoate as a colorless oil (yield 33%). MS (ESI + ) m / z 310 [M+H] + .

[0401] Preparation of (S)-2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanoic acid. [ka]

[0402] A solution of 75 mg of (S)-methyl 2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanoate (0.24 mmol, 1.00 equivalent) and 19 mg of sodium hydroxide (0.48 mmol, 2.00 equivalent) in 10.0 mL of methanol was stirred at room temperature for 3 hours. The mixture was concentrated and 10 mL of hydrochloric acid (0.1 M) was added. The mixture was extracted with 3 × 10 mL of ethyl acetate. The combined organic layer was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (1:1, v:v)) to obtain 50 mg of (S)-2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanoic acid as a white solid (yield 70%). MS (ESI + ) m / z 296 [M+H] + .

[0403] Preparation of (S)-N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanamide (I-84). [ka]

[0404] 31 mg of (S)-2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanoic acid (0.105 mmol, 1.0 equivalent) and 28.73 mg of 4-amino-N-tert-butylbenzenesulfonamide (0.126 mmol, 1.20 equivalents) were mixed in 3 mL of pyridine, to which 40 mg of EDCI (0.21 mmol, 2.00 equivalents) was added. The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted in 10 mL of water, and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: Column: YMC-Actus Triart C18, 30*250 mm, 5 μm; Mobile phase: Water (10% NH4HCO3) and ACN (from 25% ACN to 45% for 7 minutes); UV detection 254 / 220 nm. The fractions containing the product were combined, partially evaporated under vacuum, and freeze-dried overnight to obtain 18.1 mg of (S)-N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(1-oxo-3,4-dihydroisoquinoline-2(1H)-yl)-3-phenylpropanamide (I-84) as a white solid (yield 34.07%). MS (ESI + ) m / z 506 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.90 (d, 1H), 7.84-7.76 (m, 4H), 7.48-7.44 (m, 1H), 7.37-7.18 (m, 7H), 5.72 (dd, 1H), 3.85-3.78 (m, 1H), 3.74-3.68 (m, 1H), 3.54-3.47 (m, 1H), 3.29-3.24 (m, 1H), 2.97-2.88 (m, 1H), 2.78-2.70 (m, 1H), 1.20 (s, 9H).

[0405] Example 8: (S)-N-(1-(4-(N-tert-butylsulfamoyl)phenylamino)-3-(1H-indole-3-yl)-1-oxopropan-2-yl)-4-fluorobenzamide(I-1). [ka] Preparation of (S)-ethyl 2-(4-fluorobenzamide)-3-(1H-indole-3-yl)propanoate. [ka]

[0406] To a solution prepared by dissolving 2 g of (S)-ethyl 2-amino-3-(1H-indole-3-yl)propanoate hydrochloride (7.5 mmol, 1.00 equivalent) and 1.0 g of 4-fluorobenzoic acid (7.5 mmol, 1.00 equivalent) in 25 mL of anhydrous N,N-dimethylformamide at room temperature, 1.58 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (8.2 mmol, 1.10 equivalent), 1.1 g of 1-hydroxybenzotriazole (8.2 mmol, 1.10 equivalent), and 1.94 g of N,N-diisopropylethylamine (15.0 mmol, 2.00 equivalent) were added sequentially. The reaction mixture was then stirred at room temperature for 16 hours and poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (silica gel, dichloromethane:ethyl acetate (4:1, v:v)) yielded 1.9 g of (S)-ethyl 2-(4-fluorobenzamide)-3-(1H-indole-3-yl)propanoate as a white solid (yield 72%). MS (ESI + ) m / z 355 [M+H] + .

[0407] Preparation of (S)-2-(4-fluorobenzamide)-3-(1H-indole-3-yl)propanoic acid. [ka]

[0408] To a solution of 1.9 g of (S)-ethyl 2-(4-fluorobenzamide)-3-(1H-indole-3-yl)propanoate (5.4 mmol, 1.00 equivalent) in 20 mL of methanol:H2O (5:1, v:v), 258 mg of lithium hydroxide (10.8 mmol, 2.00 equivalent) was added and stirred at room temperature for 6 hours. The mixture was concentrated, 100 mL of water was added, and the pH was adjusted to 6 with 6 M HCl. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (silica gel, dichloromethane:ethyl acetate (2:1, v:v)) yielded 1.5 g of (S)-2-(4-fluorobenzamide)-3-(1H-indole-3-yl)propanoic acid as a white solid (yield 86%). MS (ESI + ) m / z 327[M+H] + .

[0409] Preparation of (S)-N-(1-(4-(N-tert-butylsulfamoyl)phenylamino)-3-(1H-indole-3-yl)-1-oxopropan-2-yl)-4-fluorobenzamide (I-1). [ka]

[0410] To a solution prepared by dissolving 100 mg of 4-amino-N-tert-butylbenzenesulfonamide (0.44 mmol, 1.00 equivalent) and 143 mg of (S)-2-(4-fluorobenzamide)-3-phenylpropanoic acid (0.44 mmol, 1.00 equivalent) in 5 mL of anhydrous N,N-dimethylformamide at room temperature, 93 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.48 mmol, 1.10 equivalent), 65 mg of 1-hydroxybenzotriazole (0.48 mmol, 1.10 equivalent), and 114 mg of N,N-diisopropylethylamine (0.88 mmol, 2.00 equivalent) were added sequentially. The reaction mixture was then stirred at room temperature for 16 hours and poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC on a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 540 μL into a 10 μm C18 OBD reverse-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 50–95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using an 8 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and freeze-dried to obtain 30 mg of (S)-N-(1-(4-(N-tert-butylsulfamoyl)phenylamino)-3-(1H-indole-3-yl)-1-oxopropan-2-yl)-4-fluorobenzamide (I-1) as a white solid (yield 13%). MS (ESI + ) m / z 537 [M+H] + . 1H NMR (400 MHz, d6-DMSO) δ 10.83 (s, 1H), 10.69 (s, 1H), 8.89 (d, J = 7.6 Hz, 1H), 7.94 (dd, J = 8.8, 5.5 Hz, 2H), 7.84 - 7.66 (m, 5H), 7.42 (s, 1H), 7.36 - 7.19 (m, 4H), 7.02 (dt, J = 28.1, 6.9 Hz, 2H), 4.87 (dd, J = 14.0, 8.3 Hz, 1H), 3.25 (m, 2H), 1.08 (s, 9H).

[0411] Example 9: N-((2S)-1-(4-(2,2-dimethylpropylsulfonimidoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-3). [ka] Preparation of 1-(2,2-dimethylpropylsulfonimidoyl)-4-nitrobenzene. [ka]

[0412] Sodium azide (16 mg, 3.3 mmol, 2.00 equivalents) was added all at once to a solution of 400 mg of 1-(neopentylsulfinyl)-4-nitrobenzene (1.66 mmol, 1.00 equivalent) dissolved in 10 mL of Eaton's reagent. The reaction mixture was stirred at 50°C for 2 hours and then poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layer was washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (silica gel, dichloromethane:ethyl acetate (2:1, v:v)) yielded 260 mg of 1-(2,2-dimethylpropylsulfonimidoyl)-4-nitrobenzene as a gray solid (yield 61%). MS (ESI + ) m / z 257 [M+H] + .

[0413] Preparation of 4-(2,2-dimethylpropylsulfonimidoyl)aniline. [ka]

[0414] To a solution of 260 mg of 1-(2,2-dimethylpropylsulfonimidoyl)-4-nitrobenzene (1.01 mmol, 1.00 equivalent) in methanol, palladium-activated carbon (52 mg wet catalyst, 10 wt.% palladium dry base) was added. The mixture was placed under hydrogen gas via a balloon and stirred at room temperature for 12 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. Purification by column chromatography (silica gel, petroleum ether:ethyl acetate (2:1, v:v)) yielded 200 mg of 4-(2,2-dimethylpropylsulfonimidoyl)aniline as a white solid (yield 87%). MS (ESI + ) m / z 227 [M+H] + .

[0415] Preparation of N-((2S)-1-(4-(2,2-dimethylpropylsulfonimidoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-3). [ka]

[0416] To a solution prepared by dissolving 200 mg of 4-(2,2-dimethylpropylsulfonimidoyl)aniline (0.88 mmol, 1.00 equivalent) and 253 mg of (S)-2-(4-fluorobenzamide)-3-phenylpropanoic acid (0.88 mmol, 1.00 equivalent) in 5 mL of anhydrous N,N-dimethylformamide at room temperature, 187 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.97 mmol, 1.10 equivalent), 130 mg of 1-hydroxybenzotriazole (0.97 mmol, 1.10 equivalent), and 227 mg of N,N-diisopropylethylamine (1.76 mmol, 2.00 equivalent) were added sequentially. The reaction mixture was then stirred at room temperature for 16 hours and poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC on a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 500 μL into a 10 μm C18 reverse-phase X-Bridge column with a diameter of 19 mm and a length of 250 mm, and eluted with a gradient of 50–95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 1 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and freeze-dried to obtain 200 mg of (N)-((2S)-1-(4-(2,2-dimethylpropylsulfonimidoyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-3) as a white solid (yield 46%). MS (ESI + ) m / z 496 [M+H] + . 1H NMR (400 MHz, d6-DMSO) δ 8.47 (dd, J = 15.4, 6.7 Hz, 1H), 7.84 (dt, J = 8.7, 6.1 Hz, 2H), 7.48 (dd, J = 14.1, 8.8 Hz, 2H), 7.35 - 7.17 (m, 6H), 7.14 (dd, J = 12.7, 7.0 Hz, 1H), 6.70 - 6.49 (m, 2H), 6.15 (d, J = 5.4 Hz, 2H), 4.60 (dt, J = 10.4, 5.3 Hz, 1H), 3.53 (dd, J = 14.5, 4.6 Hz, 1H), 3.25 (m, 2H), 2.96 (m, 1H), 0.96 (s, 9H).

[0417] Example 10: N-((2S)-1-(4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide(I-18). [ka] Preparation of (E)-2-methyl-N-(4-nitrobenzylidene)propan-2-amine. [ka]

[0418] To a solution of 1.51 g of 4-nitrobenzaldehyde (10.0 mmol, 1.00 equivalent) in 10 mL of dichloromethane, 730 mg of 2-methylpropan-2-amine (10.0 mmol, 1.0 equivalent) was added. The mixture was stirred overnight at room temperature and filtered to obtain 1.85 g of (E)-2-methyl-N-(4-nitrobenzylidene)propan-2-amine as a white solid (yield 90%). MS (ESI + ) m / z 207 [M+H] + .

[0419] Preparation of 2-methyl-N-(2,2,2-trifluoro-1-(4-nitrophenyl)ethyl)propan-2-amine. [ka]

[0420] To a mixture of 2.07 g of (E)-2-methyl-N-(4-nitrobenzylidene)propan-2-amine (10.0 mmol, 1.00 equivalent) and 780 mg of potassium difluoride (10.0 mmol, 1.00 equivalent) in 20 mL of acetonitrile at 0°C, 1.42 g of trifluoromethyltrimethylsilane (10.0 mmol, 1.00 equivalent) was added. The mixture was stirred overnight at room temperature. The mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (5:1, v:v)) to obtain 1.9 g of 2-methyl-N-(2,2,2-trifluoro-1-(4-nitrophenyl)ethyl)propan-2-amine as a pale yellow solid (yield 70%). MS (ESI + ) m / z 277 [M+H] + .

[0421] Preparation of 4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)aniline. [ka]

[0422] To a solution of 2.76 g of 1-(2,2-dimethylpropylsulfinyl)-4-nitrobenzene (10.0 mmol, 1.00 equivalent) in methanol, palladium-activated carbon (550 mg wet catalyst, 10 wt.% palladium dry base) was added. The mixture was placed under hydrogen gas via a balloon and stirred overnight at room temperature. The mixture was filtered, and the filtrate was concentrated to obtain 2.21 g of 4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)aniline as a pale yellow solid (yield 90%). MS (ESI + ) m / z 247 [M+H]+ .

[0423] Preparation of tert-butyl(2S)-1-(4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenylamino)-1-oxo-3-phenylpropane-2-ylcarbamate. [ka]

[0424] A mixture of 2.65 g of (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (10.0 mmol, 1.0 equivalent), 2.46 g of 4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)aniline (10.0 mmol, 1.00 equivalent), 2.88 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (15.0 mmol, 1.50 equivalent), 1.62 g of 1-hydroxybenzotriazole (12.0 mmol, 1.2 equivalent), and 2.58 g of N,N-diisopropylethylamine (20.0 mmol, 2.00 equivalent) in 20 mL of N,N-dimethylformamide was stirred overnight at room temperature. The mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (5:1, v:v)) to obtain 3.94 g of tert-butyl(2S)1-(4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenylamino)-1-oxo-3-phenylpropane-2-ylcarbamate as a white solid (yield 80%). MS (ESI + ) m / z 494 [M+H] + .

[0425] Preparation of (2S)-2-amino-N-(4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenyl)-3-phenylpropanamide. [ka]

[0426] A mixture of 493 mg of tert-butyl(2S)-1-4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenylamino)-1-oxo-3-phenylpropane-2-ylcarbamate (1.0 mmol, 1.00 equivalent) and 20 mL of hydrochloric acid (4.0 M HCl) in dioxane was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain 393 mg of (2S)-2-amino-N-(4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenyl)-3-phenylpropanamide as a white solid (100% yield). MS (ESI + ) m / z 394 [M+H] + .

[0427] Preparation of N-((2S)-1-(4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-18). [ka]

[0428] A mixture of 197 mg of (2S)-2-amino-N-(4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenyl)-3-phenylpropanamide (0.5 mmol, 1.0 equivalent), 70 mg of 4-fluorobenzoic acid (0.5 mmol, 1.00 equivalent), 144 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.75 mmol, 1.50 equivalent), 81 mg of 1-hydroxybenzotriazole (0.6 mmol, 1.2 equivalent), and 129 mg of N,N-diisopropylethylamine (1.0 mmol, 2.00 equivalent) in 20 mL of N,N-dimethylformamide was stirred overnight at room temperature. The mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by reverse-phase preparative HPLC on a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 500 μL into a 10 μm C18 reverse-phase XBridge column (19 mm diameter × 250 mm length) and eluted with a gradient of 50–95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 4 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 40.0 mg of (N)-((2S)-1-(4-(1-tert-butylamino)-2,2,2-trifluoroethyl)phenylamino)-1-oxo-3-phenylpropan-2-yl)-4-fluorobenzamide (I-18) as a white solid (yield 16%). MS (ESI + ) m / z 516 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.29 (s, 1H), 8.82 (d, J = 8.0 Hz, 1H), 7.98 - 7.72 (m, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 7.2 Hz, 2H), 7.32 - 7.22 (m, 4H), 7.18 (t, J = 7.3 Hz, 1H), 4.83 (td, J = 10.0, 4.8 Hz, 1H), 4.54 - 4.30 (m, 1H), 3.22 - 2.96 (m, 2H), 2.35 (t, J = 10.2 Hz, 1H), 0.96 (s, 9H).

[0429] Example 11: N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide (I-19). [ka] Preparation of tert-butyl 2-(4-(benzylthio)phenylcarbamoyl)-2,3-dihydro-1H-inden-2-ylcarbamate. [ka]

[0430] To a solution prepared by dissolving 466 mg of 4-(benzylthio)aniline (2.20 mmol, 1.00 equivalent) and 600 mg of 2-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-2-carboxylic acid (2.20 mmol, 1.00 equivalent) in 10 mL of anhydrous N,N-dimethylformamide at room temperature, 465 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.42 mmol, 1.10 equivalent), 327 mg of 1-hydroxybenzotriazole (2.42 mmol, 1.10 equivalent), and 567 mg of N,N-diisopropylethylamine (4.40 mmol, 2.00 equivalent) were sequentially added. The reaction mixture was then stirred overnight at room temperature and poured into 100 mL of water. The mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic layers were washed with 2 × 50 mL of water, then with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (4:1, v:v)) to obtain 421 mg of tert-butyl 2-(4-(benzylthio)phenylcarbamoyl)-2,3-dihydro-1H-indene-2-ylcarbamate as a white solid (yield 40%). MS (ESI + ) m / z 475 [M+H] + .

[0431] Preparation of 2-amino-N-(4-(benzylthio)phenyl)-2,3-dihydro-1H-indene-2-carboxamide hydrochloride. [ka]

[0432] 421 mg of tert-butyl 2-(4-(benzylthio)phenylcarbamoyl)-2,3-dihydro-1H-indene-2-ylcarbamate (0.87 mmol, 1.00 equivalent) was dissolved in 30 mL of hydrochloric acid (4.0 M) in dioxane and stirred at room temperature for 3 hours. The mixture was concentrated to obtain 400 mg of 2-amino-N-(4-(benzylthio)phenyl)-2,3-dihydro-1H-indene-2-carboxamide hydrochloride as a pale yellow solid (100% yield). MS (ESI + ) m / z 375 [M+H] + .

[0433] Preparation of N-(4-(benzylthio)phenyl)-2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide. [ka]

[0434] A mixture of 400 mg of -2-amino-N-(4-(benzylthio)phenyl)-2,3-dihydro-1H-indene-2-carboxamide hydrochloride (0.98 mmol, 1.00 equivalent), 137 mg of 4-fluorobenzoic acid (0.98 mmol, 1.0 equivalent), 207 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.1 mmol, 1.1 equivalent), 149 mg of 1-hydroxybenzotriazole (1.1 mmol, 1.1 equivalent), and 253 mg of N,N-diisopropylethylamine (1.96 mmol, 2.00 equivalent) in 30 mL of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (3:1, v:v)) to obtain 380 mg of N-(4-(benzylthio)phenyl)-2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide as a gray solid (yield 78%). MS (ESI + ) m / z 497 [M+H] + .

[0435] Preparation of 4-(2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide)benzene-1-sulfonyl chloride. [ka]

[0436] 270 mg of N-(4-(benzylthio)phenyl)-2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide (0.54 mmol, 1.00 equivalent), 33 mg of acetic acid (0.54 mmol, 1 equivalent), and 10 mg of water (0.54 mmol, 1 equivalent) were dissolved in 30 mL of dichloromethane. 293 mg of N-chlorosuccinimide (2.16 mmol, 4.00 equivalent) was added at 0°C. The mixture was stirred at room temperature for 2 hours and washed with 3 × 20 mL of water. The organic phase was concentrated to obtain 200 mg of 4-(2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide)benzene-1-sulfonyl chloride as a gray solid (yield 78%). MS (ESI + ) m / z 473[M+H] + .

[0437] Preparation of N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide (I-19). [ka]

[0438] To a mixture of 155 mg of 2-methylpropan-2-amine (2.12 mmol, 5.0 equivalents) and 273 mg of N,N-diisopropylethylamine (2.12 mmol, 5.00 equivalents) in 10 mL of dichloromethane, 200 mg of 4-(2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide)benzene-1-sulfonyl chloride (0.42 mmol, 1.00 equivalent) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The compound was purified by reverse-phase preparative HPLC using a Gilson GX-281. A concentrated solution of the crude product dissolved in DMSO was injected in 413 μL into a 10 μm C18 reversed-phase Waters X-SELECT 19 mm diameter × 250 mm length column and eluted with a gradient of 58-95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 45 mg of N-(4-(N-tert-butylsulfamoyl)phenyl)-2-(4-fluorobenzamide)-2,3-dihydro-1H-indene-2-carboxamide (I-19) as a white solid (yield 21%). MS (ESI + ) m / z 510[M+H] + . 1 H NMR (400 MHz, d6-DMSO) δ 10.05 (s, 1H), 8.90 (s, 1H), 8.03 (dd, J = 8.9, 5.6 Hz, 2H), 7.75 (dd, J = 21.0, 9.0 Hz, 4H), 7.37 (s, 1H), 7.33 - 7.22 (m, 4H), 7.20 - 7.15 (m, 2H), 3.75 (d, J = 16.8 Hz, 2H), 3.42 (d, J = 16.8 Hz, 2H), 1.07 (s, 9H).

[0439] Example 12: N-(1-(4-(N-tert-butylsulfamoyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-yl)-4-fluorobenzamide(I-20) [ka] Preparation of diethyl 2-acetamido-2-(2-nitrobenzyl)malonate. [ka]

[0440] To a solution of 2.17 g of diethyl 2-acetamidomalonate (10.0 mmol, 1.0 equivalent) in 30 mL of ethanol, 1.06 g of sodium ethoxide (20.0 mmol, 2.0 equivalent) was added, and the mixture was stirred at room temperature for 0.5 hours. 2.14 g of 2-nitrobenzyl bromide (10.0 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature overnight. 100 mL of water was added to the reaction mixture, and it was filtered. The solid was washed with water and dried under vacuum to obtain 2.46 g of diethyl 2-acetamido-2-(2-nitrobenzyl)malonate as a yellow solid (yield 70%). MS (ESI + ) m / z 353 [M+H] + .

[0441] Preparation of ethyl 3-acetamido-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate. [ka]

[0442] A mixture of 3.52 g of diethyl 2-acetamido-2-(2-nitrobenzyl)malonate (10.0 mmol, 1.0 equivalent), 2.65 g of ammonium chloride (50.0 mmol, 5.0 equivalent), and 2.80 g of iron powder (50.0 mmol, 5.0 equivalent) in 100 mL of ethanol was refluxed overnight and then filtered through Celite. The solvent was concentrated under vacuum to obtain 2.20 g of ethyl 3-acetamido-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate as a brown solid (yield 80%). MS (ESI + ) m / z 277 [M+H] + .

[0443] Preparation of 3-amino-3,4-dihydroquinolin-2(1H)-one.

Chem.

[0444] A solution of 2.77 g of ethyl 3-acetamido-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (10.0 mmol, 1.0 equivalent) in 50 mL of concentrated hydrochloric acid was refluxed for 3 hours. The reaction mixture was diluted with 100 mL of water and extracted with 3 portions of 100 mL of ethyl acetate. The aqueous phase was basified with saturated aqueous sodium bicarbonate and extracted with 3 portions of 100 mL of ethyl acetate. The combined organic fractions were concentrated in vacuo to give 1.30 g of 3-amino-3,4-dihydroquinolin-2(1H)-one as a brown solid (80% yield). MS (ESI + ) m / z 163 [M+H] + .

[0445] Preparation of tert-butyl 2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate.

Chem.

[0446] To a solution of 1.62 g of 3-amino-3,4-dihydroquinolin-2(1H)-one (10.0 mmol, 1.0 equivalent), 1.68 g of sodium bicarbonate (20.0 mmol, 2.0 equivalents) in 10 mL of tetrahydrofuran and 10 mL of water was added 2.18 g of di-tert-butyl dicarbonate (10.0 mmol, 1.0 equivalent), and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with 3 portions of 100 mL of ethyl acetate. The combined organic fractions were concentrated in vacuo to give 2.10 g of tert-butyl 2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate as a white solid (80% yield). MS (ESI + ) m / z 263 [M+H] + .

[0447] Preparation of tert-butyl 1-(4-(N-tert-butylsulfamoyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-ylcarbamate. [ka]

[0448] A mixture of 262 mg of tert-butyl 2-oxo-1,2,3,4-tetrahydroquinoline-3-ylcarbamate (1.0 mmol, 1.0 equivalent), 290 mg of 4-bromo-N-tert-butylbenzenesulfonamide (10.00 mmol, 1.00 equivalent), 91.5 mg of tris(dibenzylideneacetone)dipalladium (0.1 mmol, 0.1 equivalent), 115 mg of 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.2 mmol, 0.2 equivalent), and 276 mg of cesium carbonate (2.0 mmol, 2.00 equivalent) in 20 mL of dioxane was stirred overnight at 100°C. The mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (3:1, v:v)) to obtain 283 mg of tert-butyl 1-(4-(N-tert-butylsulfamoyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-ylcarbamate as a white solid (yield 60%). MS (ESI + ) m / z 474 [M+H] + .

[0449] Preparation of 4-(3-amino-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-N-tert-butylbenzenesulfonamide. [ka]

[0450] A mixture of 473 mg of tert-butyl 1-(4-(N-tert-butylsulfamoyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (1.0 mmol, 1.00 equivalent) in 20 mL of dioxane in hydrochloric acid (4.0 M HCl) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to afford 373 mg of 4-(3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)-N-tert-butylbenzenesulfonamide as a white solid (yield 100%). MS (ESI + ) m / z 374 [M+H] + .

[0451] Preparation of N-(1-(4-(N-tert-butylsulfamoyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-4-fluorobenzamide.

Chemical formula

[0452] A mixture of 187 mg of 4-(3-amino-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-N-tert-butylbenzenesulfonamide (0.5 mmol, 1.0 equivalent), 70 mg of 4-fluorobenzoic acid (0.5 mmol, 1.00 equivalent), 144 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.75 mmol, 1.50 equivalent), 81 mg of 1-hydroxybenzotriazole (0.6 mmol, 1.2 equivalent), and 129 mg of N,N-diisopropylethylamine (1.0 mmol, 2.00 equivalent) in 20 mL of N,N-dimethylformamide was stirred overnight at room temperature. The mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by reverse-phase preparative HPLC using a Gilson GX-281. 850 μL of the concentrated crude product dissolved in DMSO was injected into a 10 μm C18 reverse-phase XBridge column (19 mm diameter × 250 mm length), and eluted with a gradient of 50–95% acetonitrile in water containing 10 mmol / L ammonium carbonate. Peaks were detected by UV absorbance at 214 nm and 254 nm, and fractions were collected using a 3 mV threshold trigger on the 214 nm channel. The fractions containing the product were combined, concentrated, and lyophilized to obtain 30.0 mg of N-(1-(4-(N-tert-butylsulfamoyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-yl)-4-fluorobenzamide (I-20) as a white solid (yield 12%). MS (ESI + ) m / z 496 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 8.86 (d, J = 8.4 Hz, 1H), 7.96 (dt, J = 8.9, 2.8 Hz, 4H), 7.64 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.42 - 7.25 (m, 3H), 7.14 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.0 Hz, 1H), 6.24 (d, J = 7.6 Hz, 1H), 5.00 (ddd, J = 14.4, 8.2, 6.0 Hz, 1H), 3.35 (dd, J = 23.6, 8.9Hz, 1H), 3.16 (dd, J = 15.2, 6.0 Hz, 1H), 1.12 (s, 9H).

[0453] Example 13: N-(2-(4-(N-tert-butylsulfamoyl)phenyl)-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-yl)-4-fluorobenzamide(I-21). [ka] Preparation of diethyl 2-acetamido-2-(2-cyanobenzyl)malonate. [ka]

[0454] To a solution of 2.17 g of diethyl 2-acetamidomalonate (10.0 mmol, 1.0 equivalent) in 30 mL of ethanol, 1.06 g of sodium ethoxide (20.0 mmol, 2.0 equivalent) was added, and the mixture was stirred at room temperature for 0.5 hours. 1.94 g of 2-(bromomethyl)benzonitrile (10.0 mmol, 1.0 equivalent) was added, and the mixture was stirred at room temperature overnight. Then, 100 mL of water was added to the reaction mixture, and the mixture was filtered. The solid was washed with water and dried under vacuum to obtain 2.32 g of diethyl 2-acetamido-2-(2-cyanobenzyl)malonate as a yellow solid (yield 70%). MS (ESI + ) m / z 333 [M+H]+ .

[0455] Preparation of diethyl 2-acetamido-2-(2-(aminomethyl)benzyl)malonate. [ka]

[0456] To a solution of 3.32 g of diethyl 2-acetamido-2-(2-cyanobenzyl)malonate (10.0 mmol, 1.00 equivalent) in methanol, Raney nickel (550 mg wet catalyst, 10 wt.% palladium dry base) was added. The mixture was placed under hydrogen gas via a balloon and stirred overnight at room temperature. The mixture was filtered, and the filtrate was concentrated to obtain 3.02 g of diethyl 2-acetamido-2-(2-(aminomethyl)benzyl)malonate as a pale yellow solid (yield 90%). MS (ESI + ) m / z 337 [M+H] + .

[0457] Preparation of ethyl 4-acetamido-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-carboxylate. [ka]

[0458] A solution of 3.36 g of diethyl 2-acetamido-2-(2-(aminomethyl)benzyl)malonate (10.0 mmol, 1.00 equivalent) and 122 mg of 4-dimethylaminopyridine (1.0 mmol, 0.1 equivalent) in ethanol was refluxed overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (3:1, v:v)) to obtain 1.74 g of ethyl 4-acetamido-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-carboxylate as a white solid (yield 60%). MS (ESI + ) m / z 291 [M+H] + .

[0459] Preparation of 4-amino-4,5-dihydro-1H-benzo[c]azepine-3(2H)-one. [ka]

[0460] A solution of 2.91 g of diethyl diethyl 2-acetamidomalonate (10.0 mmol, 1.0 equivalent) in 50 mL of concentrated hydrochloric acid was refluxed for 3 hours. The reaction mixture was diluted with 100 mL of water and extracted with 3 × 100 mL of ethyl acetate. The aqueous phase was basicized with saturated sodium bicarbonate aqueous solution and extracted with 3 × 100 mL of ethyl acetate. The combined organic fraction was concentrated under vacuum to obtain 1.40 g of 3-amino-3,4-dihydroquinoline-2(1H)-one as a brown solid (yield 80%). MS (ESI + ) m / z 177 [M+H] + .

[0461] Preparation of tert-butyl 3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-ylcarbamate. [ka]

[0462] To a solution of 1.76 g of 3-amino-3,4-dihydroquinoline-2(1H)-one (10.0 mmol, 1.0 equivalent) and 1.68 g of sodium bicarbonate (20.0 mmol, 2.0 equivalents) in 10 mL of tetrahydrofuran and 10 mL of water, 2.18 g of di-tert-butyl dicarbonate (10.0 mmol, 1.0 equivalent) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with 3 × 100 mL of ethyl acetate. The combined organic fraction was concentrated under vacuum to obtain 2.20 g of tert-butyl 3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-ylcarbamate as a white solid (yield 80%). MS (ESI + ) m / z 277 [M+H] + .

[0463] Preparation of tert-butyl 2-(4-(N-tert-butylsulfamoyl)phenyl)-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-ylcarbamate. [ka]

[0464] A mixture of 276 mg of tert-butyl 2-oxo-1,2,3,4-tetrahydroquinoline-3-ylcarbamate (1.0 mmol, 1.0 equivalent), 290 mg of 4-bromo-N-tert-butylbenzenesulfonamide (10.00 mmol, 1.00 equivalent), 91.5 mg of tris(dibenzylideneacetone)dipalladium (0.1 mmol, 0.1 equivalent), 115 mg of 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.2 mmol, 0.2 equivalent), and 276 mg of cesium carbonate (2.0 mmol, 2.00 equivalent) in 20 mL of dioxane was stirred overnight at 100°C. The mixture was diluted with 100 mL of ethyl acetate and washed with 3 × 100 mL of water. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (3:1, v:v)) to obtain 292 mg of tert-butyl 2-(4-(N-tert-butylsulfamoyl)phenyl)-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-ylcarbamate as a white solid (yield 60%). MS (ESI + ) m / z 488 [M+H] + .

[0465] Preparation of 4-(4-amino-3-oxo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-yl)-N-tert-butylbenzenesulfonamide. [ka]

[0466] A mixture of 487 mg of 2-(4-(N-tert-butylsulfamoyl)phenyl)-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-ylcarbamate (1.0 mmol, 1.00 equivalent) in 20 mL of dioxane hydrochloric acid (4.0 M HCl) was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain 387 mg of 4-(4-amino-3-oxo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-yl)-N-tert-butylbenzenesulfonamide as a white solid (100% yield). MS (ESI + ) m / z 388 [M+H] + .

[0467] Preparation of N-(2-(4-(N-tert-butylsulfamoyl)phenyl)-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-4-yl)-4-fluorobenzamide. [ka]

[0468] A mixture of 194 mg of 4-(4-amino-3-oxo-4,5-dihydro-1H-benzo[c]azepine-2(3H)-yl)-N-tert-butylbenzenesulfonamide (0.5 mmol, 1.0 equivalent), 70 mg of 4-fluorobenzoic acid (0.5 mmol, 1.00 equivalent), 144 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.75 ...

Claims

1. Formula I': 【Chemistry 1】 [In the formula, Ring A is a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or an 8-10 member bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. L １ However, -S(O) ２ NH-, -S(O)NH-, -S(O)-, -S(O)(Nt-Bu)-, or -C(CF ３ )(H)NH-, R １ However, C １～６ An optionally substituted group selected from aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocyclic rings, 5-8 member saturated or partially unsaturated bridged bicyclic carbocyclic rings, 4-7 member saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 member heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R ２ is independently halogen, -CF ３ , -CN, -C(O)NHR, -NO ２ , -NHR, -NHCO(R), -NHSO ２ R, -N(R) ２ , or -OR, or an optionally substituted C １～６ aliphatic group, Each R is independently either hydrogen or optionally substituted with C. １～３ It is an aliphatic group, L ２ However, it is -C(O)N(R')-, R' is hydrogen or C １～３ It is an aliphatic group, L ３ However, it is -C(O)N(R'')-, R is hydrogen or C １～３ It is an aliphatic group, R ３ However, hydrogen or C １～３ It is aliphatic, R ４ However, it is hydrogen, R ５ However, it is hydrogen, Ring B is phenyl, Each R ６ These are independently halogen, -CN, and -NO ２ , -NHR, -N(R) ２ C replaced by -OR or any choice. １～６ It is an aliphatic group, Ring C is a phenyl ring, a 3-8 member saturated or partially unsaturated carbocyclic ring, a 4-7 member saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen and oxygen, or an 8-10 member bicyclic aryl ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Each R ７ These are independently halogen, -CN, and -NO ２ , -NHR, -N(R) ２ , -OR, or C １～６ It is an aliphatic group, Each of m, n, and p is independently 0, 1, 2, 3, or 4. Compounds indicated by, or pharmaceutically acceptable salts thereof: However, L １ ga-S(O) ２ If NH-, R １ However, it is not isopropyl, t-butyl, 1-methylcyclopropyl, 1-fluoromethylcyclopropyl, 1-difluoromethylcyclopropyl, 1-trifluoromethylcyclopropyl, or 3-methyl-3-oxetanyl. The aforementioned compound is compound: 【Chemistry 2-1】 【Chemistry 2-2】 The condition is that it is not the case.

2. Formula II: 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Formula III-a or III-c: 【Chemistry 4】 One of the compounds described in claim 1, or a pharmaceutically acceptable salt thereof.

4. L １ However, -S(O) ２ NH-, -S(O)NH-, -S(O)(Nt-Bu)-, or -C(CF ３ The compound according to any one of claims 1 to 3, wherein it is (H)NH-.

5. L １ However, -S(O) ２ The compound according to claim 3, wherein it is NH-.

6. Formula IV-a or IV-c: 【Transformation 5】 One of the compounds described in claim 1, or a pharmaceutically acceptable salt thereof.

7. Formula VI-a or VI-c: 【Transformation 6】 One of the compounds described in claim 1, or a pharmaceutically acceptable salt thereof.

8. Formula XV-a, XV-b, XV-c, XVII-a, XVII-b, XIX-a, XIX-b, XIX-c, XIX-d, XXIII-a, XXIII-b, XXV-a, XXV-b, XXV-c, or XXV-d: 【Chemistry 7-1】 【Chemistry 7-2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is any one of the above.

9. Formula XVI-a, XVI-b, XVI-c, XVIII-a, XVIII-b, XX-a, XX-b, XX-c, XX-d, XXIV-a, XXIV-b, XXVI-a, XXVI-b, XXVI-c, or XXVI-d: 【Chemistry 8-1】 【Chemistry 8-2】 The compound according to claim 8, or a pharmaceutically acceptable salt thereof, which is any one of the above.

10. Formula XX-a or XX-b: 【Chemistry 9】 The compound according to claim 8, or a pharmaceutically acceptable salt thereof.

11. R １ The compound according to any one of claims 1 to 10, wherein the compound is a 4-7 member saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted.

12. R １ The compound according to claim 11, wherein the compound is a 4-7 member saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen.

13. R １ but, 【Chemistry 10】 The compound according to any one of claims 1 to 11.

14. R ７ The compound according to any one of claims 1 to 13, wherein is a halogen, p is 1, and n is 0.

15. R ７ The compound according to any one of claims 1 to 13, wherein is fluoro, p is 1, and n is 0.

16. at least one R ２ The compound according to any one of claims 1 to 9, wherein is fluoro, methyl, or methoxy.

17. The compound according to any one of claims 1 to 9 or 16, wherein m is 0, 1, 2, or 3.

18. The compound according to any one of claims 1 to 17, wherein p is 0, 1, 2, or 3.

19. n is 1 or 2, and at least one R ７ The compound according to any one of claims 1 to 18, wherein is fluoro.

20. The compounds shown in the table below, or their pharmaceutically acceptable salts. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 【Request Item 21】 【Chemistry 11】 The compound according to claim 20, which is the compound represented by [the formula shown], or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

23. A pharmaceutical composition according to claim 22 for inhibiting USP30 in a biological sample, wherein the inhibition modulates mitochondrial homeostasis.

24. The pharmaceutical composition according to claim 22 for treating a USP30-mediated disorder, disease, or condition.

25. USP30-mediated disorders, diseases, or conditions include: neurodegenerative diseases; mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndromes; Leber hereditary optic neuropathy (LHON); neuropathy, ataxia, retinitis pigmentosa - maternally inherited Leigh syndrome (NARP-MILS); Danon disease; ischemic heart disease leading to myocardial infarction; multiple sulfatase deficiency (MSD); mucolipidosis II (ML II); mucolipidosis III (ML III); mucolipidosis IV (ML IV); GM1-Gangliosidosis (GM1); Neuronal Ceroid Lipofuscinosis (NCL1); Alpers' disease; Barth syndrome; Beta-oxidation deficiency; Carnitine-Acyl-Carnitine deficiency; Carnitine deficiency; Creatine deficiency syndrome; Coenzyme Q10 deficiency; Complex I deficiency; Complex II deficiency; Complex III deficiency; Complex IV deficiency; Complex V deficiency; COX deficiency; Chronic progressive extraocular muscle palsy syndrome (CPEO); CPT I deficiency; CPT A pharmaceutical composition according to claim 24, selected from the group consisting of: II deficiency; glutariculosis type II; Kearns-Sayer syndrome; lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency (LCHAD); Leigh disease or syndrome; fatal infant cardiomyopathy (LIC); Luft's disease; glutariculosis type II; medium-chain acyl-CoA dehydrogenase deficiency (MCHAD); myoclonus epilepsy / red rag fiber (MERRF) syndrome; mitochondrial recessive ataxia syndrome; mitochondrial cell disease; mitochondrial DNA depletion syndrome; neuromuscular gastrointestinal disorders and encephalopathy; Pearson syndrome: pyruvate carboxylase deficiency; pyruvate dehydrogenase deficiency; POLG mutation; medium-chain / short-chain 3-hydroxyacyl-CoA dehydrogenase (M / SCHAD) deficiency; and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.

26. The pharmaceutical composition according to claim 24, wherein the USP30-mediated disorder, disease, or condition is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, ischemia, stroke, Lewy body dementia, and frontotemporal dementia.

27. The pharmaceutical composition according to claim 24, wherein the USP30-mediated disorder, disease, or condition is Alzheimer's disease or Parkinson's disease.

28. The pharmaceutical composition according to claim 24, wherein the USP30-mediated disorder, disease, or condition is a neoplasm selected from the group consisting of metastatic carcinoma, multiple myeloma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, nasopharyngeal carcinoma, and leukemia.

29. The pharmaceutical composition according to claim 24, wherein the USP30-mediated disorder, disease, or condition is a cardiovascular disease, renal disease, pulmonary fibrosis, an ophthalmic condition, cancer, cognitive disorder, peroxisome-related disorder, spontaneous aging, or age-related disease.

30. The pharmaceutical composition according to claim 24, wherein the USP30-mediated disorder, disease, or condition is a peroxisome-related disorder selected from the group consisting of ataxia vasodilator variant, Heimler syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy, radicular chondrodysplasia punctate, leukodementia, Zellweger syndrome, and Zellweger spectrum disorder.

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