compounds, compositions and methods

专利摘要:
The present invention generally relates to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and methods of preparing and using them.
公开号:BR112020001591A2
申请号:R112020001591-1
申请日:2018-08-08
公开日:2020-07-21
发明作者:Robert A. Ii Craig；Javier de Vicente Fidalgo；Anthony A. Estrada；Jianwen A. Feng；Brian Fox；Chirstopher R. H. Hale；Katrina W. Lexa；Maksim Osipov；Travis Remarchuck；Zachary K. Sweeney
申请人:Denali Therapeutics Inc.；
IPC主号:

专利说明:

[001] [001] This claim claims the benefit in accordance with 35 USC §119 (e) of Provisional Application Numbers 62 / 543,307, filed on August 9, 2017, 62 / 553,728, filed on September 1, 2017 and 62 / 608,504, filed on December 20, 2017 and all of which are incorporated by reference. FIELD
[002] [002] The present description generally refers to modulators of small molecules of eukaryotic initiation factor 2B and their use as therapeutic agents, for example, in the treatment of diseases such as Alzheimer's, Parkinson's, ALS and frontotemporal dementia. FUNDAMENTALS
[003] [003] Neurodegenerative diseases such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and frontotemporal dementia (FTD) have a negative effect on the lives of millions of people.
[004] [004] Protein complexes of multiple subunit eukaryotic initiation factor 2B and eukaryotic initiation factor 2 are necessary for the initiation and regulation of protein synthesis in eukaryotic cells. The eukaryotic initiation factor 2B is composed of five subunits (, , ,  and ) and the eukaryotic initiation factor 2 is composed of three subunits (,  and ). Eukaryotic initiation factor 2B functions as a guanine nucleotide exchange factor (GEF) that catalyzes the exchange of guanosine-5'-diphosphate (GDP) with guanosine-5'-triphosphate (GTP) in the eukaryotic initiation factor 2, thus allowing GTP linked to eukaryotic initiation factor 2 to bind to the initial methionine transfer RNA and initiate protein synthesis.
[005] [005] Eukaryotic initiation factor 2B is active when complexed as a dimer of ten subunits. Eukaryotic initiation factor 2 is active when bound to GTP and inactive when bound to GDP. Besides that,
[006] [006] The interaction between eukaryotic initiation factor 2B and eukaryotic initiation factor 2 plays an important role in the integrated stress response pathway (ISR). Activation of this pathway leads in part to the expression of ATF4 (activation transcription factor 4) and the formation of stress granules. Aberrant activation of ISR is found in several neurodegenerative diseases, with a strong functional link to the pathology characterized by the DNA-binding protein (TARDBP) of the stress granule / RNA-binding protein, also known as TDP43. The activation of eIF2B inhibits the formation of stress granules dependent on ISR and ISR and is considered neuroprotective in several disease models.
[007] [007] The decrease in the activity of eukaryotic initiation factor 2B is correlated with the activation of the ISR pathway that is implicated in several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease and frontotemporal dementia. Mutations in TDP43 and other RNA-binding proteins / stress granule proteins alter the dynamics of stress granules and cause ALS. Inhibition of the ISR pathway can block and promote the dissolution of stress granules. In addition, mutations in the subunits of human eukaryotic initiation factor 2B have been identified as causing leukoencephalopathy with white matter disappearance (VWM) and infantile ataxia with central nervous system hypomyelination (CACH). In patients with VWM / CACH, white matter lesions deteriorate severely and neurological disorders are exacerbated after stress, and their eukaryotic initiation factor 2B guanine nucleotide exchange activities are generally lower than normal. DESCRIPTION
[008] [008] Compounds, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrugs, which are useful in the treatment and / or prevention of neurodegenerative diseases (for example, neurodegeneration in the disease, are provided in this document of prions).
[009] [009] In some embodiments, compounds are provided that modulate the activity of eukaryotic initiation factor 2B. In some modalities, the compounds modulate the regulation of eukaryotic initiation factor 2B. In some respects, the compounds modulate the inhibition of eukaryotic initiation factor 2B by eukaryotic initiation factor 2. In some embodiments, the compounds interfere with the interaction between eukaryotic initiation factor 2B and eukaryotic initiation factor 2. In some eukaryotic initiation factor 2 is phosphorylated in its alpha subunit eukaryotic initiation factor 2α phosphate).
[0010] [0010] In some modalities, compounds are provided that act as activators of eukaryotic initiation factor 2B, increasing their GDP / GTP nucleotide exchange activity. In some modalities, the compounds promote the formation of dimer of eukaryotic initiation factor 2B. In other modalities, the compounds enhance the activity of the guanine nucleotide exchange factor (GEF) of the eukaryotic initiation factor 2B. In other modalities, the compounds increase the activity of the guanine nucleotide exchange factor (GEF) of the eukaryotic initiation factor 2B in its GDP / eukaryotic initiation factor 2 substrate.
[0011] [0011] In some modalities, compounds are provided that de-sensitize cells to the deleterious effects of the inhibition of eukaryotic initiation factor 2B. In some modalities, the deleterious effects include the expression of ATF4 and the formation of stress granules.
[0012] [0012] In another embodiment, a pharmaceutical composition is provided which comprises a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier.
[0013] [0013] In another embodiment, a method is provided for the treatment of a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound put as described in this document, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof.
[0014] [0014] In another modality, a method is provided for the treatment of a disease or condition mediated, at least in part, by the regulation of the eukaryotic initiation factor 2B, the method comprising administering an effective amount of the pharmaceutical composition that comprises a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, stereoisomeric mixture or prodrug and a pharmaceutically acceptable carrier, for a subject in need.
[0015] [0015] In another embodiment, a method is provided to promote or stabilize the dimer formation of eukaryotic initiation factor 2B, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described in this document. or a pharmaceutically acceptable, isotopically enriched analogue salt, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier for a subject in need.
[0016] [0016] In another embodiment, a method is provided to promote eukaryotic initiation factor 2B activity, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described in this document, or a pharmaceutically acceptable salt , isotopically enriched analogue, stereoisomer, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier for a subject in need.
[0017] [0017] In another embodiment, a method is provided to desensitize cells to phosphorylation of eukaryotic initiation factor 2, the method of which comprises administering an effective amount of the pharmaceutical composition comprising a compound as described in this document, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrugs of the same, and a pharmaceutically acceptable carrier, for a subject in need.
[0018] [0018] In another embodiment, a method is provided to inhibit the integrated stress response pathway, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier for a subject in need.
[0019] [0019] In another embodiment, a method is provided to inhibit the formation of stress granules, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, analogous isotopically enriched, stereoisomer, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier for a subject in need.
[0020] [0020] In another embodiment, a method is provided to inhibit the expression of ATF4, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog. , stereoisomer, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier for a subject in need.
[0021] [0021] The description also provides compositions, including pharmaceutical compositions, kits that include the compounds and methods of use (or administration) and preparation of the compounds. The description further provides compounds or compositions thereof for use in a method to treat a disease, disorder or condition that is mediated, at least in part by eukaryotic initiation factor 2B. In addition, the description provides uses of the compounds or their compositions in the manufacture of a medicament to treat a disease, disorder or condition that is measured, at least in part by eukaryotic initiation factor 2B. DETAILED DESCRIPTION
[0022] [0022] The description below presents exemplary modalities of the present technology. It should be recognized, however, that such a description is not intended to be a limitation on the scope of this description, but rather is provided as a description of exemplary modalities.
[0023] [0023] As used in this description, the following words, phrases and symbols are generally intended to have the meanings as defined below, unless the context in which they are used indicates otherwise.
[0024] [0024] A dash ("-") that is not between two letters or symbols is used to indicate a fixation point for a substituent. For example, - C (O) NH2 is linked via the carbon atom. A dash in front or at the end of a chemical group is a matter of convenience; chemical groups can be represented with or without one or more features without losing their common meaning. A wavy line drawn across a line in a structure indicates a point of attachment for a group. Unless chemically
[0025] [0025] The prefix "Cu-v" indicates that the next group has carbon atoms from u to v. For example, "C1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.
[0026] [0026] Reference to "about" a value or parameter in this document includes (and describes) modalities that address that value or parameter per se. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. In addition, the term "about X" includes the description of "X". In addition, the singular forms "one / one" and "a / o" include references in the plural, unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds and reference to "the test" includes reference to one or more tests and their equivalents known to those skilled in the art.
[0027] [0027] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (ie, C1-20 alkyl), 1 to 12 carbon atoms (ie, C1-12 alkyl), 1 to 8 carbon atoms (ie, C1 -8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl , 3-hexyl and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by chemical name or identified by a molecular formula, all positional isomers with that number of carbons can be covered; thus, for example, "butyl" includes n-butyl, (i.e., - (CH2) 3CH3), sec-butyl (i.e., - CH (CH3) CH2CH3), isobutyl (i.e., -CH2CH (CH3) 2 ) and tert-butyl (ie -
[0028] [0028] Certain commonly used alternative chemical names can be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, etc., can also be referred to as an "alkylene" group or an "alkylene" group, an "arylene" group or an "arylenyl" group, respectively. Also, unless explicitly stated otherwise, where group combinations are referred to in this document as a fraction, for example, arylalkyl, the last group mentioned contains the atom by which the fraction is linked to the rest of the molecule.
[0029] [0029] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (ie, C2-20 alkenyl), 2 to 8 carbon atoms (ie, C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethylene, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
[0030] [0030] "Alquinyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (ie , C2-8 alkynyl), 2 to 6 carbon atoms (ie, C2-6 alkynyl) or 2 to 4 carbon atoms (ie, C2- 4 alkynyl). The term "alkynyl" also includes those groups that have a triple bond and a double bond.
[0031] [0031] "Aloxy" refers to the group "alkyl-O-". Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
[0032] [0032] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl".
[0033] [0033] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S (O) -". "Alkylsulfonyl" refers to the "alkyl-S (O) 2-" group. "Alkylsulfonylalkyl" refers to -alkyl-S (O) 2-alkyl.
[0034] [0034] "Acyl" refers to a -C (O) Ry group, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document. Examples of acyl include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl and benzoyl.
[0035] [0035] "Starch" refers doubly to a "C-starch" group that refers to the -C (O) NRyRz group and to an "N-starch" group that refers to the - NRyC (O) group Rz, where Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally substituted, as defined in this document, or Ry and Rz are considered together to form a cycloalkyl or heterocyclyl; each of which can be optionally replaced, as defined in this document.
[0036] [0036] "Amino" refers to the group -NRyRz in which Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can optionally be replaced, as defined in this document.
[0037] [0037] "Aminoalkyl" refers to the group "-alkyl-NRyRz," in which Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally replaced, as defined in this document.
[0038] [0038] "Amidino" refers to -C (NRy) (NRz2), where Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can optionally be replaced, as defined in this document.
[0039] [0039] "Aryl" refers to an aromatic carbocyclic group with a single ring (for example, monocyclic) or multiple rings (for example, bicyclic or tricyclic), including fused systems. As used herein, aryl has 6 to 20 carbon atoms in the ring (i.e., C6-20 aryl), 6 to 12 carbon atoms in the ring (i.e., C6-12 aryl) or 6 to 10 carbon atoms ( that is, C6-
[0040] [0040] "Arylalkyl" or "Aralkyl" refers to the group "aryl-alkyl-".
[0041] [0041] "Carbamoyl" refers to an "O-carbamoyl" group which refers to the -OC (O) NRyRz group and an "N-carbamoyl" group which refers to the - NRyC (O) ORz group, where Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally replaced, as defined in this document.
[0042] [0042] "Carboxyl ester" or "ester" refer to both -OC (O) Rx and - C (O) ORx, where Rx is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document.
[0043] [0043] "Cyanoalkyl" refers to an alkyl group as defined above, in which one or more (for example, one to three) hydrogen atoms are replaced by a cyan group (-CN).
[0044] [0044] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3 carbon atom (i.e., at least one non-aromatic ring). As used in this document, it has 3 to 20 ring carbon atoms (ie, C3-20 cycloalkyl), 3 to 12 ring carbon atoms (ie, C3-12 cycloalkyl), 3 to 10 carbon atoms in the ring (ie, C3-10 cycloalkyl), 3 to 8 carbon atoms in the ring (ie, C3-8 cycloalkyl), or 3 to 6 carbon atoms in the ring (ie, C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, heptanyl bicycles [2.2.1], octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-cyclo [2.2.1] heptanyl and the like. In addition, the term cycloalkyl is intended to cover any non-aromatic ring that can be fused to an aryl ring, regardless of attachment to the rest of the molecule. In addition, it also includes "spirocycloalkyl" when there are two positions for substitution on the same carbon atom, for example, spiro [2.5] octanyl, spiro [4.5] decanyl, or spiro [5.5] undecanila.
[0045] [0045] "Cycloalkoxy" refers to "-O-cycloalkyl".
[0046] [0046] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".
[0047] [0047] "Cycloalkylalkoxy" refers to "-O-alkyl-cycloalkyl".
[0048] [0048] "Guanidino" refers to -NRyC (= NRz) (NRyRz), where each Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document.
[0049] [0049] "Hydrazino" refers to -NHNH2.
[0050] [0050] "Imino" refers to a -C (NRy) Rz group in which Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document.
[0051] [0051] "Imido" refers to a group –C (O) NRyC (O) Rz, where Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally replaced, as defined in this document.
[0052] [0052] "Halogen" or "halo" refers to atoms occupying group VIIA of the periodic table, such as fluorine, chlorine, bromine or iodine.
[0053] [0053] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more (for example, one to five or one to three) hydrogen atoms are replaced by a halogen. For example, when a residue is replaced with more than one halogen, it can be referred to using a prefix corresponding to the number of halogen fractions attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted by two ("di") or three ("tri") halo groups, which may be, but not necessarily, the same halogen. Examples of haloalkyl include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.
[0054] [0054] "Haloalkyl" refers to a group as defined above, in which one or more (for example, one to five or one to three) hydrogen atoms are replaced by a halogen.
[0055] [0055] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more (for example, one to five or one to three) hydrogen atoms are replaced by a hydroxy group.
[0056] [0056] "Heteroalkyl" refers to an alkyl group in which one or more (for example, one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by same or different heteroatomic group, as long as the point of attachment to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes a saturated unbranched or branched chain having carbon and heteroatoms. For example, 1, 2 or 3 carbon atoms can be replaced independently by the same or different heteroatomic group. Heteroatomic groups include, but are not limited to -NRy-, -O-, -S-, -S (O) -, -S (O) 2- and the like, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document. Examples of heteroalkyl groups include, for example, ethers (for example -CH2OCH3, -CH (CH3) OCH3, -CH2CH2OCH3, - CH2CH2OCH2CH2OCH3, etc.), thioether (for example, -CH2SCH3, - CH (CH3) SCH3, -CH2CH2SCH3 , -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g. -CH2S (O) 2CH3, -CH (CH3) S (O) 2CH3, -CH2CH2S (O) 2CH3, - CH2CH2S (O) 2CH2CH2OCH3, etc.) and amino acids (for example, -CH2NRyCH3, - CH (CH3) NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyCH3, etc., where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or one of which may be heteroaryl each; optionally substituted, each of which can be optionally substituted, as defined in this document. As used in this document), heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms carbon; and 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom.
[0057] [0057] "Heteroalkylene" refers to a divalent alkyl group (ie alkylene) in which one or more (for example, one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatomic group. "Heteroalkylene" groups must have at least one carbon and at least one heteroatomic group within the chain. The term "heteroalkylene" includes an unbranched or branched saturated chain having carbon and heteroatoms. As an example, 1, 2 or 3 carbon atoms can be replaced independently by the same or different heteroatomic group. Heteroatomic groups include, but are not limited to -NRy-, -O-, -S-, -S (O) -, -S (O) 2- and the like, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document. Examples of heteroalkylene groups include, for example, -CH2OCH2-, -CH (CH3) OCH2-, -CH2CH2OCH2-, -CH2CH2OCH2CH2OCH2-, -CH2SCH2-, -CH (CH3) SCH2-, -CH2CH2SCH2-, -CH2CH2S2- CH2S (O) 2CH2-, -CH (CH3) S (O) 2CH2-, -CH2CH2S (O) 2CH2-, -CH2CH2S (O) 2CH2CH2OCH2-, -CH2NRyCH2-, -CH (CH3) NRyCH2-, -CH2CH2NRyCH2- , -CH2CH2NRyCH2CH2NRyCH2-, etc., wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. As used herein, the term "heteroalkylene" does not include groups such as amides or other functional groups with an oxo present in one or more carbon atoms.
[0058] [0058] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring hetero atoms independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl) or 3 to 8 carbon atoms in the ring (i.e., heteroaryl C3-8 heteroaryl); and 1 to 5 hetero atoms in the ring, 1 to 4 hetero atoms, 1 to 3 hetero atoms in the ring, 1 to 2 hetero atoms in the ring, or 1 hetero atoms in the ring, independently selected from nitrogen, oxygen and sulfur. In certain cases, heteroaryl includes 5 to 10 membered ring systems, 5 to 7 membered ring systems, or 5 to 6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring hetero atoms, 1 to 2 ring hetero atoms, or 1 ring hetero atoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, for example, cridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothia-diazolyl, benzonafururan, benzoxazolyl, benzothienyl (benzothiophenyl), benzazotriazolyl, imidazole, benzo [4] 2-a] pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxy-oxirolol, oxadiazol, 1-oxadiazol 1-oxopyrazinyl, 1-oxopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, py-
[0059] [0059] "Heteroarylalkyl" refers to the "heteroaryl-alkyl-" group.
[0060] [0060] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring hetero atoms selected independently from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups and spiroheterocyclyl groups. A heterocyclyl can be a single ring or multiple rings in which the multiple rings can be fused, bridged or spiro, and can comprise one or more fractions of oxo (= O) or N-oxide (-O-). Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the bond (that is, it can be attached through a carbon atom or a hetero atom). In addition, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, whose ring can be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. As used in this document, heterocyclyl has 2 to 20 ring carbon atoms (ie, C2-20 heterocyclyl), 2 to 12 ring carbon atoms (ie, C2-12 heterocyclyl), 2 to 10 carbon atoms in the ring (i.e., C2-10 heterocyclyl), 2 to 8 carbon atoms in the ring
[0061] [0061] "Heterocyclylalkyl" refers to the "heterocyclyl-alkyl-" group.
[0062] [0062] "Oxima" refers to the group -CRy (= NOH) in which Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document.
[0063] [0063] "Sulfonyl" refers to the group -S (O) 2Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.
[0064] [0064] "Sulfinyl" refers to the group -S (O) Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which can be optionally replaced, as defined in this document. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.
[0065] [0065] "Sulfonamido" refers to the groups -SO2NRyRz and -NRySO2Rz, where Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which can be optionally replaced, as defined in this document.
[0066] [0066] The terms "optional" or "optionally" mean that the event or circumstance described later may or may not occur and the description includes cases in which said event or circumstance occurs and cases in which it does not. Also, the term "optionally substituted" refers to any one or more (for example, one to five or one to three) hydrogen atoms in the designated atom or group may or may not be replaced by a different fraction of hydrogen.
[0067] [0067] In certain modalities, Ry and Rz, as used in this document, are optionally replaced. In certain embodiments, Ry and Rz, as used in this document, are not replaced.
[0068] [0068] The term "substituted" used in this document means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and / or heteroalkyl) in that at least one hydrogen atom is replaced by a bond to an atom other than hydrogen such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, starch, amino, amidino, aryl, aralkyl, azido, carbamoo , carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadine, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxus, N-oxide or -Si (Ry) 3 where each Ry is independently hydrogen, alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.
[0069] [0069] In certain embodiments, "substituted" includes any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups above, in which one or more (for example, one to five or one to three) atoms of hydrogen are independently replaced by deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC (= O) Rh, -NRgC ( = O) NRgRh, - NRgC (= O) ORh, -NRgS (= O) 1-2Rh, -C (= O) Rg, -C (= O) ORg, -OC (= O) ORg, - OC ( = O) Rg, -C (= O) NRgRh, -OC (= O) NRgRh, -ORg, -SRg, -S (= O) Rg, -S (= O) 2Rg, -OS (= O) 1 -2Rg, -S (= O) 1-2ORg, -NRgS (= O) 1-2NRgRh, = NSO2Rg, = NORg, -S (= O) 1- g 2NR Rh, -SF5, -SCF3 or -OCF3. In certain embodiments, "substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by -C (= O) Rg, -C (= O) ORg, -C (= O) NRgRh , - CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, and / or heteroarylalkyl, and / or heteroarylalkyl. In certain embodiments, "substituted" also means any of the above groups in which one or more (for example, one to five or one to three) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro , oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,
[0070] [0070] Polymers or similar undefined structures obtained by defining substituents with other additional substituents ad infinitum (for example, a substituted aryl having a substituted alkyl that is substituted with a substituted aryl group, which is additionally substituted by a substituted heteroalkyl group, etc.) are not intended to be included in this document. Unless otherwise stated, the maximum number of serial substitutions for the compounds described in this document is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to substituted aryl ((substituted aryl) aryl). Similarly, the above definitions are not intended to include disallowed substitution patterns (for example, methyl substituted with 5 fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). Such inadmissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined in this document.
[0071] [0071] In certain modalities, as used in this document, the phrase "one or more" refers to one to five. In certain modalities, as used in this document, the phrase "one or more" refers to one to three.
[0072] [0072] Any compound or structure provided in this document is also intended to represent unmarked forms, as well as forms of isotopically marked compounds. These forms of compounds can also be called "isotopically enriched analogs". The isotopically marked compounds have structures represented in this document
[0073] [0073] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described in this document, in which one or more (for example, one to five or one to three) hydrogens are / are replaced by deuterium, such as hydrogen in a carbon atom. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5 (12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, using starting materials in which one or more (for example, one to five or one to three) hydrogens have been replaced by deuterium.
[0074] [0074] The deuterium compounds or substituted therapeutics of the description may have enhanced properties of DMPK (drug metabolism and pharmacokinetics), related to distribution, metabolism and excretion (ADME). Substitution by heavier isotopes, such as deuterium,
[0075] [0075] The concentration of such heavier isotope, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of this description, any atom not specifically designated as a specific isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen in its naturally abundant isotopic composition. Therefore, in the compounds of this description, any atom specifically designated as deuterium (D) is intended to represent deuterium.
[0076] [0076] In many cases, the compounds of this description are capable of forming acidic and / or basic salts due to the presence of amino and / or carboxyl groups or groups similar to these.
[0077] [0077] Also provided are a pharmaceutically acceptable salt, isotopically enriched analogue, deuterated analogue, stereoisomer, mixture of stereoisomers and prodrugs of the compounds described in this document. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in the preparation of a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
[0078] [0078] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological efficacy and properties of the given compound, and that are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with an organic acid.
[0079] [0079] The term "hydrate" refers to the complex formed by combining a compound described in this document and water.
[0080] [0080] A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the description. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and ethanolamine.
[0081] [0081] Some of the compounds exist as tautomers. Tautomers are in balance with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the balance between the tautomers, the compounds are understood by someone ordinarily skilled in the art as comprising amide tautomers and imidic acid. Thus, amide-containing compounds are understood to include their tautomers of imidic acid. Likewise, compounds containing imidic acid are understood to include their amide tautomers.
[0082] [0082] The compounds of the invention, or the pharmaceutically acceptable salts thereof, include an asymmetric center and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry , as (R) - or (S) - or, as (D) - or (L) - for amino acids. The present invention is intended to include all possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) - and (S) -, or (D) - and (L) - isomers can be prepared using chiral syntones or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racmate of a salt or derivative) using, for example, liquid chromatography. high pressure with chiral phase (HPLC). When the compounds described in this document contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both the Z and E geometric isomers.
[0083] [0083] A "stereoisomer" refers to a compound consisting of the same atoms linked by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present invention contemplates several stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers, whose molecules are mirrored images not superimposable to each other.
[0084] [0084] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other.
[0085] [0085] The relative centers of the compounds, as represented in this document, are indicated graphically using the "thick bond" style (bold or parallel lines) and the absolute stereochemistry is represented using wedge bonds (bold or bold lines) parallel).
[0086] [0086] "Prodrugs" means any compound that releases a drug of active origin according to Formula I or any other formula described in this document in vivo when that prodrug is administered to a mammalian subject. Prodrugs of a compound described in this document are prepared by modifying functional groups present in the compound described in this document, such that the modifications can be cleaved in vivo to release the original compound. Prodrugs can be prepared by modifying the functional groups present in the compounds in such a way that the modifications are cleaved, both in routine manipulation and in vivo, to the parent compounds. Prodrugs include compounds described in this document in which a hydroxy, amino, carboxyl or sulfhydryl group in a compound described in this document is attached to any group that can be cleaved in vivo to regenerate the free hydroxy, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (eg, acetate, formate and benzoate), amides, guanidines, carbamates (eg, N, N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. The preparation, selection and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of A.C.S. Symposium Series; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated by reference into this document.
[0087] [0087] Compounds that modulate the eukaryotic initiation factor 2B are provided in this document.
[0088] [0088] In certain embodiments, a Formula I compound is provided:
[0089] [0089] In certain embodiments, a compound of Formula IA is provided:
[0090] [0090] In certain embodiments, when R3 is optionally substituted aryl or optionally substituted heteroaryl, z is 1, X1 is O and L is optionally substituted heteroaryl, L is not replaced by -L1-R14, where L1 is alkylene optionally substituted, optionally substituted heteroalkylene, or -O-, and R14 is hydrogen, optionally substituted aryl or optionally substituted heteroaryl.
[0091] [0091] In some embodiments, when z is 1, X1 is O, R3 is not optionally substituted aryl or optionally substituted heteroaryl.
[0092] [0092] In certain embodiments, when z is 0 and X1 is a bond, then R3 is not hydrogen or alkyl. In certain embodiments, when z is 0 and X1 is
[0093] [0093] In certain embodiments, when R3 is optionally substituted aryl or optionally substituted heteroaryl, z is 1, X1 is O and L is optionally substituted heteroaryl, L is not replaced by a group where: L1 is a C1-6 alkylene, 2 to 7 membered heteroalkylene, or -O-, where each C1-6 alkylene or 2 to 7 membered heteroalkylene is optionally substituted with 1 to 5 Rx; B is hydrogen, phenyl or heteroaryl of 5 to 6 members, where each phenyl or heteroaryl of 5 to 6 members is optionally substituted with 1-5 RY; each Rx is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano , -ORA, -NRBRC, -NRBC (O) RD, - C (O) NRBRC, -C (O) RD, -C (O) OH, -C (O) ORD, -SRE, -S (O) RD, and -S (O) 2RD; each RY is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo- C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyan, -ORA, -NRBRC, -NRBC (O) RD, -C (O) NRBRC, -C (O) RD, -C (O) OH, -C (O) ORD, - S (RF) m, -S (O) RD, -S (O) 2RD, and G1; or 2 RY groups on adjacent atoms together with the atoms to which they are attached, form a 3 to 7 membered fused cycloalkyl, heterocycloalkyl, 3 to 7 membered aryl, or 5 to 6 membered fused heteroaryl optionally substituted by 1-5 Rx ; each G1 is independently 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl, 5 to 6 membered aryl or heteroaryl, where each 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl, 5 to 7 membered 6 heteroaryl-members is optionally substituted with 1-3 Rz; each RZ is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -ORA, -NRBRC, -NRBC (O) RD, -C (O ) NRBRC, -C (O) RD, -C (O) OH, -C (O) ORD and -S (O) 2RD; and RA is, in each occurrence, independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, -C (O) NRBRC, -C (O) RD, -C (O) OH or -C (O) ORD each of RB and RC is independently hydrogen or C1-C6 alkyl; RB and RC together with the atom to which they are attached, form a 3 to 7 membered heterocyclyl ring optionally substituted by 1 to 3 Rz; each RD is independently C1-C6 alkyl or halo-C1-C6 alkyl; each RE is independently hydrogen C1-C6 alkyl or halo-C1-C6 alkyl; each RF is independently hydrogen, C1-C6 alkyl or halo; and m is 1, 3 or 5.
[0094] [0094] In certain embodiments, L is an optionally substituted heteroaryl ring.
[0095] [0095] In certain embodiments, L is an optionally substituted five-membered C2-4 heteroaryl ring.
[0096] [0096] In certain embodiments, L is a five-membered C2-4 heteroaryl ring optionally substituted with 1 to 3 atoms in the nitrogen ring.
[0097] [0097] In certain embodiments, L is an optionally substituted triazole, oxazole, imidazole, oxadiazole or isoxazole.
[0098] [0098] In certain embodiments, L is an optionally substituted heterocyclyl ring.
[0099] [0099] In certain embodiments, L is an optionally substituted five-membered C2-4 heteroaryl ring.
[00100] [00100] In certain embodiments, L is a five-membered C2-4 heteroaryl ring optionally substituted with 1 to 3 atoms in the nitrogen ring.
[00101] [00101] In certain embodiments, L is an optionally substituted dihydroisoxazole or an optionally substituted oxazolidine.
[00102] [00102] In certain embodiments, L is additionally replaced by one to five R13 in which each R13 is independently selected from halo, cyano, oxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy.
[00103] [00103] In certain embodiments, L is heteroalkylene optionally substituted with one to six R10.
[00104] [00104] In certain embodiments, L is a heteroalkylene of 2 to 4 straight chain atoms.
[00105] [00105] In certain embodiments, L is a heteroalkylene having 1 to 3 linear chain atoms with carbon chain atoms and a chain hetero atom selected from O, NRy and S.
[00106] [00106] In certain embodiments, L is -CH2O-, -CH2OCH2-, -CH2CH2O-, or -CF2CH2O-.
[00107] [00107] In certain embodiments, when L is heteroalkylene, then the point of attachment of the heteroalkylene to the bridged cycloalkyl is through a carbon atom. In certain embodiments, when L is heteroalkylene, the point of attachment of the heteroalkylene to the bridged cycloalkyl may be through a carbon atom or a heteroatom. In certain embodiments, when L is heteroalkylene, the point of attachment of the heteroalkylene to -R2 can be through a carbon atom or a heteroatom.
[00108] [00108] In certain embodiments, R3 and R4, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R11.
[00109] [00109] In certain embodiments, a compound of Formula II: A R2 is provided
[00110] [00110] In certain embodiments, R3 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which, except hydrogen, is optionally substituted by one or more R11; each of R4 and R5 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, each of which, except hydrogen, is optionally independently replaced by one or more halo, oxo, acetyl, amino or hydroxyl; and y is 1, 2, 3, 4, 5 or 6.
[00111] [00111] In certain modalities it is a compound of Formula IIA:
[00112] [00112] In certain modalities it is a compound of Formula IIB:
[00113] [00113] In certain modalities of Formula II, IIA or IIB, R2 is C3-10 cycloalkyl optionally substituted with one or more R11. In certain modalities, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with one or more R11. In certain modalities of Formula II, IIA or IIB, each R11 is independently halo, cyano, oxo - OR6, -SR6, -SF5, -NR6R7, C1-12 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R6, -C (O) OR6, -OC (O) OR6, -OC (O) R6, -C (O) NR6R7, -OC (O) NR6R7, -NR6C (O) NR7R8, -S ( O) 1-2R6, -S (O) 1-2NR6, -NR6S (O) 1-2R7, -NR6S (O) 1-2NR7R8, -NR6C (O) R7 or –NR6C (O) OR7, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R11 is independently optionally substituted with one or more R12. In certain modalities of Formula II, IIA or IIB, R2 is C3-10 cloalkyl optionally substituted with -OR6 to R6 is C1-12 alkyl optionally substituted with halo.
[00114] [00114] In certain modalities of Formula II, IIA or IIB, R3 is aryl or heteroaryl, each optionally substituted with one or more R11. In certain modalities of Formula II, IIA or IIB, R3 is phenyl optionally substituted with one or more halos, cyano, nitro, oxo, -OR6, -SR6, -SF5, -NR6R7, C1-12 alkyl, C2 -12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R6, -C (O) OR6, -OC (O) OR6, -OC (O) R6, -C (O) NR6R7, -OC (O) NR6R7, -NR6C (O) NR7R8, -S (O) 1-2R6, -S (O) 1-2NR6, -NR6S (O) 1-2R7, -NR6S (O) 1-2NR7R8, -NR6C (O) R7 or –NR6C (O) OR7. In certain embodiments of Formula II, IIA or IIB, R3 is phenyl optionally substituted with halo. In certain embodiments of Formula II, IIA or IIB, R2 is C3-10 cycloalkyl optionally substituted with -OR6, R6 is C1-12 alkyl optionally substituted with halo, and R3 is phenyl optionally substituted with one or more R11.
[00115] [00115] In certain embodiments, ring A is an optionally substituted heteroaryl.
[00116] [00116] In certain embodiments, ring A is optionally substituted five-membered C2-4 heteroaryl.
[00117] [00117] In certain embodiments, ring A is a five-membered C2-4 heteroaryl ring optionally substituted with 1 to 3 atoms in the nitrogen ring and optionally 1 or 2 atoms of oxygen and / or sulfur. In certain modalities, ring A is five-membered C2-4 heteroaryl optionally substituted with 1 to 3 atoms in the nitrogen ring.
[00118] [00118] In certain embodiments, ring A is an optionally substituted triazole, oxazole, imidazole, oxadiazole, benzoxazole, pyrazole, triazole, thiadiazole, tetrazole or isoxazole. In certain embodiments, ring A is an optionally substituted triazole, oxazole, imidazole, oxadiazole or isoxazole.
[00119] [00119] In certain embodiments, ring A is an optionally substituted heterocyclyl ring.
[00120] [00120] In certain embodiments, ring A is an optionally substituted five-membered C2-4 heterocyclyl ring.
[00121] [00121] In certain embodiments, ring A is a five-membered C2-4 heterocyclyl ring optionally substituted with 1 to 3 atoms in the nitrogen ring and optionally 1 or 2 atoms of oxygen and / or sulfur. In certain embodiments, ring A is five-membered C2-4 heterocyclyl optionally substituted with 1 to 3 atoms in the nitrogen ring.
[00122] [00122] In certain embodiments, ring A is an optionally substituted pyrrolidine, imidazolidine, dihydropyrrole, oxathiazolidine, dihydroisoxazole or oxazolidine. In certain embodiments, ring A is an optionally substituted dihydroisoxazole or an optionally substituted oxazolidine.
[00123] [00123] In certain embodiments, ring A can be additionally replaced by one to five R13, where each R13 is independently selected from halo, cyan, oxo, thioxo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy. In certain embodiments, ring A can be additionally substituted by one to five R13, where each R13 is independently selected from halo, cyano, oxo, C1-6 alkyl, C1-6-alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy.
[00124] [00124] In certain embodiments, ring A is not replaced (that is, it is not additionally replaced in addition to R2). In certain embodiments, ring A is no longer substituted and R2 is C3-10 cycloalkyl optionally substituted with one or more R11. In certain embodiments, ring A is a five-membered C2-4 heteroaryl ring optionally substituted with 1 to 3 atoms in the nitrogen ring and optionally 1 or 2 atoms of oxygen and / or sulfur. In certain embodiments, ring A is five-membered C2-4 heteroaryl optionally unsubstituted with 1 to 3 atoms in the nitrogen ring. In certain modalities, ring A is a five-membered C2-4 heteroaryl ring optionally unsubstituted with 1 to 3 atoms in the nitrogen ring and optionally 1 or 2 atoms of oxygen and / or sulfur. In certain embodiments, ring A is five membered C2- 4 heteroaryl optionally unsubstituted with 1 to 3 atoms in the nitrogen ring.
[00125] [00125] In certain modalities, R2 is hydrogen or halo. In certain modalities, R2 is hydrogen.
[00126] [00126] In certain embodiments, R2 is C1-12 alkyl, C1-12 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkoxy, heterocyclyl or aryl, each of which is optionally substituted with one to six R11.
[00127] [00127] In certain embodiments, R2 is C3-10 cycloalkyl optionally substituted with one to six R11.
[00128] [00128] In certain embodiments, R2 is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, methyl, ethyl, propyl, methoxy or cyclobutoxy, each optionally substituted by one to six R11. In certain embodiments, R2 is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, methyl, ethyl, propyl, methoxy or cyclobutoxy, each optionally substituted by one to six R10.
[00129] [00129] In certain modalities, R2 is replaced by one to six R11. In certain embodiments, R2 is replaced by at least one R11.
[00130] [00130] In certain embodiments, R2 is C3-10 cycloalkyl substituted by C1-6 haloalkoxy. In certain embodiments, R2 is cycloalkyl substituted by trifluoromethoxy. In certain embodiments, R2 is 3- (trifluoromethoxy) cyclobutyl.
[00131] [00131] In certain embodiments, R2 is C3-10 cycloalkyl replaced by (C1-6 haloalkoxy) methyl. In certain embodiments, R2 is cycloalkyl substituted by (trifluoromethoxy) methyl. In certain embodiments, R2 2 - ((trifluoromethoxy) methyl) cyclopropyl.
[00132] [00132] In certain embodiments, R11 is hydroxyl, halo (C1-6 alkoxy), halo, cycloalkyl, cycloalkoxy, phenyl, C1-6 alkoxycarbonyl, cyano, halo (C1-6 alkyl), halo (C1-6 alkoxy ) cycloalkoxy, halo (C1-6 alkoxy) alkyl, halo (heterocyclyl) or halophenoxy.
[00133] [00133] In certain embodiments, R11 is 1,1,1-trifluoroethyl, 1,1-difluoroethyl, triazol-2-yl, trifluoromethylthio, trifluoromethoxy, (3,3-difluoropyrrolidin-1-yl) methyl, 2,2, 2-trifluoro-1-methyl-ethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3- (trifluoro-methyl) azetidin-1-yl, chlorine, difluoromethoxy, difluoromethyl, fluoro, methyl, tert-butoxycarbonyl , trifluoromethoxymethyl or cyclopropyl.
[00134] [00134] In certain embodiments, R2 is (4-chloro-3-fluoro-phenoxy) methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, 3- (difluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) cyclobutoxymethyl, 3- (trifluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) propyl, 3- (trifluoromethyl) cyclobutyl, 3-cyanocyclobutyl, 3,3-difluoro-1-methyl -propyl, 4-chloro-3-fluoro-phenyl, 4-
[00135] [00135] In certain embodiments, R2 is (4-chloro-3-fluoro-phenoxy) methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, 3- (difluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) cyclobutoxymethyl, 3- (trifluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) propyl, 3- (trifluoromethyl) cyclobutyl, 3- cyanocyclobutyl, 3,3-difluoro-1-methyl-propyl , 4-chloro-3-fluoro-phenyl, 4-chlorophenyl, benzyl, cyanocyclobutyl, cyclobutoxymethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopropyl, cyclopropylethyl, cyclopropylmethyl, hydroxycyclutyl, methyl, N-tert-butoxy-butoxy-methyl-butoxy -3-yl, N-tert-butoxy (carbonyl) pyrrolidin-3-yl, tetrahydrofuranyl, trifluoroethyl, trifluoromethoxy, (trifluoromethoxy) cyclobutoxy, trifluoromethoxyethyl, trifluoromethoxymethyl, 3- (1,1-difluoroethyl), - (1,1,1-trifluoroethyl) azetidinyl, 3- (triazol-2-yl) cyclobutyl, 3- (trifluoromethylthio) cyclobutyl or 3- (cyclopropyl) cyclobutyl.
[00136] [00136] In the embodiments, R2 is (4-chloro-3-fluoro-phenoxy) methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, 3- (difluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) cyclobutoxymethyl, 3- (trifluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) propyl, 3- (trifluoromethyl) cyclobutyl, 3-cyano-cyclobutyl, 3,3-difluoro-1-methyl-propyl, 4-chloro-3-fluoro-phenyl, 4-chlorophenyl, benzyl, cyanocyclobutyl, cyclobutoxymethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopropyl, cyclopropylethyl, cyclopropylmethyl, hydroxycyclobutyl, methyl, N-tert-butoxy (carbonyl) 3-yl, N-tert-butoxy (carbonyl) pyrrolidin-3-yl, tetrahydrofuranyl, trifluoroethyl, trifluoromethoxy, (trifluoromethoxy) cyclobutoxy, trifluoromethoxyethyl, trifluoromethoxymethyl, 3- (1,1-difluoroethyl) cyclobutyl (1,1,1-trifluoroethyl) azetidinyl, 3- (triazol-2-yl) cyclobutyl, 3- (trifluoromethylthio) cyclobutyl, 3- (cyclopropyl) cyclobutyl, (3,3-difluoroazetidin-1-yl) methyl , (3.3- difluo-
[00137] [00137] In certain embodiments, R2 is (4-chloro-3-fluoro-phenoxy) methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, 3- (difluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) cyclobutoxymethyl, 3- (trifluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) propyl, 3- (trifluoromethyl) cyclobutyl, 3- cyanocyclobutyl, 3,3-difluoro-1-methyl-propyl , 4-chloro-3-fluoro-phenyl, phenyl, 3- (trifluoromethyl) phenyl, 2-hydroxymethyl-4- (trifluoromethyl) phenyl, 2-fluoro-4- (trifluoromethyl) phenyl, 3-fluoro-4- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 2,4-difluorophenyl, 4-chloro-2,6-difluorophenyl, 4-chloro-2,3-difluorophenyl, 4-chloro-2,5-diflu- orophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-2-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro- 2-fluororo-phenyl, 5- (trifluoromethyl) -2-pyridyl, 6- (trifluoromethyl) -2-pyridyl, 2- (trifluoromethyl) pyrimidin-5-yl, 5-fluoropyridin-3-yl, 1 , 2,3-triazol-2-yl) cic lobut-3-yl, 1,2,3-triazol-2-yl) cyclobut-1-yl, 2-hydroxy-4- (trifluoromethyl) phenyl, 2-cyano-4- (trifluoromethyl) phenyl, 2, 2-difluorobenzo [d] [1,3] dioxol-5-yl, 3 - ((tert-butyldimethyl-lil) oxy) cyclobutyl, 5- (trifluoromethyl) -4,5-dihydrooxazol-2-yl, 2-methoxycarbonyl -4- (trifluoromethyl) phenyl, 2- (trifluoromethoxy) ethoxy, 4-chlorophenyl, benzyl, 2-cyanocyclobutyl, 2-hydroxycyclobutyl, cyclobutoxymethyl, cyclobutyl, cyclobutyl, cyclopentyl, cyclopropyl, cyclopropyl, cyclopropyl, cyclopropyl, cyclopropyl , N-tert-butoxy (carbonyl) azetidin-3-yl, N-tert-butoxy (carbonyl) pyrrolidin-
[00138] [00138] In certain embodiments, R2 is 3- (1,1-difluoroethyl) cyclobutyl, 3- (1,1,1-trifluoroethyl) azetidinyl, 3- (triazol-2-yl) cyclobutyl, 3- (trifluoromethylthio) ci - clobutyl or 3- (cyclopropyl) cyclobutyl.
[00139] [00139] In certain embodiments, L or ring A is (4-chloro-3-fluoro-phenoxy) methyl] -1,3,4-oxadiazol-2-yl, 1- (3-cyanocyclobutyl) triazole- 4-yl, 1- (3-hydroxy-cyclobutyl) triazol-4-yl, 1- (4-chlorophenyl) triazol-4-yl, 1-benzyltriazol-4-yl, 1-cyclo-butyltriazole-4-yl, 1H-1,2,3-triazol-4-yl, 2- (3-cyanocyclobutyl) triazol-4-yl, 2- (trifluoromethoxy) ethyl] -1,3,4-oxadiazol-2-yl, 2 -cyclobutyltriazole-4-yl, 3 - [(trifluoromeoxy) cyclobutoxy] -imidazol-1-yl, 3-cyanocyclobutyl) triazol-4-yl, 3-cyclobutyloxyzol-5-yl, 4- (cyclobutylmethyl) imidazole -1-yl, 4- [3- (trifluoromethoxy) cyclobutyl] imidazol-1-yl, 4-cyclobutylimidazol-1-yl, 4-cyclobutyloxazol-2-yl, 5 - ((4-chloro-3-flu - orophenoxy) methyl) -4H-1,2,4-triazol-3-yl, 5- (1-fluorocyclopropyl) -1,3,4-oxadiazol-2-yl, 5- (2-cyclopropylethyl) -1, 3,4-oxadiazol-2-yl, 5- (2,2-difluorocyclopropyl) - 1,3,4-oxadiazol-2-yl, 5- (2,2,2-trifluoroethyl) -1,3,4- oxadiazol-2-yl, 5- (3-cyanocyclobutyl) -1,3,4-oxadiazol-2-yl, 5- (3,3-difluoro-1-methyl-propyl) -1,3,4- oxadiazole - 2-yl, 5- (4-chloro-3-fluoro-phenyl) -1,3,4-oxadiazol-2-yl, 5- (cyclobutoxymethyl) -
[00140] [00140] In certain modalities, when R2 replaces cyclobutyl, the substitute in cyclobutyl is cis. In certain embodiments, the substituent on cyclobutyl is trans.
[00141] [00141] In certain modalities, X1 is O. In certain modalities, X1 is a link.
[00142] [00142] In certain embodiments, z is 0 and X1 is a link.
[00143] [00143] In certain embodiments, z is 0, X1 is a bond and R3 is C1-12 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by one or more R11.
[00144] [00144] In certain embodiments, R3 is C1-12 alkyl, which is optionally substituted with one or more R11.
[00145] [00145] In certain modalities, z is 0. In certain modalities, z is 1.
[00146] [00146] In certain embodiments, R3 is C3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by one or more R11.
[00147] [00147] In certain embodiments, R3 is C3-10 cycloalkyl, aryl or heteroaryl, each of which is optionally substituted with one or more R11.
[00148] [00148] In certain embodiments, R3 is cyclobutyl, triazolyl or phenyl, each of which is optionally substituted with one or more R11.
[00149] [00149] In certain modalities, R3 is a cyclobutyl. In certain modalities, R3 is cyclobutyl and R11 is trifluoromethoxy.
[00150] [00150] In certain embodiments, R3 is optionally substituted phenyl.
[00151] [00151] In certain embodiments, R3 is phenyl optionally substituted with one or more substituents selected independently from halo, cyano, C1-12 alkyl optionally substituted with one or more halo and C1-12 alkoxy optionally substituted with one or more halos.
[00152] [00152] In certain embodiments, R3 is phenyl substituted by chlorine, fluorine or a combination thereof.
[00153] [00153] In certain embodiments, R3 is 4-chlorophenyl, 4-chloro-3-fluorophenyl or trifluoromethoxycyclobut-2-yl.
[00154] [00154] In certain embodiments, R3 is 4-chlorophenyl, 4-chloro-3-fluorophenyl, trifluoromethoxycyclobut-2-yl (5-chloro-3-pyridyl) methyl, 1- (2,2,2-trifluoroethyl) azeti- din-3-yl, 2- (trifluoromethoxy) ethyl, 2-spiro [2.3] hexan-5-yl, 3- (trifluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) cyclobutyl] methyl, 3- (trifluoromethoxy) cyclopen tila, 3- (trifluoromethoxymethyl) cyclobutyl, 3-fluorophenyl, 4-cyclopropylphenoxy, 4-fluorophenyl or 6,6-difluoro-3-bicyclo [3.1.0] hexanyl.
[00155] [00155] In certain embodiments, R3 is 3,4-difluorophenyl, 2- (trifluoromethyl) pyridin-5-yl, 4- (trifluoromethyl) phenyl, 2- (4-fluoro-1H-pyrazol-1-yl) ethyl, 2- (trifluoro-methoxy) ethyl, 1- (2,2,2-trifluoroethyl) piperidin-4-yl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 6-chlorochroman-2-yl, 6- fluorochroman-2-yl, 5-chlorobenzo [d] oxazol-2-yl, 6- (trifluoromethyl) quinolin-2-yl, 3-chloroquinolin-7-yl, 7-chloroquine-lin-3-yl, 6-chloroquinolin -2-yl, 7-fluoroimidazo [1,2-a] pyridin-2-yl, 6-fluoropyrazolo [1,5-a] pyridin-2-yl, 3- (2H-1,2,3- triazol-2-yl) cyclobutyl, 3- (trifluoromethoxy) phenyl, 5-chlorobenzo [d] thiazol-2-yl, 7-chloro- [1,2,4] triazolo [1,5-a] pyridin-2- ila, 7-chloroimidazo [1,2-b] pyridazin-2-yl, 5-fluorobenzo [d] oxazol-2-yl, 7-bromoimidano [1,2-a] pyridin-2-yl, 6- fluoroimidazo [1,2-a] pyridin-2-yl, 7-chloropyrrolo [1,2-c] pyrimidin-3-yl, 7-chloroisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-bromoisoquin-
[00156] [00156] In certain embodiments, R4 and R5 are H. In certain embodiments, R4 and R5 are each independently H, alkyl optionally substituted with hydroxy.
[00157] [00157] In certain modalities R1 is H.
[00158] [00158] In certain embodiments, a compound of Formula III is provided:
[00159] [00159] In certain embodiments, a compound of Formula IV is provided:
[00160] [00160] In certain embodiments, a compound of Formula V is provided:
[00161] [00161] In certain modalities it is a compound of Formula VI:
[00162] [00162] In certain embodiments, a compound of Formula IIIA is provided:
[00163] [00163] In certain modalities, a compound of Formula IVA is provided:
[00164] [00164] In certain embodiments, a Formula VA compound is provided:
[00165] [00165] In certain modalities it is a compound of Formula VIA:
[00166] [00166] In certain modalities of Formula III, IV, V, VI, IIIA, IVA, VA or VIA, each R11 1 is independently halo, cyan, oxo, -OR6, -SR6, -SF5, - NR6R7, C1-12 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R6, -C (O) OR6, -OC (O) OR6, -OC (O) R6, -C (O) NR6R7, -OC (O) NR6R7, - NR6C (O) NR7R8, -S (O) 1-2R6, -S (O) 1-2NR6, -NR6S (O) 1-2R7, -NR6S (O) 1-2NR7R8, - NR6C (O) R7 or –NR6C (O) OR7, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R11 is independently optionally substituted with one or more R12. In certain embodiments of Formula III, IV, V, VI, IIIA, IVA, VA or VIA, R2 is C3-10 cycloalkyl optionally substituted with -OR6 and R6 is C1-12 alkyl optionally substituted with halo.
[00167] [00167] In certain modalities of Formula III, IV, V, VI, IIIA, IVA, VA or VIA, R3 is aryl or heteroaryl, each optionally substituted with one or more R11. In certain modalities of Formula III, IV, V, VI, IIIA, IVA, VA or VIA, R3 is phenyl optionally substituted with one or more halos, cyan, nitro, oxo, -OR6, -SR6, -SF5, -NR6R7, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R6, -C (O) OR6, - OC (O) OR6, -OC ( O) R6, -C (O) NR6R7, -OC (O) NR6R7, -NR6C (O) NR7R8, -S (O) 1- 6 2R, -S (O) 1-2NR6, -NR6S (O) 1 -2R7, -NR6S (O) 1-2NR7R8, -NR6C (O) R7 or - NR6C (O) OR7. In certain modalities of Formula III, IV, V, VI, IIIA, IVA, VA or VIA, R3 is phenyl optionally substituted with halo.
[00168] [00168] In certain embodiments, L or ring A is,,
[00169] [00169] In certain modalities of Formulas I, IA or II, ring A is optionally substituted heteroaryl and R2 is optionally substituted cycloalkyl.
[00170] [00170] In certain modalities of Formulas I, IA or II, ring A is optionally substituted heteroaryl and R2 is cyclopropyl, cyclobutyl or cyclopentyl, optionally substituted by halo, oxo, amino, hydroxyl, cyano, alkyl, alkenyl , alkynyl or alkoxy, where the alkyl, alkenyl, alkynyl and alkoxy are independently optionally substituted by oxo, halo, amino or hydroxyl.
[00171] [00171] In certain embodiments, a compound selected from Table 1 is provided: Table 1 Ex. Compound 1 2 3
[00172] [00172] In certain modalities, a compound selected from Table 2 is provided: Table 2 F F F N THE N THE THE N H THE F F F F F F N THE N THE THE N H THE F F
[00173] [00173] In certain embodiments, a compound is provided to have the structure or a salt, isotypically enriched analogue, prodrug, stereoisomer or a mixture of stereoisomers thereof. In certain embodiments, the salt is the HCl salt.
[00174] [00174] In certain modalities, a compound is provided to have the structure or a salt thereof. In certain embodiments, the salt is the HCl salt.
[00175] [00175] In certain modalities, a compound is provided to have the structure or a salt thereof. In certain embodiments, the salt is the HCl salt.
[00176] [00176] "Treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. The beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (for example, decreasing one or more symptoms resulting from the disease or condition, and / or decreasing the measure of the disease or condition); b) delay or interrupt the development of one or more clinical symptoms associated with the disease or condition (for example, stabilize the disease or condition, prevent or delay the worsening or progression of the disease or condition, and / or prevent or delay the spread (for example, metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (for example, improving the disease state, providing partial or total remission of the disease or condition, increasing the effect of another medication, slowing the progression of the disease). - increases, increasing the quality of life and / or prolonging survival.
[00177] [00177] "Prevention" or "prevent" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. The compounds may, in some modalities, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
[00178] [00178] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described in this document can be useful for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In specific modalities, the subject is a human being.
[00179] [00179] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, isotypically enriched analogue, stereoisomer, stereoisomer mixture or prodrug thereof means to make treatment effective when administered to a subject, in order to provide a therapeutic benefit such as an improvement in symptoms or slowing down disease progression. For example, a therapeutically effective amount may be an amount sufficient to lessen a symptom of a disease or condition as described in this document. The therapeutically effective amount may vary depending on the subject, disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the manner of administration, which can be readily determined by someone ordinarily versed. in the technique.
[00180] [00180] The methods described in this document can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described in this document can be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include, in vitro cell cultures and biological samples, including fluid or tissue samples obtained from individuals. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine and saliva. In this context, the compounds and compositions described in this document can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described in this document can be used ex vivo to determine the ideal schedule and / or dosage for administering a compound of the present description for a given indication, cell type, individual and other parameters. The information collected from such use can be used for experimental or clinical purposes to define protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described in this document may be suitable are described below or will become apparent to those skilled in the art. The selected compounds can further be characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties can be examined using methods commonly known to those skilled in the art.
[00181] [00181] In certain embodiments, the compounds disclosed in this document can be used to treat cell proliferative disorders, including cancerous and non-cancerous cell proliferative disorders. The treatment of cell proliferative disorders may include, but is not limited to, inhibition of cell proliferation, including rapid proliferation. It is contemplated that the compounds described in this document can be used to treat any type of cancer, including, but not limited to, carcinomas, sarcomas, lymphomas, leukemias and germ cell tumors. Examples of cancer include, but are not limited to, adrenocortical carcinoma, anal cancer, appendix cancer, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma or malignant fibrous histiocytoma, brain cancer (for example, brain stem glioma , asthocytoma (eg cerebellar, cerebral, etc.), atypical teratoid / rhabdoid tumor, embryonic tumors of the central nervous system, malignant glioma, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, parenchymal pineal tumors of differentiation intermediary, supratentorial and / or pinoblastoma primitive neuroectodermal tumors, visual and / or hypothalamic glioma, brain and spinal cord tumors, etc.), breast cancer, bronchial tumors, carcinoid tumor (for example, gastrointestinal tumor, etc. ), unknown primary carcinoma, cervical cancer, chordoma, chronic myeloproliferative disorders, colon cancer, colorectal cancer, embryonic tumors, cancer central nervous system er, endometrial cancer, ependymoma, esophageal liver cancer, Ewing tumor family, eye cancer (eg, intraocular melanoma, retinoblastoma, etc.), gallbladder cancer, gastric cancer, tumor gastrointestinal (eg, carcinoid tumor, stromal (gastrointestinal) tumor, stromal cell tumor, etc.), germ cell tumor (eg, extracranial, extragonadal, ovarian, etc.), gestational trophoblastic tumor, cancer head and neck, hepatocellular cancer, hypopharyngeal cancer, hypothalamic and visual glioma, intraocular melanoma, islet tumors, Kaposi's sarcoma, kidney cancer, large cell tumors, laryngeal cancer (e.g. acute lymphoblastic, acute myeloid, etc. .), leukemia (e.g., myeloid, acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogen, chronic myeloid, multiple myeloid, hairy cell, etc.), lip cancer and / or oral cavity cancer, liver cancer, lung cancer (for example, non-small cells, small cells, etc.), lymphoma (for example, AIDS-related, Burkitt, cutaneous Tcell, Hodgkin, non-Hodgkin, primary central nervous system, cutaneous T cells , Waldenstrom's macroglobulinemia, etc.), malignant fibrous bone histiocytoma and / or osteosarcoma, medulloblastoma, meduloepithelioma, Merkel cell carcinoma, mesothelioma, metastatic cancer of the squamous neck, mouth cancer, neoplasia syndrome multiple endocrine, plasma cell neoplasia / multiple myeloma, fungal mycoses, myelodysplastic, myelodysplastic diseases (eg, myeloproliferative, chronic disorders, etc.), cancer of the nasal cavity and / or paranasal sinus, nasopharyngeal cancer, neuroblastoma, bu-cancer ; oral cavity cancer, oropharyngeal cancer; osteosarcoma and / or malignant fibrous histiocytoma of the bone; ovarian cancer (for example, ovarian epithelial cancer, ovarian germ cell tumor, tumor of low ovarian malignant potential, etc.), pancreatic cancer (eg islet cell tumors, etc.), papillomatosis, cancer of paranasal sinus and / or nasal cavity, parathyroid cancer, penile cancer, pharynx cancer, pheochromocytoma, pineal parenchymal tumors of intermediate differentiation, primitive supratentorial neuroectodermal tumors and pinoblastoma, pituitary tumor, plasma cell neoplasia / multiple myeloma, pleuropulmonary blast, prostate cancer, rectal cancer, renal cell cancer, transitional cell cancer, respiratory tract carcinoma involving the nut gene on chromosome 15, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (eg, family of Ewing tumors, Kaposi, soft tissue, uterine, etc.), Sézary syndrome, skin cancer (eg, non-melanoma, melanoma, Merkel cell, etc.), cancer of the small intestine, squamous cell carcinoma, squamous cell cancer of the neck with hidden primary metastatic, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and / or thymic carcinoma, cancer of the thymus thyroid, transitional cell cancer of the kidney, pelvis and / or ureter (for example, trophoblastic tumor, carcinoma of an unknown primary site, urethral cancer, uterine cancer, endometrial, uterine sarcoma, etc.), vaginal cancer, glioma hypothalamic and / or visual pathway, vulvar cancer, Wilms' tumor and the like. Examples of non-cancerous cell proliferative disorders include, but are not limited to, fibroadenoma, adenoma, intraductal papilloma, nipple adenoma, adenosis, fibrosis disease or breast disorders, plasma cell proliferative disorder (PCPD), restenosis, atherosclerosis, rheumatoid arthritis, myofibromatosis, fibrous hamartoma, proliferative disorders of granular lymphocytes, benign prostatic hyperplasia, heavy chain diseases (HCDs), lymphoproliferative disorders, psoriasis, idiopathic pulmonary fibrosis, scleroderma, hepatic cirrhosis, glomerulonephritis, nephropathy mesangial proliferative, membranoproliferative glomerulonephritis, hemangiomas, vascular and non-vascular intra-vascular proliferative disorders and the like.
[00182] [00182] In certain embodiments, the compounds disclosed in this document can be used to treat lung injuries and / or lung inflammation.
[00183] [00183] In certain embodiments, the compounds disclosed in this document can be used to treat cancer, precancerous syndromes and diseases / injuries associated with response pathways to activated unfolded proteins, such as Alzheimer's disease, neuropathic pain, injury spinal cord, traumatic brain injury, ischemic stroke, stroke, Parkinson's disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob disease, insomnia
[00184] [00184] In the modalities, the compounds disclosed in this document can be used to treat or decrease the severity of cancer, Alzheimer's disease, stroke, type 1 diabetes, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, infarction myocardium, cardiovascular disease, atherosclerosis, arrhythmias or age-related macular degeneration.
[00185] [00185] In certain embodiments, the compounds disclosed in this document can be used to treat neuropathic pain.
[00186] [00186] In certain embodiments, the compounds disclosed in this document can be used to treat or decrease the severity of eye diseases / angiogenesis. In certain modalities, eye disease includes vascular leakage (for example, edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as rubeosis irides, neovascular glaucoma, pterygium, vascularized glaucoma filter bubbles, conjunctival papilloma), choroidal neovascularization (for example, age-related neovascular macular degeneration (AMD), myopia, previous uveitis, trauma or idiopathic), macular edema (eg, post-surgical macular edema, macular edema secondary to uveitis, including inflammation of the retina and / or choroidal, macular edema secondary to diabetes and occlusive
[00187] [00187] In certain embodiments, the compounds disclosed in this document can be used to treat viral infections (for example, to prevent the initiation of viral protein synthesis). Exemplary viruses that can be treated using the compounds disclosed in this document include, but are not limited to, picornaviridae (eg, poliovirus), reoviridae (eg, rotavirus), togaviridae (eg, encephalitis virus, virus yellow fever, rubella virus, etc.), orthomyxoviridae (for example, flu virus), paramyxoviridae (for example, respiratory syncytial virus, measles virus, mumps virus, parainfluenza virus, etc.), rhabdoviridae (for example, rabies virus), coronaviridae, bunyaviridae, flaviviridae, filaviridae and bunavaviridae, aravaviridae, arenavirus, retroviridae (for example, human T-cell lymphotropic viruses (HTLV), human immunodeficiency virus (HIV), etc.), papovaviridae (for example, pililoma virus), adenoviridae (for example, adenovirus), herpesviridae (for example, herpes simplex virus) and poxyiridae (for example, smallpox virus). In certain embodiments, viral infection is caused by the hepatitis B virus, hepatitis C virus and / or HIV.
[00188] [00188] In certain embodiments, the compounds disclosed in this document can be used to treat disorders associated with viral infections. These disorders include, but are not limited to, neurological symptoms (eg, encephalitis, meningoencephalitis, paralysis, myelopathy, neuropathy, aseptic meningitis, hemiparesis, dementia, dysphagia, lack of muscle coordination, impaired vision, coma etc.), symptoms of cachexia (for example, inflammatory cell infiltration, perivascular cuff of blood vessels, demyelination, necrosis, reactive gliosis, etc.), symptoms of gastroenteritis (eg, diarrhea, vomiting, cramps, etc.), symptoms of hepatitis ( nausea, vomiting, pain in the right upper quadrant, elevated levels of liver enzymes (eg, AST, ALT, etc.), jaundice, etc.), symptoms of hemorrhagic fever (eg, headache, fever, chills, body aches, diarrhea, vomiting, dizziness, confusion, abnormal behavior, pharyngitis, conjunctivitis, red face, red neck, hemorrhage, organ failure, etc.), oncogenic symptoms (eg, sarcomas, leukemias and the like, as well like disease s "rare" malignancies, for example, Kaposi's sarcoma, oral skin leukoplakia, lymphomas, etc.), symptoms of immunodeficiency (eg, opportunistic infections, emaciation, rare neoplasms, neurological disease, fever, diarrhea, skin rashes , etc.), lesions (for example, warts (for example, common wart, flat wart, deep hyperkeratotic palmoplantar wart, deep hyperkeratotic palmoplantar wart, superficial mosaic type palmoplantar wart, etc.)), epidermodysplasia, mucosal lesions, ulcers and systemic symptoms (eg fever, chills, headache, muscle pain, bone pain, joint pain, pharyngitis, tonsillitis, sinusitis, otitis, bronchitis, pneumonia, bronchopneumonia, nausea, vomiting, increased salivation, skin rash, macules, lymphadenopathy, arthritis, ulcers, photosensitivity, weight loss, irritability, restlessness, anxiety, coma, death, etc.).
[00189] [00189] In certain embodiments, the compounds disclosed in this document can be used to treat disorders characterized by unwanted synthesis and / or abnormal accumulation of one or more mutant and / or wild-type proteins. It is contemplated that the compounds disclosed in this document that can inhibit the initiation of translation and, thus, reduce the load on the protein folding machine and, consequently, reduce the severity of the disorder. Disorders associated with unwanted synthesis and / or abnormal accumulation of one or more mutant and / or wild-type proteins include, but are not limited to, Tay-Sachs disease, cystic fibrosis, phenylketonuria, Fabry disease, Alzheimer's, Huntington's disease, Parkinson's disease, frontotemporal dementia, congophilic angiopathy, prion-related disorders (ie, transmissible spongiform encephalopathies, such as Creutzfeldt-Jacob disease, kuru, fatal familial insomnia, scrapie, bovine spongiform encephalopathy , etc.) and the like.
[00190] [00190] It is contemplated that the compounds and compositions disclosed in this document are capable of inhibiting neuronal cell death, as in prion disease. Generally, the method includes administering a therapeutically effective amount of a compound or composition as described herein, to a patient in need.
[00191] [00191] In some modalities, the disorder is a neurodegenerative disease. The term "neurodegenerative disease" refers to a disease or medical condition in which the functioning of an individual's nervous system is compromised. Examples of neurodegenerative diseases include, for example, Alexander disease, Alper disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), encepha- bovine spongiform lopathy (BSE), Canavan's disease, Cockayne's syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, dementia with Lewy corpuscles, Machado-Joseph's disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Prion's disease, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined spinal cord degeneration of pernicious anemia, squ izophrenia, spinocerebellar ataxia (various types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski's disease, insulin resistance or Tabes dorsalis.
[00192] [00192] Other modalities include the use of the compounds presently disclosed in therapy. Some modalities include its use in the treatment of a neurodegenerative disease.
[00193] [00193] In other embodiments, the compounds currently disclosed for use in the treatment of Alzheimer's disease, Parkinson's disease, dementia or ALS are provided.
[00194] [00194] In other embodiments, the use of the compounds presently disclosed for the manufacture of a medicament to treat a neurodegenerative disease is provided.
[00195] [00195] In other modalities, the use of the compounds currently disclosed is provided for the manufacture of a medicine for the treatment of Alzheimer's disease, Parkinson's disease, dementia or ALS.
[00196] [00196] Also included in this document are kits that include a compound of the description, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof and suitable packaging. In certain embodiments, a kit additionally includes instructions for use. In one aspect, a kit includes a compound of the description, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof and a label and / or instructions for using the compounds in the treatment of indications, including diseases or conditions described in this document.
[00197] [00197] Manufacture articles are also provided in this document which include a compound described in this document or a pharmaceutically salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof in a suitable container. The container can be a vial, jar, ampoule, pre-filled syringe and intravenous bag.
[00198] [00198] The compounds provided in this document are normally administered in the form of pharmaceutical compositions. Thus, pharmaceutical compositions containing one or more of the compounds described in this document or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof and one or more pharmaceutically acceptable vehicles selected from among vehicles, adjuvants are also provided in this document. and excipients. Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17a. Ed. (1985); and Modern Pharmaceutics, Marcell Dekker, Inc. 3a. ed. (GS Banker and CT Rhodes, Eds.).
[00199] [00199] The pharmaceutical compositions can be administered in single or multiple doses. The pharmaceutical composition can be administered by several methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition can be administered by intra-arterial, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or as an inhalant injection.
[00200] [00200] One mode of administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described in this document can be incorporated for administration by injection include,
[00201] [00201] Oral administration may be another route for administration of the compounds described in this document. Administration can be, for example, by enteric coated capsules or tablets. When making pharmaceutical compositions that include at least one compound described or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, prodrug thereof, the active ingredient is usually diluted by an excipient and / or closed in. of a vehicle that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material, which acts as a vehicle, vehicle or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.
[00202] [00202] Some examples of suitable excipients include, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, po-livinylpyrrolidone, cellulose, sterile water , syrup, and methylcellulose. Formulations can include lubricating agents, such as talc, magnesium stearate and mineral oil; wetting agents; suspending and emulsifying agents; preserving agents, such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
[00203] [00203] Compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched stereoisomer analog, mixture of stereoisomers or prodrug thereof can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer coated reservoirs or drug polymer matrix formulations. Another formulation for use in the methods described in this document employs transdermal delivery devices ("patches"). Transdermal patches can be used to provide continuous or batch infusion of the compounds described in this document in controlled quantities. The construction and use of transdermal patches for the administration of pharmaceutical agents is well known in the art. Such plasters can be constructed for continuous, pulsatile or on-demand administration of pharmaceutical agents.
[00204] [00204] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt , isotopically enriched analog, mix of stereoisomer or prodrug. When referring to these preformulation compositions as homogeneous, the active ingredient can be dispersed evenly throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules.
[00205] [00205] The tablets or pills of the compounds described in these documents can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action, or to protect against acidic stomach conditions. For example, the tablet or pill may include an internal dosage component and an external dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the internal component to pass intact in the duodenum or to have a delayed release. A variety of materials can be used for such enteric layers or coatings, such materials, including a series of polymeric acids and polymeric acid mixtures with such materials, such as shellac, cetyl alcohol and cellulose acetate.
[00206] [00206] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described herein. In some modalities, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents can be nebulized by the use of inert gases. The nebulized solutions can be inhaled directly from the nebulizer device or the nebulizer device can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension or powder compositions can also be administered, preferably orally or nasally, from devices that distribute the formulation in an appropriate manner.
[00207] [00207] The specific dose level of a compound of the present application for any particular individual will depend on a variety of factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration , route of administration and rate of excretion, combination of drugs and the severity of the disease in particular in the subject being treated. For example, a dosage can be expressed as a number of milligrams of a compound described in this document per kilogram of the subject's body weight (mg / kg). Dosages between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, a dosage between 0.5 and 60 mg / kg may be appropriate. In some embodiments, a dosage of about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or about 0, 01 to about 10 mg of compound per kg of body weight may be appropriate. Standardization according to the subject's body weight is particularly useful when adjusting dosages between subjects of very different size, such as when using the drug in children and human adults or when converting an effective dosage into a non-human subject, such as a dog, for a dosage suitable for a human subject.
[00208] [00208] The compounds can be prepared using the methods disclosed in this document and their routine modifications, which will be evident from the present description and methods well known in the art. Conventional and well-known synthetic methods can be used in addition to the teachings described in this document. The synthesis of typical compounds described in this document can be carried out as described in the following examples. If available, reagents and starting materials can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.
[00209] [00209] It will be appreciated that typical or preferred process conditions are given (ie reaction temperatures, times, molar ratios of reagents, solvents, pressures, etc.), other process conditions may also be used, unless otherwise stated . Optimal reaction conditions may vary with the specific reagents or solvents used, but such conditions can be determined by a person skilled in the art through routine optimization procedures.
[00210] [00210] In addition, conventional protecting groups may be necessary to prevent certain functional groups from suffering unwanted reactions. Protection groups suitable for various functional groups, as well as conditions suitable for protecting and unprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW and Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Inter-science and references cited there.
[00211] [00211] In addition, the compounds of this description may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers. All of these stereoisomers (and enriched mixtures) are included in the scope of this description, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents known in the art. Alternatively, a racemic mixture of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
[00212] [00212] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures or obvious modifications to them, described in standard reference texts, such as Fieser and Fieser's Reagents for
[00213] [00213] In certain embodiments, a method of preparing a compound of Formula I is provided, comprising coupling a compound of Formula 1-A: 1-A with a compound of Formula 2-A: 2-A under suitable conditions to provide a Formula 3-A: 3-A compound and coupling a Formula 3-A compound to a suitable reagent in combination with a Formula R2-C (O) 2H acid under reaction formation conditions ring (when L is a ring) or coupling reaction conditions, optionally in combination with reduction (when L is heteroalkylene) to provide the compound of Formula I, where R1, R3, R4, R5, R10, x, y, z and X1 are defined in this document, R50 is H, -NHNH2 or an leaving group and LG is leaving group (for example, C1-6 alkoxy or halo). In addition, compounds of Formula I where L is heteroalkylene can be provided by coupling a compound of Formula 3A to a compound of Formula R2-OH suitably functionalized (for example, when L comprises an O), optionally in combination with a reduction step.
[00214] [00214] The following reaction shown in Scheme I illustrates a general method that can be used for the synthesis of the compounds disclosed in this document. In Scheme I, R1, R3, R4, R5, R10, x, y and X1 are as defined in this document, R50 is H or an output group, PG is a protection group and LG is an output group (for example, example, C1-6 alkoxy or halo). Scheme I
[00215] [00215] With reference to Scheme I, compound 1-2 can be prepared by reacting compound 1-1, where R50 is -NHNH2, with a suitable reagent under conditions of ring formation reaction with a car acid - properly substituted boxy to provide oxadiazole 1-2. Deprotection of compound 1-2 provides compound 1-3, followed by coupling with a compound of Formula 1-4 suitably substituted to provide compound 1-5. In certain embodiments, compound 1-3 is converted to a salt (for example, the HCl salt) prior to coupling with a Formula 1-4 compound. properly replaced.
[00216] [00216] The appropriate starting materials and reagents (ie diamines, esters and acids) can be purchased or prepared by methods known to those skilled in the art. EXAMPLES
[00217] [00217] The following examples are included to demonstrate the specific modalities of the description. It should be appreciated, by those skilled in the art, that the techniques disclosed in the examples that follow represent techniques for operation, as well as the practice of description and, thus, can be considered to constitute the specific modes for their practice. However, those versed in the technique must, in the light of this description, appreciate that many changes can be made in the specific modalities that are disclosed and still obtain an equal or similar result without departing from the spirit and scope of the description. General Experimental Methods
[00218] [00218] All solvents used were commercially available and were used without further purification. The reactions were typically carried out using anhydrous solvents under an inert nitrogen atmosphere.
[00219] [00219] NMR spectroscopy: 1H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz or one of the following instruments: a Bruker Avance 400 instrument equipped with DUAL 400MHz S1 probe, a Bruker Avance 400 instrument equipped with 6 S1 400 MHz 5 mm probe 1H-13C ID, a Bruker Avance III 400 instrument with nanobay equipped with a direct 5mm BBFO Broadband probe, a Bruker Mercury NMR spectrometer Plus 400 equipped with a probe
[00220] [00220] Thin layer chromatography: Where thin layer chromatography (TLC) has been used, it refers to TLC on silica gel using F254 silica gel plates (Merck), Rf is the distance covered by the compound divided by the distance traveled by the solvent on a TLC plate. Column chromatography was performed using an automatic rapid chromatography system on silica gel cartridges or in the case of reverse phase chromatography on C18 cartridges. Thin layer chromatography (TLC) was performed on Alchram® (Silica gel 60 F254) from Mancherey-Nagel and UV was typically used to visualize the spots. Additional methods of visualization have also been employed in some cases. In these cases, the TLC plate was developed with iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing well), ninhydrin (commercially available from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g (NH4) 6Mo7O24.4H2O, 5 g (NH4) 2Ce (IV) (NO3) 6 in 450 mL of water and 50 mL of concentrated H2SO4) to view the compound.
[00221] [00221] Mass Chromatography by Liquid Chromatography and Analysis by HPLC: the analysis by HPLC was performed in the Shimadzu 20AB HPLC system with a photodiode array detector and Luna-C18 (2) 2.0 × 50 mm column, 5 µm at a flow rate of 1.2 mL / min with a gradient solvent mobile phase A (MPA, H2O + 0.037% (v / v) TFA): mobile phase B (MPB, ACN + 0.018% (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS was detected at 220 and 254 nm or evaporative light dispersion detection (ELSD) was used as well as positive electrospray ionization (MS). Semi-preparative HPLC was performed for any acidic or neutral condition.
[00222] [00222] General procedure A, T3P coupling: To a flask containing amine (1 eq) and carboxylic acid (1.5 eq) in DMF or EtOAc (0.1 M-0.2 M) was added N-methylimidazole, di -isopropylethylamine or triethylamine (3.0- 5.0 eq) followed by T3P solution (1.5-3.0 eq., 50% in EtOAc). The resulting reaction mixture was stirred at room temperature for 4 h, at which time a 1M NaOH solution was added followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using flash chromatography on silica or reverse phase HPLC to provide the desired product.
[00223] [00223] The following compounds were prepared using General Procedure A and were used to prepare the compounds disclosed in this document: tert-butyl (3- (2- (3,4-difluorophenoxy) acetamido) bicycles [1.1.1] pen-tan-1-yl) carbamate and tert-butyl N- [1 - [[2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetyl] amino] -3-bicycle [1.1.1] pentanyl] carbamate .
[00224] [00224] General procedure B, Hydrazide formation: To a suspension of the methyl ester (1 eq) in EtOH (0.25-0.1M) was added hydrazine hydrate (3-5 eq) and the reaction mixture was heated to 90 ° C overnight. The reaction mixture was cooled to room temperature, causing the product to crystallize from the solution. This solid was collected by removing the supernatant. If the product did not crystallize, the solution was concentrated and the crude product was sufficiently pure to be used in the subsequent steps.
[00225] [00225] General procedure C, Formation of oxadiazole: To a solution of hydrazide (1 eq) and carboxylic acid (1.5 eq) in EtOAc or MeCN (0.1M) was added NEt3 (5 eq) followed by T3P solution ( 3 eq). The resulting reaction mixture was heated to 100 ° C in a sealed flask overnight. The reaction mixture was diluted with saturated NaHCO3 and EtOAc solution. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC.
[00226] [00226] General procedure D, Acyl Chloride: To a flask containing carboxylic acid (1 eq) and DMF (0.05 eq) in DCM (0.1 M-0.2 M), oxalyl chloride ( 1.2 eq) at 0 oC. The resulting reaction mixture was stirred at 0 oC for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was used directly.
[00227] [00227] Or: The solution of acid (1 eq) in SOCl2 (0.5 M) was stirred at 85 ° C for 3 h. The reaction mixture was concentrated under reduced pressure to provide the crude product that was used directly.
[00228] [00228] General procedure E, α-bromoketone: To a solution of acyl chloride (1 eq) in MeCN (0.1 M) and THF (0.1 M) was added TMSCHN2 (1.5 eq) in DCM (0.1 M) at 0 oC and the reaction mixture was stirred at 0 ° C for 1 h. To the mixture was added aq. HBr (1.1 eq, 48% solution), at which time H2O was added followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was used directly or purified using flash chromatography on silica to provide the desired product.
[00229] [00229] General Procedure F, Bromoketone Alkylation: To a flask containing primary amine (1 eq) and α-bromoketone (1 eq) in MeCN (0.1 M-0.2 M) was added Na2CO3 (4 eq). The resulting reaction mixture was heated at 40 oC for 2 h. The reaction mixture was cooled to room temperature and H2O was added followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was used directly or purified using flash chromatography on silica to provide the desired product.
[00230] [00230] The following compounds were prepared using General Procedure F and were used to prepare the compounds disclosed in this document: N- (3 - ((2-oxo-2- (3- (trifluoromethyl) phenyl) ethyl) amino ) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3 - ((2- (2,4-difluorophenyl) -2-oxoethyl) amino ) bicycle [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoro-methoxy) cyclobutoxy) acetamide, N- (3 - ((2- (4-fluorophenyl) -2-oxoethyl) amino ) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- ((2- (3-fluorophenyl) -2-oxoethyl) amino ) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoro-methoxy) cyclobutoxy) acetamide, N- (3 - ((2- (3,4-difluorophenyl) -2-oxoethyl ) amino) bi- cycle [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- ((2- (4-chlorophenyl) -2-oxoethyl ) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoro-methoxy) cyclobutoxy) acetamide, N- (3 - ((2- (3-fluoro-4-methylphenyl) -2-oxoethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutó xi) acetamide, N- (3 - ((2- (4-chlorophenyl) -2-oxoethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3- trans- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3 - ((2- (4-fluoro-2-methylphenyl) - 2-oxoethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- ( trifluoromethoxy) cyclobutoxy) acetamide, 2- (3,4-difluorophenoxy) -N- (3 - ((2-oxo-2- (3- (trifluoromethoxy) cyclo-butyl) ethyl) amino) bicycle [1.1.1 ] pentan-1-yl) acetamide, N- (3 - ((2- (4-chloro-2-fluorophenyl) -2-oxoethyl) amino) bicycle [1.1.1] pentan-1-yl) -2 - (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3 - ((2-oxo-2- (3- (trifluoromethyl) phenyl) ethyl) amino) bicyclo [1.1.1] pentan-1- il) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3 - ((2- (2-fluoro-4- (trifluoromethyl) phenyl) -2-oxoethyl) amino) bicycle [1.1.1 ] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3 - ((2- (3-fluoro-4- (trifluoromethyl) phenyl) -2-oxoethyl) amino) bicycles [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclo-butoxy) acetamide, N- (3 - ((2-oxo-2- (4- (trifluoromethyl) phenyl) ethyl) amino) bicycle [1.1.1] pentan-1-yl) -2- (3 -cis- (trifluoromethoxy) cyclobutoxy) acetamide, and N- (3 - ((2-oxo-2- (3-cis- (trifluoromethoxy) cyclobutyl) ethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- ((6- (trifluoromethyl) pyridin-3-yl) oxy) acetamide.
[00231] [00231] General procedure G, Formylation: To a solution of Ac2O (2 eq) in formic acid (0.1 M) was added secondary amine (1 eq) in DCM
[00232] [00232] The following compounds were prepared using General Procedure G and were used to prepare the compounds disclosed in this document: N- (3- (N- (2-oxo-2- (3- (trifluoromethyl) phenyl) ethyl ) formamido) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- (N- (2- (2,4-difluorophenyl) -2 -oxoethyl) formamido) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- (N- (2- (4-fluorophenyl) -2 -oxoethyl) formalized) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- (N- (2- (3- fluorophenyl) -2-oxoethyl) formamido) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- (N- (2- (3, 4-difluorophenyl) -2-oxoethyl) formamido) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- (N- (2- (4-chlorophenyl) -2-oxoethyl) formamide) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- (N- (2- (3-fluoro-4-methylphenyl) -2-oxoethyl) formamide) bicyclo [1.1.1] pentan-1-yl ) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- (N- (2- (4-chlorophenyl) -2-oxoethyl) formamo) bicyclo [1.1.1] pentan-1 -yl) -2- (3-trans- (trifluoromethoxy) cyclobutoxy) ace-tamide, N- (3- (N- (2- (4-fluoro-2-methylphenyl) -2-oxoethyl) formamide) bicycles [1.1 .1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, 2- (3,4-difluorophenoxy) -N- (3- (N- (2-oxo-2 - (3- (trifluoromethoxy) cyclobutyl) ethyl) formamido) bicyclo [1.1.1] pentan-1-yl) acetamide, tert-butyl (3 - ((2- (4-chlorophenyl) -2-oxoethyl) amino ) bicycles [1.1.1] pentan-1-yl) carbamate, N- (3- (N- (2- (4-chloro-2-fluorophenyl) - 2-oxoethyl) formamide) bicycles [1.1.1] pentan- 1-yl) -2- (3-cis- (trifluoromethoxy) cyclo-butoxy) acetamide, N- (3- (N- (2- (4-fluoro-3-methylphenyl) -2-oxoethyl) formamide) bicy- clo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide, N- (3- (N-
[00233] [00233] General procedure H, Cyclization of Formats: To a solution of tertiary amine (1 eq) in AcOH (0.1 M) was added CH3COONH4 (5 eq) and the reaction mixture was heated at 110 oC for 15 h, moment where it was sitting. NaHCO3 was added followed by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using p-HPLC.
[00234] [00234] The following compound was prepared using General Procedure H and was used to prepare the compounds disclosed in this document: tert-butyl (3- (4- (4-chlorophenyl) -1H-imidazol-1-yl) bicycle [1.1 .1] pentan-1-yl) carbamate. INTERMEDIATE 1 Methyl 3 - [[2- (4-chlorophenoxy) acetyl] amino] bicycle [1.1.1] pentane-1-carboxylate
[00235] [00235] Prepared using General Procedure A using methyl 3-aminobicyclo [1.1.1] pentane-1-carboxylate salt (255 mg, 1.0 mmol), 2- (4-chlorophenoxy) acetic acid (224 mg, 1.2 mmol), N-methylimidazole (246 mg, 3.0 mmol) and T3P (382 mg, 1.2 mmol) in DMF (2 mL). LC-MS m / z: = 310.1 [M + H] +. 1H-NMR (400 MHz, CDCl3): δ 7.24 - 7.30 (m, 2 H), 6.89 - 6.96 (m, 1 H), 6.81 - 6.88 (m, 2 H), 4.39 (s, 2 H), 3.66 - 3.74 (m, 3 H), 2.36 - 2.47 (m, 6 H).
[00236] [00236] Prepared using General Procedure A using methyl 3-aminobicyclo [1.1.1] pentane-1-carboxylate trifluoroacetate salt (1.06 g, 4.14 mmol), 2- (4-chloro-3 acid) -fluoro-phenoxy) acetic (1.02 g, 4.97 mmol), DIPEA (1.61 g, 12.4 mmol) and T3P (1.58 g, 4.97 mmol) in DMF 8.3 mL) . 1H-NMR (400 MHz, DMSO-d6): δ ppm 7.33 (t, J = 8.60 Hz, 1 H), 6.84 (br s, 1 H), 6.76 (dd, J = 10.14, 2.87 Hz, 1 H), 6.64 - 6.71 (m, 1 H), 4.40 (s, 2 H), 3.71 (s, 3 H), 2.44 (s, 6 H). INTERMEDIATE 3 2- (4-chlorophenoxy) -N - [1- (hydrazinocarbonyl) -3-bicycle [1.1.1] pentanil] aceamide
[00237] [00237] Prepared using General Procedure B, using methyl 3- [[2- (4-chlorophenoxy) acetyl] amino] bicyclo [1.1.1] pentane-1-carboxylate (270 mg, 0.87 mmol), hydrate hydrazine (131 mg, 2.6 mmol) in EtOH (3.5 mL). LC-MS m / z: = 310.1 [M + H] +. INTERMEDIATE 4 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanyl] acetamide
[00238] [00238] Prepared using General Procedure B, using methyl 3- [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] bicyclo [1.1.1] pentane-1-carboxylate (1.46 g, 4.5 mmol), hydrazine hydrate (669 mg, 13.3 mmol) in EtOH (18 mL). LC-MS m / z: = 328.1 [M + H] +. INTERMEDIATE 5 tert-butyl 3-cis-hydroxycyclobutanecarboxylate
[00239] [00239] A mixture of tert-butyl 3-oxocyclobutanecarboxylate (70.0 g, 411 mmol) in MeOH (700 mL) was added NaBH4 (15.6 g, 411 mmol) at - 30 ° C under N2 for 2 h. The reaction mixture was stirred at -30 ° C for 0.5 h. The reaction mixture was quenched by the addition of ice with sat. NH4Cl
[00240] [00240] To a reaction flask equipped with a stir bar and covered with aluminum foil in a water bath were added AgOTf (134.3 g, 523 mmol), Selectfluor (92.6 g, 261 mmol), KF (40 , 5 g, 697 mmol) and tert-butyl 3-cis-hydroxycyclobutanecarboxylate (30.0 g, 174 mmol) under N2. Then, EtOAc (1000 mL), 2-fluoropyridine (50.7 g, 523 mmol) and TMSCF3 (74.3 g, 523 mmol) were added dropwise in succession, keeping the internal temperature below 30 oC using a water bath. The reaction mixture was stirred at 25 ° C for 12 h. The reaction mixture was filtered through a plug of silica and the filtrate was concentrated under reduced pressure. The residue was washed with MTBE (800 ml) and filtered. The filtrate was washed with 1 N CuSO4 (3 × 300 mL) and the organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel. 1H-NMR (400 MHz, CDCl3): δ 4.60- 4.48 (m, 1H), 2.69-2.53 (m, 3H), 2.52-2.37 (m, 2H), 1.46 (s, 9H). 3-cis- (trifluoromethoxy) cyclobutanecarboxylic acid
[00241] [00241] To a solution of tert-butyl 3-cis- (trifluoromethoxy) cyclobutanocarboxylate (24.0 g, 100.0 mmol) in DCM (250 mL) was added TFA (77.0 g, 675 mmol). The mixture was stirred at 40 ° C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 ml), washed with H2O (3 × 30 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. 1H-NMR (400 MHz, DMSO-d6): δ 12.39 (s, 1H), 4.74 (quin, J = 7.44 Hz, 1 H), 2.76-2.64 (m, 1H ), 2.63-2.53 (m, 2H), 2.33-2.21 (m, 2H).
[00242] [00242] A mixture of 3-benzyloxycyclobutanone (100.0 g, 567 mmol) in MeOH (1000 mL) was added NaBH4 (21.5 g, 567 mmol) at -30 ° C under N2 for 2 h. The reaction mixture was stirred at -30 ° C for 0.5 h. The reaction mixture was quenched by the addition of ice and sat. NH4Cl (600 mL) slowly at 0 ° C over 0.5 h. The reaction mixture was concentrated under reduced pressure to leave the aqueous phase which was extracted with EtOAc (3 x 200 ml). The combined organics were washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a mixture of diastereomers in favor of the cis product. 1H-NMR (400 MHz, CDCl3): δ 7.32-7.18 (m, 5H), 4.35 (s, 2H), 3.83 (quin, J = 7.17 Hz, 1H), 3 , 56 (quin, J = 6.95 Hz, 1H), 2.69-2.60 (m, 2H), 1.91-1.82 (m, 2H). tert-butyl 2- (3-cis- (benzyloxy) cyclobutoxy) acetate
[00243] [00243] To a mixture of 3-cis- (benzyloxy) cyclobutanol (19.7 g, 110 mmol), tert-butyl 2-bromoacetate (32.3 g, 165 mmol), tetrabutylammonium hydrogen sulfate (1.9 g, 5.5 mmol) and water (10 mL) in toluene (400 mL) NaOH (66.3 g, 1.6 mol) in water (120 mL) was added. The reaction mixture was stirred at 25 ° C for 4 h. The reaction mixture was quenched by adding ice water (120 ml) and extracted with MTBE (3 x 50 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was used directly. 1 H-NMR (400 MHz, CDCl3): δ 7.39-7.27 (m, 5H), 4.42 (s, 2H), 3.89 (s, 2H), 3.75-3.62 (m, 2H), 2.65 (dtd, J = 9.26, 6.28, 6.28, 3.31 Hz, 2H), 2.09-2.00 (m, 2H), 1.48 (s, 9H). tert-butyl 2- (3-cis-hydroxycyclobutoxy) acetate
[00244] [00244] To a solution of tert-butyl 2- (3-cis- (benzyloxy) cyclobutoxy) acetate (27.0 g, 92.4 mmol) in MeOH (350 mL) was added Pd / C (3.0 g , 10% by weight of Pd on carbon) under N2. The reaction mixture was degassed under vacuum, purged with H2 three times and stirred under H2 (50 psi) at 50 ° C for 12 h.
[00245] [00245] To a reaction flask equipped with a stir bar and covered with aluminum foil in a water bath were added AgOTf (57.2 g, 222 mmol), Selectfluor (39.4 g, 111 mmol), KF (17 , 2 g, 297 mmol) and tert-butyl 2- (3-cis-hydroxycyclobutoxy) acetate (15.0 g, 74.2 mmol) under N2. Then, EtOAc (600 mL), 2-fluoropyridine (21.6 g, 222 mmol) and TMSCF3 (31.6 g, 222 mmol) were added dropwise in succession, maintaining the internal temperature below 30 oC using a water bath. The reaction mixture was stirred at 25 ° C for 12 h. The reaction mixture was filtered through a plug of silica and the filtrate was concentrated under reduced pressure. The residue was washed with MTBE (800 mL) and filtered. The residue was purified by column chromatography on silica gel. 1H-NMR (400 MHz, CDCl3): δ 4.35- 4.22 (m, 1H), 3.90 (s, 2H), 3.81-3.69 (m, 1H), 2.86- 2.72 (m, 2H), 2.40-2.23 (m, 2H), 1.49 (s, 9H). 2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetic acid
[00246] [00246] To a solution of tert-butyl 2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetate (11.5 g, 42.6 mmol) in DCM (100 mL) was added TFA (30.8 g , 270 mmol) under N2. The reaction mixture was stirred at 40 ° C for 2 h and then concentrated under reduced pressure. The residue was dissolved in DCM (30 ml), washed with H2O (3 × 30 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was used directly. 1H-NMR (400 MHz, CDCl3): δ 4.26-4.19 (m, 1H), 4.00 (s, 2H), 3.73-3.70 (m, 1H), 2.77- 2.74 (m, 2H), 2.27-2.24 (m, 2H). INTERMEDIATE 7 N-methoxy-N-methyl-2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetamido
[00247] [00247] To a solution of 2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetic acid (1.6 g, 7.7 mmol) in EtOAc (50 mL) was added N, N-diisopropylethyl- mine (4.47 mL, 25.7 mmol) followed by T3P (2.4 g, 7.7 mmol, 50% in EtOAc). The resulting reaction mixture was stirred 10 min and N, O-dimethylhydroxylamine hydrochloride (500 mg, 5.13 mmol) was added. The reaction mixture was stirred at 23 ° C for 4 h. The reaction mixture was quenched by the addition of sat. NH4Cl and extracted with EtOAc (3 x 25 mL) The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was sufficiently pure and was used directly. 1H-NMR (400 MHz; CDCl3): δ 4.29 (t, J = 7.3 Hz, 1H), 4.21 (s, 2H), 3.83 (td, J = 7.0, 1, 1 Hz, 1H), 3.71 (s, 3H), 3.21 (s, 3H), 2.83 (dtd, J = 9.8, 6.6, 3.2 Hz, 2H), 2, 38-2.32 (m, 2H). 2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetaldehyde
[00248] [00248] To a cooled solution of N-methoxy-N-methyl-2- [3-cis- (trifluoro-methoxy) cyclobutoxy] acetamide (100 mg, 0.39 mmol) in THF (3.9 mL) a - 78 ° C, diisobutylaluminum hydride (0.78 mL, 0.78 mmol, 1 M in hexane) was added. The reaction mixture was stirred at -78 ° C for 2 h. The reaction mixture was quenched by the addition of anhydrous EtOAc (1.0 ml) and sat. NH4Cl (3 mL) and then removed from the cooling bath and allowed to stir for 15 min. The reaction mixture was then diluted with water (20 ml) and extracted with Et2O (3 x 15 ml). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude aldehyde was used immediately and without further purification. INTERMEDIATE 8 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine tert-butyl (3- (hydrazinecarbonyl) bicycle [1.1.1] pentan-1-yl) carbamate
[00249] [00249] To a solution of methyl 3 - ((tert-butoxycarbonyl) amino) bicycle [1.1.1] pentane-1-carboxylate (1.0eq) in 2-propanol (1.0 M) was added NH2NH2 • H2O (3.0 eq) in one portion at 0 ° C. The mixture was stirred at 85 ° C for 12 h. The reaction mixture was cooled to 25 ° C and filtered. The filter cake was washed with 2-propanol and dried under reduced pressure to provide the desired product. LC-MS: m / z: 242.1 [M + H] +. tert-butyl (3- (2- (3-cis- (trifluoromethoxy) cyclobutane-1-carbonyl) hydrazine-1-carbonyl) bicyclo [1.1.1] pentan-1-yl) carbamate
[00250] [00250] For a suspension of 3-cis- (trifluoromethoxy) cyclobutane-1-carboxylic acid (1.1 eq; ratio 8: 1 to 10: 1 of cis- to trans-) in anhydrous N, N-dimethylformamide (DMF ) (1.1 M) TEA (4.0 eq) and T3P (2.0 eq, 50% in EtOAc) were added dropwise at 0 ° C. The reaction mixture was heated to 20 ° C and stirred for 1 h. The reaction mixture was then cooled to 0 ° C and tert-butyl (3- (hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl) carbamate (275 g, 1.14 mol, 1 eq) was added to the mixture reaction in portions at 0 ° C. The reaction mixture was stirred for 12 h at 25 oC. The reaction was suppressed by adding sat. NaHCO3. The mixture was further stirred at 40 ° C for 10 min and filtered immediately. The filter cake was washed with water and dried under reduced pressure at 45 ° C. The crude product was used directly. LC-MS: m / z: 408.1 [M + H] +. tert-butyl (3- (5- (3-cis- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadiazol-2-yl) bi- cycle [1.1.1] pentan-1-yl) carbamate
[00251] [00251] To a suspension of tert-butyl (3- (2- (3-cis- (trifluoromethoxy) cyclo-butane-1-carbonyl) hydrazine-1-carbonyl) bicycles [1.1.1] pentan-1-yl) carbamate (1.0 eq) in MeCN (0.25 M) K2CO3 (powder, 325 mesh, 5.0 eq) was added [note: Cs2CO3 can be used in place of K2CO3 powder], 4 Å Molecular Sieves ( 1: 1 w / w) and p-toluenesulfonyl chloride (TsCl) (2.5 eq) at 25 ° C. The resulting reaction mixture was heated to 80 ° C and stirred for 3 h. The reaction mixture was cooled to 25 ° C and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in MeCN (0.6 M) at 70 ° C and water (0.4 M) was added to the solution in one portion. The mixture was stirred for 15 min at 20 ° C and filtered. The filter cake was washed with water and was dissolved in dichloromethane. The solution was dried over filtered Na2SO4 and
[00252] [00252] For tert-butyl (3- (5- (3-cis- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadazole-2-yl) bicycles [1.1.1] pentan-1-yl) carbamate (1.0 eq) was added to HCl (20 eq, 4 M in EtOAc) in a portion at 0 ° C. The reaction mixture was stirred at 25 ° C for 12 h. The reaction mixture was concentrated under reduced pressure to provide an 8: 1 to 10: 1 diastereomeric mixture of 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazole-2 -il] bicycles [1.1 .1] pentan-3-amine favoring 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicycles [1.1.1 ] pentan-3-amine. The crude residue was used directly. LC-MS: m / z: 290.0 [M + H] +. INTERMEDIATE 9 N- (3-ethynylbicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide N- (3-formylbicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide
[00253] [00253] To a solution of N- (3- (hydroxymethyl) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (430 mg, 1.39 mmol) in DCM (5.0 mL) at 0 ° C DMP (649 mg, 1.53 mmol) was added in portions. The mixture was heated to 15 ° C and was stirred for 12 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel. 1 H-NMR (400 MHz, CDCl3): δ 9.66 (s, 1H), 6.88 (br s, 1H), 4.37-4.25 (m, 1H), 3.80 (s, 2H), 3.73-3.70 (m, 1H), 2.83-2.80 (m, 2H), 2.40 (s, 6H), 2.30-2.20 (m, 2H) .
[00254] [00254] To a solution of N- (3-formylbicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (240 mg, 0.78 mmol) in MeOH ( 5.0 mL) at 0 ° C K2CO3 (324 mg, 2.34 mmol) and dimethyl (1-diazo-2-oxopropyl) phosphonate (210 mg, 1.09 mmol) were added, and the mixture was heated to 15 ° C and stirred for 4 h. The reaction mixture was diluted with water (10 ml) and was concentrated under reduced pressure to remove MeOH. The aqueous phase was extracted with EtOAc (3 x 5 ml), the combined organics were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to deliver the title compound. 1H-NMR (400 MHz, CDCl3): δ 6.80 (br s, 1H), 4.36-4.31 (m, 1H), 3.79 (s, 2H), 3.76-3.65 (m, 1H), 2.83-2.80 (m, 2H), 2.41 (s, 6H), 2.31-2.20 (m, 2H), 2.17 (s, 1H). EXAMPLE 1 2- (4-Chlorophenoxy) -N- [3- (5-tetrahydrofuran-3-yl-1,3,4-oxadiazol-2-yl) -1-bi- cycle [1.1.1] pentanil ] acetamide
[00255] [00255] Prepared using General Procedure C, using 2- (4-chlorophenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (20 mg, 0.06 mmol) , tetrahydro-3-furoic acid (11 mg, 0.1 mmol), NEt3 (33 mg, 0.32 mmol) and T3P (62 mg, 0.19 mmol) in EtOAc (0.5 mL). 1H-NMR (400 MHz; CDCl3): δ 7.26-7.22 (m, 2H), 6.97-6.92 (m, 1H), 6.84-6.80 (m, 2H), 4.38-4.34 (m, 2H), 4.12-4.05 (m, 1H), 4.00-3.57 (m, 4H), 2.59-2.47 (m, 6H ), 2.36-2.29 (m, 2H). LC-MS: m / z: 390.2 [M + H] +. EXAMPLE 2 2- (4-Chlorophenoxy) -N- [3- (5-tetrahydrofuran-2-yl-1,3,4-oxadiazol-2-yl) -1-bi- cycle [1.1.1] pentanil ] acetamide
[00256] [00256] Prepared using General Procedure C, using 2- (4-chlorophenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (20 mg, 0.06 mmol) , tetrahydro-2-furoic acid (11 mg, 0.1 mmol), NEt3 (33 mg, 0.32 mmol) and T3P (62 mg, 0.19 mmol) in EtOAc (0.5 mL). 1H-NMR (400 MHz; CDCl3): δ 7.27-7.23 (m, 2H), 6.95 (s, 1H), 6.85-6.81 (m, 2H), 5.10- 5.07 (m, 1H), 4.38 (s, 2H), 4.00-3.89 (m, 2H), 2.61 (s, 6H), 2.35-2.29 (m, 2H), 2.16 - 1.95 (m, 2H). LC-MS: m / z: 390.2 [M + H] +. EXAMPLE 3 2- (4-chlorophenoxy) -N- [3- [5- [cis-3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadazol-2-yl] -1-bicycles [1.1. 1] pentanil] acetamide
[00257] [00257] 2- (4-chlorophenoxy) -N- [1- (hydrazinecarbonyl) -3-bicyclo [1.1.1] pentaanyl] acetamide (200 mg, 0.65 mmol), 3-cis- (trifluoromethoxy acid) ) cyclobutane carboxylic (131 mg, 0.71 mmol; 8: 1 to 10: 1 ratio of cis- to trans-) and triethylamine (NEt3) (0.45 mL, 3.23 mmol) were dissolved in EtOAc (2.6 ml) and T3P solution (0.58 ml, 1.94 mmol, 50% in EtOAc) was added. The resulting reaction mixture was heated to 100 ° C overnight, cooled to room temperature and was diluted with sat. aq. NaHCO3 solution (10 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase prep HPLC to deliver the desired product as a clear oil. 1H-NMR (400 MHz; CDCl3): δ 7.33-7.29 (m, 2H), 7.03 (s, 1H), 6.91-6.87 (m, 2H), 4.76- 4.69 (m, 1H), 4.44 (s, 2H), 3.39-3.30 (m, 1H), 2.92-2.84 (m, 2H), 2.74-2, 68 (m, 2H), 2.67 (s, 6H). LC-MS m / z: = 458.20 [M + H] +.
[00258] [00258] Alternatively, a mixture of 2- (4-chlorophenoxy) acetic acid (50 mg, 0.27 mmol), 2- (4-chlorophenoxy) acetic acid (50 mg, 0.27 mmol), NEt3 (123 mg , 1.21 mmol) and T3P (185 mg, 0.29 mmol, 50% purity) in DCM (1 mL) was stirred at 0 ° C for 1 h. To the mixture was added 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine salt HCl (8: 1 to 10: 1 favoring the cis-diastereomer) (70 mg, 0.24 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 12 h. To the reaction was added sat. aq. NaHCO3 (4 ml). The aqueous phase was extracted with DCM (5 ml, 3 ml). The combined organic phase was washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title of the compound. EXAMPLE 4 2- (4-chlorophenoxy) -N- [3- [5- (2,2,2-trifluoroethyl) -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1 ] pentanil] acetamide
[00259] [00259] Prepared using General Procedure C, using 2- (4-chlorophenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (25 mg, 0.08 mmol) , 3,3,3-trifluoropropanoic acid (16 mg, 0.12 mmol), NEt3 (41 mg, 0.40 mmol) and T3P (77 mg, 0.24 mmol) in EtOAc (0.8 mL). 1H-NMR (400 MHz; CDCl3): δ 7.33-7.29 (m, 2H), 7.03 (s, 1H), 6.91-6.87 (m, 2H), 4.45 ( s, 2H), 3.77 (q, J = 9.6 Hz, 2H), 2.69 (s, 6H). LC-MS m / z: = 402.11 [M + H] +. EXAMPLE 5 2- (4-Chlorophenoxy) -N- [1- [5- (cyclobutoxymethyl) -1,3,4-oxadiazol-2-yl] -3-bicyclo [1.1.1] pentanyl] acetamide
[00260] [00260] Prepared using General Procedure C, using 2- (4-chloro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (25 mg, 0.08 mmol) , 2- (cyclobutoxy) acetic acid (16 mg, 0.12 mmol), NEt3 (41 mg, 0.40 mmol) and T3P (77 mg, 0.24 mmol) in EtOAc (0.8 mL). 1H-NMR (400 MHz; CDCl3): δ 7.34-7.30 (m, 2H), 7.01 (s, 1H), 6.91-6.87 (m, 2H), 4.60 ( s, 2H), 4.44 (s, 2H), 4.12-4.05 (m, 1H), 2.68 (s, 6H), 2.28-2.20 (m, 2H), 2 , 04 - 1.93 (m, 2H), 1.79-1.70 (m, 1H), 1.57-1.50 (m, 1H). LC-MS m / z: = 404.21 [M + H] +. EXAMPLE 6 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- [cis-3- (trifluoromethoxy) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -3- bicycle [1.1.1] pentanil] acetamide
[00261] [00261] 3-cis- (trifluoromethoxy) cyclobutanecarboxylic acid (138 mg, 0.75 mmol; 8: 1 to 10: 1 ratio of cis-to trans-), 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinecarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (164 mg, 0.50 mmol) and NEt3 (0.35 mL, 2.5 mmol) were dissolved in MeCN (4, 0 mL) and solution of
[00262] [00262] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 4,4-difluoro-2-methyl-butanoic acid (26 mg, 0.18 mmol), NEt3 (62 mg, 0.61 mmol) and T3P (117 mg, 0.37 mmol) in EtOAc (1.0 ml). 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.79 (dd, J = 10.2, 2, 9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 6.03 (tdd, J = 56.3, 5.3, 4.0 Hz , 1H), 4.46-4.42 (m, 2H), 3.39-3.30 (m, 1H), 2.67 (s, 6H), 2.50 (ddddd, J = 21.6 , 14.6, 13.4, 8.1, 4.0 Hz, 1H), 2.26-2.12 (m, 1H), 1.48 (d, J = 7.1 Hz, 3H). LC-MS m / z: = 430.18 [M + H] +. EXAMPLE 8 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- (1-cyclopropylethyl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1 ] pentanil] acetamide
[00263] [00263] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicycles [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 2-cyclopropylacetic acid (21 mg, 0.18 mmol), NEt3
[00264] [00264] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinicarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), trans-2-methylcyclopropanecarboxylic acid (18 mg, 0.18 mmol), NEt3 (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1, 0 mL). 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.81-6.78 (m, 1H), 6 , 71 (ddd, J = 8.9, 2.8, 1.3 Hz, 1H), 4.44 (s, 2H), 2.63 (s, 6H), 1.85 (dd, J = 8 , 8, 4.4 Hz, 1H), 1.54-1.48 (m, 1H), 1.34-1.29 (m, 1H), 1.23 (d, J = 6.0 Hz, 3H), 0.95 (ddd, J = 8.6, 6.1, 4.9 Hz, 1H). LC-MS m / z: = 392.15 [M + H] +. EXAMPLE 10 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- (1-fluorocyclopropyl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1 ] pentanil] acetamide
[00265] [00265] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 1-fluorocyclopropanecarboxylic acid (19 mg, 0.18 mmol), NEt3 (62 mg, 0.61 mmol) and T3P (117 mg, 0.37 mmol) in EtOAc (1.0 mL). 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.80 (dd, J = 10.2, 2, 8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.45 (s, 2H), 2.70 (s, 6H), 1, 68-1.60 (m, 2H), 1.49-1.43 (m, 2H). LC-MS m / z: = 396.2 [M + H] +. EXAMPLE 11
[00266] [00266] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 2-cyclopropylacetic acid (18 mg, 0.18 mmol), NEt3 (62 mg, 0.61 mmol) and T3P (117 mg, 0.37 mmol) in EtOAc (1.0 mL) . 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.80 (dd, J = 10.2, 2, 8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.44 (s, 2H), 2.76 (d, J = 7.1 Hz, 2H), 2.67 (s, 6H), 1.21-1.11 (m, 1H), 0.66-0.61 (m, 2H), 0.34-0.30 (m, 2H), LC-MS m / z: = 392.2 [M + H] +. EXAMPLE 12 N- [3- [5- (4-chloro-3-fluoro-phenyl) -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanyl] -2- [cis-3- (trifluoromethoxy) cyclobutoxy] acetamide Step 1: tert-butyl N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] carbamate
[00267] [00267] Prepared using General Procedure B, using methyl 3- (tert-butoxycarbonylamino) bicyclo [1.1.1] pentane-1-carboxylate (241 mg, 1.0 mmol), hydrazine hydrate (150 mg, 3.0 mmol) in EtOH (5.0 mL). Step 2: tert-butyl N- [1- [5- (4-chloro-3-fluoro-phenyl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1] pentanyl] carbamate
[00268] [00268] Prepared using General Procedure C, using tert-butyl N - [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] carbamate (30 mg, 0.12 mmol), 4- acid chloro-3-fluoro-benzoic (33 mg, 0.19 mmol), NEt3 (63 mg, 0.62 mmol) and T3P (119 mg, 0.37 mmol) in EtOAc (1.2 mL). Step 3: 1- [5- (4-chloro-3-fluoro-phenyl) -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine; 2,2,2-trifluoroacetic acid
[00269] [00269] tert-butyl N- [1- [5- (4-chloro-3-fluoro-phenyl) -1,3,4-oxadiazol-2-yl] -3-bi-cycle [1.1.1] pentanil ] carbamate (35 mg, 0.09 mmol) was dissolved in CH2Cl2 (0.9 mL) at room temperature and trifluoroacetic acid (105 mg, 0.92 mmol) was added. The reaction mixture was stirred at room temperature for
[00270] [00270] Prepared using General Procedure A using methyl 3-aminobicyclo [1.1.1] pentane-1-carboxylate trifluoroacetate salt (35 mg, 0.09 mmol), 2- [3-cis- (trifluoromethoxy) acid cyclobutoxy] acetic (23 mg, 0.11 mmol), NEt3 (27 mg, 0.27 mmol) and T3P (34 mg, 0.27 mmol) in EtOAc (0.9 mL), 1H-NMR (400 MHz; CDCl3): δ 7.86-7.80 (m, 2H), 7.58-7.55 (m, 1H), 6.98 (s, 1H), 4.36 (quintet, J = 7.1 Hz, 1H), 3.86 (s, 2H), 3.75 (quintet, J = 6.8 Hz, 1H), 2.89-2.82 (m, 2H), 2.70 (s, 6H ), 2.34-2.26 (m, 2H), LC-MS m / z: = 476.4 [M + H] +. EXAMPLE 13 Terc-butyl 3- [5- [3 - [[2- (4-Chloro-3-fluoro-phenoxy) acetyl] amino] -1-bicycle [1.1.1] pentanyl] -1,3,4- oxadiazol-2-yl] azetidine-1-carboxylate
[00271] [00271] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 1-tert-butoxycarbonylazetidine-3-carboxylic acid (37 mg, 0.18 mmol), NEt3 (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.2 ml). 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.80 (dd, J = 10.2, 2, 8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.45 (s, 2H), 4.34 (t, J = 8.8 Hz, 2H), 4.27-4.23 (m, 2H), 4.03-3.96 (m, 1H), 2.68 (s, 6H), 1.48 (s, 9H), LC -MS m / z: = 437.2 [M + H –t-Bu] EXAMPLE 14 Terc-butyl 3- [5- [3 - [[2- (4-Chloro-3-fluoro-phenoxy) acetyl] amino ] -1-bicycle [1.1.1] pentanil] -1,3,4-oxadiazol-2-yl] pyrrolidine-1-carboxylate
[00272] [00272] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (39 mg, 0.18 mmol), NEt3 (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.2 mL). 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H),
[00273] [00273] 3- [5- [3 - [[2- (4-Chloro-3-fluoro-phenoxy) acetyl] amino] -1-bicyclo [1.1.1] pentanil] -1,3,4- tert-Butyl oxadiazol-2-yl] azetidine-1-carboxylate (34 mg, 0.07 mmol) dissolved in CH2Cl2 (0.7 mL) at room temperature, followed by cooling the reaction mixture to 0 ° C. Subsequently, trifluoroacetic acid (118 mg, 1.03 mmol) was added dropwise. After 4 h, the reaction was stopped by adding saturated NaHCO3 and the resulting biphasic reaction mixture was then diluted with sat. NaHCO3 and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was used for the next transformation without further purification.
[00274] [00274] The crude residue was dissolved in EtOAc (0.9 ml). H2O (0.5 mL) and NaHCO3 (29 mg, 0.34 mmol) were then added sequentially and the reaction was cooled to 0 ° C. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (19 mg, 0.08 mmol) was then added dropwise. After 6 h, the reaction mixture was diluted with EtOAc and sat. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. 1H NMR (400 MHz; CDCl3): δ 7.37 (t, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.80 (dd, J = 10.2, 2.9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.45 (s, 2H), 4.06-3.94 (m, 3H) , 3.65 (t, J = 6.7 Hz, 2H), 3.11 (q, J = 9.3 Hz, 2H), 2.67 (s, 6H), LC-MS m / z: = 475.30 [M + H] +. EXAMPLE 16
[00275] [00275] Terc-butyl 3- [5- [3 - [[2- (4-Chloro-3-fluoro-phenoxy) acetyl] amino] -1-bicyclo [1.1.1] pentanil] -1.3 , 4-oxadiazol-2-yl] pyrrolidine-1-carboxylate (38 mg, 0.07 mmol) dissolved in CH2Cl2 (0.7 mL) at room temperature, followed by cooling the reaction mixture to 0 ° C. Subsequently, trifluoroacetic acid (128 mg, 1.12 mmol) was added dropwise. After 4 h, the reaction was stopped by adding saturated NaHCO3 and the resulting biphasic reaction mixture was then diluted with sat. NaHCO3 and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was used for the next transformation without further purification.
[00276] [00276] The crude residue was dissolved in EtOAc (0.9 ml). H2O (0.5 mL) and NaHCO3 (32 mg, 0.38 mmol) were then added sequentially and the reaction mixture was cooled to 0 ° C. 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.08 mmol) was then added dropwise. After 6 h, the reaction mixture was diluted with EtOAc and sat. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.80 (dd, J = 10.2, 2, 9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.44 (s, 2H), 3.65 (dq, J = 9.7 , 7.2 Hz, 1H), 3.34 (t, J = 8.6 Hz, 1H), 3.18 (dtt, J = 14.3, 9.5, 4.8 Hz, 2H), 3 .07 (td, J = 8.4, 5.4 Hz, 1H), 3.00 (dd, J = 9.3, 7.4 Hz, 1H), 2.86 (q, J = 7.7 Hz, 1H), 2.66 (s, 6H), 2.38 (dddd, J = 13.0, 9.7, 7.7, 6.8 Hz, 1H), 2.26 (dddd, J = 13.1, 8.0, 6.4, 5.3 Hz, 1H), LC-MS m / z: = 489.34 [M + H] +. EXAMPLE 17
[00277] [00277] 2- (4-Chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg, 0.12 mmol) was dissolved in EtOAc (1.2 mL) at room temperature followed by the addition of NEt3 (62 mg, 0.61 mmol) and cyclopropanecarbonyl chloride (19 mg, 0.18 mmol). After 30 min, the consumption of the starting material was completed by HPLC analysis and T3P (233 mg, 0.37 mmol) was added. The resulting reaction mixture was heated to 100 ° C in a sealed flask overnight. The reaction mixture was diluted with NaHCO3 solution and saturated EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. 1H NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.79 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.44 (s, 2H), 2.64 (s, 6H), 2.18 -2.11 (m, 1H), 1.16 (s, 4H), LC-MS m / z: = 378.24 [M + H] +. EXAMPLE 18 2- (4-chloro-3-fluoro-phenoxy) -N - [3- [5- (2,2-difluorocyclopropyl) -1,3,4-oxadazole-2-yl] -1- bicycle [1.1.1] pentanil] acetamide
[00278] [00278] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 2,2-difluorocyclopropanecarboxylic acid (22 mg, 0.18 mmol), NEt3 (62 mg, 0.61 mmol), and T3P (233 mg, 0.37 mmol) in EtOAc (1, 2 mL). 1H NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.80 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.45 (s, 2H), 2.95 (ddd, J = 11.5, 10.0, 7.9 Hz, 1H), 2.67 (s, 6H), 2.25 (dtd, J = 12.3, 8.1, 5.4 Hz, 1H), 2.13-2 , 05 (m, 1H), LC-MS m / z: = 414.12 [M + H] +. EXAMPLE 19 and 20
[00279] [00279] For a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-formyl-3-bicyclo [1.1.1] pentanil) acetamide (900 mg, 3.02 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (813 mg, 4.23 mmol) in MeOH (20 mL) K2CO3 (1.25 g, 9.07 mmol) was added at 20 ° C under N2 . The mixture was stirred at 20 ° C for 16 h. The mixture was poured into ice water (20 ml) and extracted with EtOAc (3 x 15 ml). The combined organic phase was washed with brine (15 ml), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: MTBE = 1: 0 to 3: 1) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.33 (t, J = 8.60 Hz, 1 H), 6.82 (br s, 1 H), 6.75 (dd, J = 10.29 , 2.89 Hz, 1 H), 6.67 (ddd, J = 8.88, 2.85, 1.19 Hz, 1 H), 4.38 (s, 2 H), 2.43-2 , 47 (m, 6 H), 2.19 (s, 1 H). Step 2: 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (1H-triazol-4-yl) -3-bicyclo [1.1.1] pentanil] acetamide
[00280] [00280] For a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanyl) acetamide (80 mg, 0.27 mmol) and CuSO4 (0.4 mg, 0.003 mmol) in t-BuOH (3 mL) and H2O (1 mL) was added TMSN3 (33 mg, 0.29 mmol), benzoic acid (3 mg, 0.027 mmol) and ascorbate of sodium (1 mg, 0.005 mmol) at 20 ° C under N2. The mixture was stirred at 80 ° C for 32 h. The mixture was cooled to 20 ° C and poured into ice water (5 ml) and extracted with EtOAc (3 × 2 ml). The combined organic phase was washed with brine (2 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (1H-triazol-4-yl) -3-bicyclo [1.1.1] pentanyl] acetamide was used in the next step without further purification. LC-MS m / z: = 337.1 [M + H] +.
[00281] [00281] For a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (1H-triazol-4-yl) -3-bicycle [1.1.1] pentanyl] acetamide (71 mg , 211 µmol) and bromocyclobutane (43 mg, 316 µmol, 30 µL) in DMF (1 ml) Cs2CO3 (206 mg, 633 µmol) was added at 20 ° C under N2. The mixture was stirred at 80 ° C for 6 h. The mixture was poured into ice water (3 ml) and extracted with EtOAc (3 x 1 ml). The combined organic layer was washed with brine (3 x 1 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (2-cyclobutyltriazol-4-yl) -3-bicyclo [1.1.1] pentanil] acetamide as the first eluting isomer. 1H-NMR (400 MHz, CDCl3): δ 7.41 (s, 1 H), 7.34 (t, J = 8.53 Hz, 1 H), 6.90 (br s, 1 H), 6 , 79 (dd, J = 10.29, 2.89 Hz, 1 H), 6.71 (br d, J = 9.16 Hz, 1 H), 5.06 (quin, J = 8.28 Hz , 1 H), 4.42 (s, 2 H), 2.64-2.76 (m, 2 H), 2.45-2.55 (m, 8 H), 1.82-1.98 (m, 2 H), LC-MS m / z: = 391.3 [M + H] +.
[00282] [00282] 2- (4-Chloro-3-fluoro-phenoxy) -N- [1- (1-cyclobutyltriazol-4-yl) -3-bicyclo [1.1.1] pentanyl] acetamide as the second eluting isomer . 1H-NMR (400 MHz, CDCl3): δ 7.42 (s, 1 H), 7.34 (t, J = 8.53 Hz, 1 H), 6.94 (br s, 1 H), 6 , 78 (dd, J = 10.29, 2.76 Hz, 1 H), 6.70 (br d, J = 8.91 Hz, 1 H), 5.03 (quin, J = 8.47 Hz , 1 H), 4.43 (s, 2 H), 2.59 (br t, J = 8.66 Hz, 4 H), 2.53 (s, 6 H), 1.90 - 2.02 (m, 2 H), LC-MS m / z: = 391.3 [M + H] +. EXAMPLE 21 2- (4-chloro-3-fluorophenoxy) -N- (3- (5-cyclopentyl-4,5-dihydroisoxazol-3-yl) bi- cycle [1.1.1] pentan-1-yl) acetamide Step 1: 2- (4-chloro-3-fluoro-phenoxy) -N- [3- (hydroxymethyl) -1-bicyclo [1.1.1] pentanil] acetamide
[00283] [00283] For a solution of methyl 3 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] bicyclo [1.1.1] pentane-1-carboxylate (795 mg, 2.43 mmol) in THF (30 mL) LiBH4 (159 mg, 7.28 mmol) was added at 0 ° C under N2, then the mixture was stirred at 20 ° C for 16 h. The reaction mixture was stopped with NH4Cl (10 mL) sat. and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired product. 1H-NMR (400 MHz; CDCl3): δ 7.33 (t, J = 8.60 Hz, 1 H), 6.84 (br s, 1 H), 6.77 (dd, J = 10.29 , 2.89 Hz, 1 H), 6.68 (ddd, J = 8.88, 2.79, 1.13 Hz, 1 H), 4.39 (s, 2 H), 3.74 (br d, J = 3.76 Hz, 2 H), 2.10 (s, 6 H). Step 2: 2- (4-chloro-3-fluorophenoxy) -N- (3-formylbicyclo [1.1.1] pentan-1-yl) acetamide
[00284] [00284] For a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydroxymethyl) -3-bicyclo [1.1.1] pentanil] acetamide (450 mg, 1.50 mmol) in anhydrous CH2Cl2 (20 mL) DMP (669 mg, 1.58 mmol) was added at 0 ° C, the mixture was stirred at 10 ° C for 5 h. The reaction solution was stopped by adding sat NaHCO3. and extracted with CH2Cl2 (3 x 10 mL). The organic layers were combined, washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. 1H-NMR (400 MHz; CDCl3): δ 9.68 (s, 1 H), 7.32-7.36 (m, 1 H), 6.87 (br s, 1 H), 6.75 - 6.78 (m, 1 H), 6.68 - 6.70 (m, 1 H), 4.40 (s, 2 H), 2.44 (s, 6 H). Step 3: (E) -2- (4-chloro-3-fluorophenoxy) -N- (3 - ((hydroxyimino) methyl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00285] [00285] For a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-formyl-3-bi-cycle [1.1.1] pentanyl) acetamide (500 mg, 1.68 mmol) in EtOH (3 ml), NH2OH.HCl (210 mg, 3.02 mmol) and NaOAc (234 mg, 2.86 mmol) were added. After addition, the mixture was stirred at 85 ° C for 3 h. The reaction mixture was stopped with the addition of NaHCO3 (10 mL) sat. at 0 ° C and then concentrated under reduced pressure. The residue was diluted with H2O (10 ml) and extracted with EtOAc (3 × 5 ml). The combined organic layers were washed with brine (5 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. 1H-NMR (400 MHz; CDCl3): δ 7.50 (s,
[00286] [00286] For a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- [1 - [(E) -hydroxy-iminomethyl] -3-bicycle [1.1.1] pentanyl] acetamide (50 mg , 0.16 mmol) in DMF (1 mL) NCS (23 mg, 0.18 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h and then stirred at 20 ° C for 1 h. The mixture was used for the next step without further purification. Step 5: 2- (4-chloro-3-fluorophenoxy) -N- (3- (5-cyclopentyl-4,5-dihydroisoxazol-3-yl) bicycle [1.1.1] pentan-1-yl ) acetamide
[00287] [00287] For a solution of (Z) -3 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -N-hydroxy-bicyclo [1.1.1] pentane-1 -carboxyidoyl (56 mg, 0.16 mmol) in DMF (1 mL) was added dropwise vinylcyclopentane (19 mg, 0.19 mmol) and NEt3 (23 mg, 0.22 mmol) at 0 ° C. After addition, the mixture was stirred at 0 ° C for 30 min and then stirred at 20 ° C for 30 min. The reaction mixture was stopped with H2O (0.2 ml) at 0 ° C and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1H-NMR (400 MHz; CDCl3): δ 7.33 (t, J = 8.60 Hz, 1 H), 6.88 (br s, 1 H), 6.77 (dd, J = 10.25 , 2.76 Hz, 1 H), 6.69 (br d, J = 8.82 Hz, 1 H), 4.41 - 4.49 (m, 1 H), 4.40 (s, 2 H ), 2.94 (dd, J = 16.87, 10.25 Hz, 1 H), 2.58 (dd, J = 16.76, 8.60 Hz, 1 H), 2.39 (s, 6 H), 2.01-2.12 (m, 1 H), 1.76-1.90 (m, 1 H), 1.54-1.74 (m, 5 H) 1.31-1 , 42 (m, 1 H), 1.14-1.29 (m, 1 H), LC-MS m / z: = 407.3 [M + H] +. EXAMPLE 22 2- (4-chloro-3-fluorophenoxy) -N- (3- (5-cyclopentylisoxazol-3-yl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00288] [00288] For a solution of (Z) -3 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -N - hydroxy-bicyclo [1.1.1] pentane- 1-carboxyidoyl (56 mg, 0.16 mmol) in DMF (1 mL) was added dropwise with ethylcyclopentane (18 mg, 0.19 mmol) and NEt3 (23 mg, 0.22 mmol) at 0 ° C . After addition, the mixture was stirred at 0 ° C for 30 min and then stirred at 20 ° C for 30 min. The mixture was added to a sealed tube and then stirred at 70 ° C for 11 h. The reaction mixture was stopped with H2O (0.2 ml) at 0 ° C and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1H-NMR (400 MHz; CDCl3): δ 7.34 (t, J = 8.60 Hz, 1 H), 6.90 (s, 1 H), 6.78 (dd, J = 10.25, 2.76 Hz, 1 H), 6.66-6.73 (m, 1 H), 5.83 (s, 1 H), 4.42 (s, 2 H), 3.12-3.22 (m, 1 H), 2.50 (s, 6 H), 2.08 (br d, J = 8.60 Hz, 2 H), 1.64-1.83 (m, 6 H), LC -MS m / z: = 405.3 [M + H] +. EXAMPLE 23 2- (4-chloro-3-fluorophenoxy) -N- (3- (5-cyclobutyl-4,5-dihydroisoxazol-3-yl) bi-cycle [1.1.1] pentan-1-yl) acetamide
[00289] [00289] For a solution of (E) -2- (4-chloro-3-fluorophenoxy) -N - (3 - ((hydroxy-imino) methyl) bicycles [1.1.1] pentan-1-yl ) acetamide (50 mg, 0.16 mmol) in dry 1,4-dioxane (5 mL) was added vinylcyclobutane (131 mg, 1.60 mmol), t-BuOCl (35 mg, 0.32 mmol), NaI ( 48 mg, 0.32 mmol) and 2,6-lutidine (0.037 mL, 0.32 mmol) at 20 ° C, then the mixture was stirred at 20 ° C for 48 h. The mixture was stopped with sat. NH4Cl. (5 ml) and extracted with EtOAc (3 x 5 ml). The organic layer was washed with brine (5 ml), then dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC to give the desired product. LC-MS m / z: = 393.4 [M + H] +. EXAMPLE 24 2- (4-chloro-3-fluorophenoxy) -N- (3- (5-cyclopentylisoxazol-3-yl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00290] [00290] For a solution of 2- (4-chloro-3-fluorophenoxy) -N- (3- (5-cyclobutyl- 4,5-dihydroisoxazol-3-yl) bicycle [1.1.1] pentan-1 -yl) acetamide (20 mg, 0.05 mmol) in 1,4-dioxane (3 mL) DDQ (23.1 mg, 0.1 mmol) was added, the reaction was heated to reflux for 12 h under O2. The reaction was cooled, filtered over a pad of celite and washed with EtOAc (2 x 5 mL). The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1H-NMR (400 MHz; CDCl3): δ 7.34 (t, J = 8.60 Hz, 1 H), 6.91 (s, 1 H), 6.78 (dd, J = 10.29, 2.76 Hz, 1 H), 6.67-6.73 (m, 1 H), 5.88 (s, 1 H), 4.42 (s, 2 H), 3.61 (quin, J = 8.56 Hz, 1 H), 2.51 (s, 6 H), 2.33-2.43 (m, 2 H), 2.20-2.32 (m, 2 H), 1, 91-2.11 (m, 2 H), LC-MS m / z: = 391.3 [M + H] +. EXAMPLE 25 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (5-cyclobutyl-1,3,4-oxadiazol-2-yl) -3-bicyclo [1.1.1] pentanil ] acetamide
[00291] [00291] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide acid (45 mg, 0.14 mmol), cyclobutanecarboxylic acid (17 mg, 0.16 mmol), NEt3 (56 mg, 0.55) and T3P (87.5 mg, 0.27 mmol) in EtOAc (2 mL). 1H-NMR (400 MHz, CDCl3): δ 7.34 (t, J = 8.60 Hz, 1 H), 6.98 (s, 1 H), 6.78 (dd, J = 10.23, 2.82 Hz, 1 H), 6.69 (ddd, J = 8.88, 2.79, 1.13 Hz, 1 H), 4.43 (s, 2 H), 3.72 (quin, J = 8.41 Hz, 1 H), 2.65 (s, 6 H), 2.38-2.53 (m, 4 H), 1.95-2.23 (m, 2 H), LC -MS m / z: = 392.3 [M + H] +. EXAMPLE 26 2- (4-Chloro-3-fluorophenoxy) -N- (3- (3-cyclopentylisoxazol-5-yl) bicyclo [1.1.1] pentan-1-yl) acetamide Step 1: Cyclobutanecarbaldehyde oxime
[00292] [00292] To a solution of cyclobutanecarbaldehyde (500 mg, 5.94 mmol) in EtOH (20 mL) was added NaOAc (829 mg, 10.1 mmol) and NH2OH • HCl (744 mg, 10.7 mmol). The mixture was stirred at 80 ° C for 5 h. The reaction mixture was diluted with H2O (40 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (40 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give cyclobutanecarbaldehyde oxime which was used directly in the next step. 1H-NMR (400 MHz, CDCl3): δ 1.82-1.93 (m, 4 H) 1.95-2.03 (m, 5 H) 2.06-2.12 (m, 9 H) 2.13-2.23 (m, 5 H) 2.24-2.33 (m, 2 H) 2.97-3.20 (m, 2
[00293] [00293] To a solution of cyclobutanecarbaldehyde oxime (200 mg, 2.02 mmol) in DMF (8 mL) NCS (323 mg, 2.42 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 2 h. The reaction solution was used directly for the next step. Step 3: 2- (4-chloro-3-fluorophenoxy) -N- (3- (3-cyclopentylisoxazol-5-yl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00294] [00294] To a solution of N - hydroxycyclobutanecarboxy-methyl chloride (73 mg, 0.54 mmol) in DMF (3.5 mL) was added 2- (4-chloro-3-fluoro-phenoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanil) acetamide (80 mg, 0.27 mmol) and NEt3 (41 mg, 0.41 mmol). The mixture was stirred at 60 ° C for 5 h. After the reaction was complete, the reaction mixture was purified by preparative HPLC to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 1.83-2.06 (m, 2 H) 2.09-2.21 (m, 2 H) 2.23-2.35 (m, 2 H) 2.46 (s, 6 H) 3.51 (quin, J = 8.38 Hz, 1 H) 4.34 (s, 2 H) 5.89 (s, 1 H) 6.62 (dd, J = 8.93, 1.65 Hz, 1 H) 6.70 (dd, J = 10.14, 2.87 Hz, 1 H) 6.82 (s, 1 H) 7.26 (t, J = 8.60 Hz, 1 H), LC-MS m / z: = 391.3 [M + H] +. EXAMPLE 27 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (4-cyclobutyloxazol-2-yl) -3-bicyclo [1.1.1] pentanyl] acetamide
[00295] [00295] For a mixture of 3 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] bi-cycle [1.1.1] pentane-1-carboxamide (0.1 g, 0.32 mmol) in DMPU (5 mL) was added 2-bromo-1-cyclobutyl-ethanone (113 mg, 0.64 mmol) at 20 ° C under N2. The mixture was stirred at 150 ° C for 5 h. The mixture was poured into cold water (10 ml). The aqueous phase was extracted with EtOAc (3 x 5 ml). The combined organic phase was washed with brine (5 x 5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1H-NMR (400 MHz; CDCl3): δ 7.30-7.40 (m, 2 H), 6.91 (s, 1 H), 6.78 (dd, J = 10.29, 2.89 Hz, 1 H), 6.66-
[00296] [00296] To a mixture of 2- (cyclobutoxy) acetic acid (967 mg, 7.43 mmol) in CH2Cl2 (20 mL) T3P (6.45 g, 10.13 mmol, 50% in EtOAc) and NEt3 was added (3.42 g, 33.78 mmol) at 0 ° C under N2. After 1 h, methyl 3-aminobicyclo [1.1.1] pentane-1-carboxylate HCl salt (1.2 g, 6.76 mmol) was added to the solution at 0 ° C, then the mixture was stirred at 20 ° C for 15 h. The mixture of the reaction was adjusted to pH = 7-8 with NaHCO3 sat. and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 6.89 (s, 1 H), 3.91 - 4.02 (m, 1 H), 3.77 (s, 2 H), 3.69 (s , 3 H), 2.47-2.48 (m, 1 H), 2.41 (s, 6 H), 2.17-2.27 (m, 2 H), 1.88-2.01 (m, 2 H), 1.68-1.79 (m, 1 H), 1.46-1.59 (m, 1 H). Step 2: 2- (cyclobutoxy) -N- [1- (hydroxymethyl) -3-bicyclo [1.1.1] pentanil] aceamide
[00297] [00297] For a mixture of methyl 3 - [[2- (cyclobutoxy) acetyl] amino] bicycle [1.1.1] pentane-1-carboxylate (0.7 g, 2.76 mmol) in THF (20 mL ) LiBH4 (120 mg, 5.53 mmol) was added at 0 ° C under N2, then the mixture was stirred at 20 ° C for 16 h. The reaction mixture was stopped with NH4Cl (50 ml) sat. and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: MTBE = 100: 1 to 0: 1) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 6.88 (s, 1 H), 3.90-4.04 (m, 1 H), 3.78 (s, 2 H), 3.73 (s , 2 H), 3.22 (s, 1 H), 2.18-2.27 (m, 2 H), 2.05-2.09 (m, 6 H), 1.86-2.01 (m, 2 H), 1.67-1.80 (m, 1 H), 1.42-1.60 (m, 2 H). Step 3: 2- (cyclobutoxy) -N- (1-formyl-3-bicyclo [1.1.1] pentanil) acetamide
[00298] [00298] For a mixture of 2- (cyclobutoxy) -N- [1- (hydroxymethyl) -3-bicyclo [1.1.1] pentanil] acetamide (0.35 g, 1.55 mmol) in CH2Cl2 (10 mL) the Dess-Martin reagent (692 mg, 1.63 mmol) was added at 0 ° C under N2, then the mixture was stirred at 20 ° C for 4 h. The mixture was adjusted to pH = 7-8 with saturated NaHCO3. The aqueous phase was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was suspended with MTBE, then filtered and the filtrate was concentrated under reduced pressure to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 9.68 (s, 1 H), 3.87-4.13 (m, 1 H), 3.79 (s, 3 H), 2.41 (s , 6 H), 2.22 (s, 3 H), 1.97 (d, J = 7.78 Hz, 3 H), 1.66-1.82 (m, 2 H), 1.26 ( s, 8 H), 1.20 (s, 5 H). Step 4: 2- (cyclobutoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanil) acetamide
[00299] [00299] To a mixture of 2- (cyclobutoxy) -N- (1-formyl-3-bicyclo [1.1.1] pentanil) acetamide (300 mg, 1.34 mmol) in MeOH (6 mL) was added K2CO3 ( 557 mg, 4.03 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (361 mg, 1.88 mmol) at 20 ° C under N2, then the mixture was stirred at 20 ° C for 16 H. The reaction mixture was diluted with H2O (10 ml) and extracted with EtOAc (3 × 8 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired product. 1H- NMR (400 MHz, CDCl3): δ 6.86 (s, 1 H), 3.96 (quin, J = 7.22 Hz, 1 H), 3.76 (s, 2 H), 2, 41 (s, 6 H), 2.18-2.27 (m, 2 H), 2.16 (s, 1 H), 1.88-2.00 (m, 2 H), 1.73 ( q, J = 10.14 Hz, 1 H), 1.44-1.61 (m, 1 H).
[00300] [00300] For a mixture of 2- (cyclobutoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanil) acetamide (50 mg, 0.23 mmol) and 1-azido-4-chloro-benzene (53 mg, 0.34 mmol) in t-BuOH (1 mL) and H2O (2 mL) were added sodium ascorbate (0.9 mg, 0.0046 mmol), benzoic acid (3 mg, 0.023 mmol) and CuSO4 (364 mg, 0.0023 mmol) at 20 ° C, the mixture was stirred at 80 ° C for 5 h. The reaction mixture was diluted with H2O (5 ml) and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product, 1H-NMR (400 MHz, CDCl3): δ 7.75 (s, 1 H), 7.62-7.70 (m, 2 H), 7, 45-7.54 (m, 2 H), 6.99 (s, 1 H), 3.99 (quin, J = 7.18 Hz, 1 H), 3.81 (s, 2 H), 2 , 54 (s, 6 H), 2.17-2.31 (m, 2 H), 1.89-2.06 (m, 2 H), 1.75 (q, J = 10.04 Hz, 1 H), 1.48-1.63 (m, 1 H), LC-MS m / z: = 373.3 [M + H] +. EXAMPLE 29 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- (3-cyanocyclobutyl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1 ] pentanil] acetamide
[00301] [00301] For a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazino-carbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (0.07 g, 0 , 21 mmol) and 3-cyanocyclobutanecarboxylic acid (32 mg, 0.26 mmol) in EtOAc (3 mL) were added T3P (272 mg, 0.43 mmol, 50% in EtOAc) and NEt3 (86 mg , 0.85 mmol) at 20 ° C under N2. The mixture was stirred at 80 ° C for 16 h. After that, NEt3 (108 mg, 1.07 mmol) and p-TsCl (81 mg, 0.43 mmol) were added to the solution at 20 ° C, then the mixture was stirred at 80 ° C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to deliver the desired product. 1H-NMR (400 MHz, CDCl3): 7.35 (t, J = 8.60 Hz, 1 H), 7.04 (s, 1 H), 6.79 (dd, J = 10.25, 2 , 76 Hz, 1 H), 6.66 - 6.73 (m, 1 H), 4.47 (s, 2 H), 3.80 (quin, J = 9.10 Hz, 1 H), 3 , 16-3.39 (m, 1 H), 2.82-2.91 (m, 4 H), 2.64-2.71 (m, 6 H), LC-MS m / z: = 417 , 3 [M + H] +.
[00302] [00302] To a solution of 3-hydroxycyclobutanocarbonitrile (0.2 g, 2.06 mmol) in CH2Cl2 (2 mL) was added MsCl (283 mg, 2.47 mmol) and NEt3 (312 mg, 3.09 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 3 h. The reaction mixture was diluted with CH2Cl2 (60 ml) and then washed with NaHCO3 (3 x 20 ml) and brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 5.00-4.90 (m, 1H), 3.03 (s, 3H), 2.96-2.67 (m, 5H). Step 2: 2- (4-chloro-3-fluorophenoxy) -N- (3- (hydroxymethyl) bicyclo [1.1.1] pen-tan-1-yl) acetamide
[00303] [00303] For a solution of methyl 3 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] bicyclo [1.1.1] pentane-1-carboxylate (500 mg, 1.53 mmol ) in THF (10 mL) LiBH4 (99 mg, 4.58 mmol) was added at 0 ° C. The mixture was stirred at 20 ° C for 20 h. The reaction mixture was stopped with NH4Cl (60 ml) sat. at 0 ° C and then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.33 (t, J = 8.6 Hz, 1H), 6.82 (s, 1H), 6.77 (dd, J = 2.9, 10, 4 Hz, 1H), 6.72-6.65 (m, 1H), 4.39 (s, 2H), 3.74 (s, 2H), 2.10 (s, 6H), LC-MS m / z: = 300.1 [M + H] +. Step 3: 2- (4-chloro-3-fluorophenoxy) -N- (3-formylbicyclo [1.1.1] pentan-1-yl) acetamide
[00304] [00304] For a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydroxymethyl) -3-bicyclo [1.1.1] pentanil] acetamide (370 mg, 1.23 mmol) in CH2Cl2 (10 mL) DMP (549 mg, 1.30 mmol) was added at 0 ° C under N2. The mixture was stirred at 20 ° C for 4 h. The reaction mixture was stopped with NaHCO3 (60 ml) sat. at 0 ° C and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 9.68 (s, 1H), 7.34 (t, J = 8.6 Hz, 1H), 6.90 (br s, 1H), 6.77 ( dd, J = 2.8, 10.2 Hz, 1H), 6.68 (ddd, J = 1.2, 2.8, 8.9 Hz, 1H), 4.41 (s, 2H), 2 , 49-2.41 (m, 6H). Step 4: 2- (4-chloro-3-fluorophenoxy) -N- (3-ethynylbicyclo [1.1.1] pentan-1-yl) acetamide
[00305] [00305] For a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-formyl-3-bi-cycle [1.1.1] pentanyl) acetamide (450 mg, 1.51 mmol) in MeOH (10 ml) 1-diazo-1-dimethoxyphosphoryl-propan-2-one (406 mg, 2.12 mmol) and K2CO3 (626, 4.53 mmol) were added. The mixture was stirred at 20 ° C for 15 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.33 (t, J = 8.7 Hz, 1H), 6.82 (br s, 1H), 6.75 (dd, J = 2.9, 10 , 3 Hz, 1H), 6.67 (ddd, J = 1.2, 2.8, 8.9 Hz, 1H), 4.38 (s, 2H), 2.49-2.39 (m, 6H), 2.19 (s, 1H), LC-MS m / z: = 294.3 [M + H] +. EXAMPLE 32 N- (3- (1H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) -2- (4-chloro-3-fluorophenoxy) acetamide
[00306] [00306] A mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanil) acetamide (120 mg, 0.408 mmol), TMSN3 (70 mg , 0.612 mmol), sodium ascorbate (0.2 mg, 0.008 mmol), CuSO4 (1 mg, 0.008 mmol) and benzoic acid (5 mg, 0.041 mmol) in t-BuOH (0.5 mL) and H2O (1 mL) were stirred at 80 ° C for 40 h under N2 in a pressure vessel. For the reaction mixture, H2O (60 ml) was added and then extracted with EtOAc (3x 20 ml). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the desired product. 1H-NMR (400 MHz, CD3OD): δ 7.69 (s, 1H), 7.39 (t, J = 8.7 Hz, 1H), 6.95 (dd, J = 2.6, 11, 0 Hz, 1H), 6.84 (dd, J = 2.8, 8.9 Hz, 1H), 4.50 (s,
[00307] [00307] A mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (1H-triazol-4-yl) -3-bicycle [1.1.1] pentanyl] acetamide (40 mg, 0.118 mmol), cis- (3-cyanocyclobutyl) methanesulfonate (41 mg, 0.13 mmol) and K2CO3 (32 mg, 0.23 mmol) in DMF (2 mL) was stirred at 100 ° C for 13 h at a pressure vessel. The mixture was filtered through a pad of celite and purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.37-7.31 (m, 1H), 6.91 (s, 1H), 6.78 (dd, J = 2.8, 10.2 Hz, 1H), 6.74- 6.67 (m, 1H), 5.43-5.29 (m, 1H), 4.42 (s, 2H), 3.44 -3.32 (m, 1H), 3.14-3.03 (m, 2H), 2.99-2.90 (m, 2H), 2.50 (s, 6H), LC-MS m / z: = 416.6 [M + H] +. EXAMPLE 34 2- (4-chloro-3-fluorophenoxy) -N- (3- (1 - ((trans) -3-cyanocyclobutyl) -1H-1,2,3-triazol-4-yl) bicycle [1.1. 1] pentan-1-yl) acetamide Step 1: 3-azidocyclobutanocarbonitrile
[00308] [00308] A solution of PPh3 (405 mg, 1.54 mmol) and DIAD (312 mg, 1.54 mmol) in THF (3 mL) was stirred at 0 ° C for 0.5 h. A solution of 3-hydroxy-cyclobutanocarbonitrile (100 mg, 1.03 mmol) and DPPA (340 mg, 1.24 mmol) in THF (1 mL) was added dropwise to the solution. The mixture was heated to 25 ° C and then stirred at 25 ° C for 15 h. To the reaction mixture, H2O (2 ml) was added and then extracted with EtOAc (2 ml). The combined organic layers were washed with brine (2 ml) to give a solution of 3-azidocyclobutanecarbonitrile in THF (4 ml) and EtOAc (2 ml). Step 2: 2- (4-chloro-3-fluorophenoxy) -N- (3- (1 - ((trans) -3-cyanocyclobutyl) -1H- 1,2,3-triazol-4-yl) bicycle [1.1 .1] pentan-1-yl) acetamide
[00309] [00309] A mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanil) acetamide (40 mg, 0.13 mmol), ascorbate of sodium (1 mg, 0.005 mmol), CuSO4 (1 mg, 0.002 mmol), benzoic acid (3 mg, 0.03 mmol)
[00310] [00310] A mixture of (3-cyanocyclobutyl) methanesulfonate (300 mg, 1.71 mmol) and NaI (769 mg, 5.14 mmol) in DMF (2 mL) was stirred at 110 ° C for 15 h. To the reaction mixture, H2O (60 ml) was added and then extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (20 ml), dried over filtered Na2SO4 and concentrated under reduced pressure to give 3-iodocyclobutanocarbonitrile. 1H-NMR (400 MHz, CDCl3): δ 4.72-4.63 (m, 1H), 4.46-4.35 (m, 1H), 3.53-3.42 (m, 1H), 3.21-3.03 (m, 4H), 3.00-2.91 (m, 3H), 2.88-2.80 (m, 1H). Step 2: 3-azidocyclobutanecarbonitrile
[00311] [00311] A mixture of 3-iodocyclobutanocarbonitrile (300 mg, 1.45 mmol) and NaN3 (188 mg, 2.90 mmol) in DMF (2 mL) was stirred at 80 ° C for 15 h under N2. For the reaction mixture H2O (8 ml) was added and then extracted with EtOAc (2x 4 ml). The combined organic layers were washed with brine (2 x 4 ml) to give 3-azidocyclobutanecarbonitrile as a yellow liquid in EtOAc. Step 3: 2- (4-chloro-3-fluorophenoxy) -N- (3- (1 - ((cis) -3-cyanocyclobutyl) -1H- 1,2,3-triazol-4-yl) bicycle [1.1 .1] pentan-1-yl) acetamide
[00312] [00312] A mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanil) acetamide (60 mg, 0.204 mmol), sodium ascorbate ( 2 mg, 0.008 mmol), CuSO4 (1 mg, 0.004 mmol), benzoic acid (5 mg, 0.041 mmol) and 3-azidocyclobutanocarbonitrile (74 mg, 0.612 mmol) in t-BuOH (0.5 mL) and H2O (1 mL) were stirred at 80 ° C for 40 h in a microwave tube. For the reaction mixture, H2O (30 ml) was added and then extracted with EtOAc (3x 10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was separated by SFC to provide the desired product. 1H-NMR (400 MHz, CD3OD): δ 8.80 (s, 1H), 7.97 (s, 1H), 7.38 (t, J = 8.7 Hz, 1H), 6.94 (dd , J = 2.9, 11.0 Hz, 1H), 6.83 (ddd, J = 1.2, 2.9, 8.9 Hz, 1H), 5.15-5.08 (m, 1H ), 4.49 (s, 2H), 3.28-3.19 (m, 1H), 3.06-2.93 (m, 4H), 2.44 (s, 6H), LC-MS m / z: = 416.4 [M + H] +. EXAMPLE 36 2- (4-chloro-3-fluorophenoxy) -N- (3- (2 - ((cis) -3-cyanocyclobutyl) -2H-1,2,3-triazol-4-yl) bicycle [1.1. 1] pentan-1-yl) acetamide
[00313] [00313] A mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (1H-triazol-4-yl) -3-bicycle [1.1.1] pentanyl] acetamide (120 mg, 0.35 mmol), 3-iodocyclobutanocarbonitrile (110 mg, 0.53 mmol) and Cs2CO3 (348 mg, 1.07 mmol) in DMF (2 mL) was stirred at 80 ° C for 15 h under N2. To the mixture, H2O (30 ml) was added and then extracted with EtOAc (3x 10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H- NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.35 (t, J = 8.6 Hz, 1H), 6.92 (s, 1H), 6.79 (dd , J = 2.9, 10.3 Hz, 1H), 6.71 (dd, J = 2.3, 8.4 Hz, 1H), 5.12-4.97 (m, 1H), 4, 43 (s, 2H), 3.20-3.07 (m, 2H), 3.05-2.91 (m, 3H), 2.51 (s, 6H), LC-MS m / z: = 416.4 [M + H] +. EXAMPLE 37 N- (3- (5 - ((4-chloro-3-fluorophenoxy) methyl) -4H-1,2,4-triazol-3-yl) bicyclo [1.1.1] pentan-1-yl ) Tert-butyl -2-cyclobutoxyacetamide Step 1: tert-butyl 2-cyclobutoxyacetate
[00314] [00314] To a solution of cyclobutanol (20 g, 277 mmol) in THF (400 mL) NaH (12.20 g, 305 mmol, 60% purity) was added at 0 ° C under N2. The mixture was stirred at 0 ° C for 1 h. To the mixture, tert-butyl 2-bromoa-ketate (59.5 g, 305 mmol) was added at 0 ° C under N2. The mixture was stirred at 20 ° C for 4 h. The reaction mixture was stopped with sat. NH4Cl (600 mL). at 0 ° C and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 2- (cyclobutoxy) acetate. Step 2: 2-cyclobutoxyacetic acid
[00315] [00315] To a solution of tert-butyl 2- (cyclobutoxy) acetate (20 g, 107 mmol) in CH2Cl2 (300 mL) was added TFA (48.98 g, 429 mmol). The mixture was stirred at 40 ° C for 4 h. To the reaction mixture was added NaHCO3 sat. at 0 ° C until pH = 9 and then extracted with MTBE (3 × 200 mL). The water layer was adjusted to pH = 3 with 2M HCl, then extracted with EtOAc (3 × 200 ml), then washed with brine (200 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2- ( cyclo-butoxy) acetic. 1H-NMR (400 MHz, CDCl3): δ 4.11 - 4.00 (m, 3H), 2.30-2.19 (m, 2H), 2.07-1.95 (m, 2H), 1.79-1.67 (m, 1H), 1.59-1.46 (m, 1H). Step 3: methyl 3- (2-cyclobutoxyacetamido) bicyclo [1.1.1] pentane-1-carbo-xylate
[00316] [00316] A mixture of 2- (cyclobutoxy) acetic acid (879 mg, 6.76 mmol), T3P (5.37 g, 8.44 mmol, 50% in EtOAc) and NEt3 (2.85 g, 28, 2 mmol) in CH2Cl2 (20 mL) was stirred at 0 ° C for 1 h. To the mixture was added methyl 3-
[00317] [00317] For a mixture of methyl 3 - [[2- (cyclobutoxy) acetyl] amino] bicyclo [1.1.1] pentane-1-carboxylate (200 mg, 0.79 mmol) in EtOH (5 mL) was NH2NH2.H2O (403 mg, 7.90 mmol) was added at 0 ° C. The mixture was stirred at 80 ° C for 12 h. The mixture was concentrated under reduced pressure to give the desired product. 1H-NMR (400 MHz, CD3OD): δ 3.99 (quin, J = 7.3 Hz, 1H), 3.77 (s, 2H), 2.31 (s, 6H), 2.25-2 , 17 (m, 2H), 2.01-1.90 (m, 2H), 1.71 (q, J = 10.3 Hz, 1H), 1.61-1.59 (m, 1H), 1.60-1.49 (m, 1H), LC-MS m / z: = 254.3 [M + H] +. Step 5: 2- (4-chloro-3-fluorophenoxy) acetimidamide
[00318] [00318] To a mixture of NH4Cl (2.30 g, 43.0 mmol) in Toluene (15 mL) AlMe3 (2.5 M, 8.60 mL) was added. The mixture was stirred at 25 ° C for 1 h. To the mixture was added ethyl 2- (4-chloro-3-fluoro-phenoxy) acetate (1.0 g, 4.30 mmol) in toluene (5 mL). The mixture was stirred at 90 ° C for 14 h. The reaction mixture was stopped with MeOH (60 ml) at 0 ° C. The mixture was stirred at 20 ° C for 2 h, then filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was dissolved in CH2Cl2: MeOH (60 ml, v: v = 10: 1) and stirred at 25 ° C for 1 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give the desired product. 1H-NMR
[00319] [00319] A mixture of 2- (cyclobutoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (50 mg, 0.197 mmol), 2- (4-chloro-3 -fluoro-phenoxy) acetamidine (80 mg, 0.394 mmol) and K2CO3 (54.56 mg, 0.394 mmol) in MeOH (3 mL) was stirred at 70 ° C for 15 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.31-7.27 (m, 1H), 7.25 (d, J = 3.7 Hz, 1H), 6.84 (dd, J = 2, 9, 10.6 Hz, 1H), 6.76 (ddd, J = 1.1, 2.8, 8.9 Hz, 1H), 5.17 (s, 2H), 4.05 - 3.98 (m, 1H), 3.92 (s, 2H), 2.70 (s, 6H), 2.29-2.22 (m, 2H), 2.03-1.94 (m, 2H), 1.77 (br d, J = 9.9 Hz, 1H), 1.62-1.53 (m, 1H), LC-MS m / z: = 421.4 [M + H] +. EXAMPLE 38 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- (cyclobutylmethyl) -1,3,4-oxadiazol-2-yl] - 3-bicycle [1.1.1] pentanyl ] acetamide
[00320] [00320] For a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazino-carbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (100 mg, 0.31 mmol) and 2-cyclobutylacetic acid (42 mg, 0.37 mmol) in EtOAc (5 mL) T3P (388 mg, 0.62 mmol, 50% in EtOAc) and NEt3 (124 mg, 1.22 mmol) were added at 20 ° C, then the mixture was stirred at 80 ° C for 16 h, then T3P (194 mg, 0.61 mmol, 50% in EtOAc) was added to the mixture and the mixture was stirred at 80 ° C for 16 h. The mixture was adjusted to pH = 7-8 with sat. NaHCO3. The aqueous phase was extracted with EtOAc (3 x 8 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): 7.34 (t, J = 8.60 Hz, 1 H), 6.98 (s, 1 H), 6.77 (dd, J = 10.23, 2 , 82 Hz, 1 H), 6.69 (ddd, J = 8.85, 2.82, 1.25 Hz, 1 H), 4.43 (s, 2 H), 2.87-2.96 (m, 2 H), 2.76
[00321] [00321] For a mixture of N- (1-amino-3-bicyclo [1.1.1] pentanil) -2- (4-chloro-3-fluoro-phenoxy) acetamide • HCl (300 mg, 934.07 µmol) and 2-bromo-1-cyclobutyl-ethanone (330 mg, 1.87 mmol) in CH3CN (10 mL) Na2CO3 (396 mg, 3.74 mmol) was added at 20 ° C under N2. The mixture was heated to 40 ° C and stirred for 7 h. The mixture was added with water (15 ml). The aqueous phase was extracted with EtOAc (3 x 8 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH2Cl2: MeOH = 100: 0 to 10: 1) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.30-7.35 (m, 1 H), 6.80 (br s, 1 H), 6.74-6.77 (m, 1 H), 6.67 (ddd, J = 8.93, 2.87, 1.21 Hz, 1 H), 4.39 (s, 2 H), 3.46 (s, 2 H), 3.23-3 , 32 (m, 1 H), 2.15-2.32 (m, 7 H), 2.13 (s, 6 H), 1.81 - 2.10 (m, 4 H), LC-MS m / z: = 381.2 [M + H] +. Step 2: 2- (4-chloro-3-fluoro-phenoxy) -N- [3- (4-cyclobutylimidazol-1-yl) -1-bi- cycle [1.1.1] pentanyl] acetamide
[00322] [00322] 2- (4-chloro-3-fluoro-phenoxy) -N- [1 - [(2-cyclobutyl-2-oxo-ethyl) amino] -3-bicycle [1.1.1] pentanyl] acetamide (40 mg, 105.03 µmol) and NEt3 (15 mg, 157.55 µmol, 21.93 µL) were taken into a microwave tube in formamide (6.78 g, 150.53 mmol, 6.00 mL) under N2. The sealed tube was heated at 100 ° C for 30 min under microwave. The reaction was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 8.96 (d, J = 1.54 Hz, 1 H), 7.54-7.57 (m, 1 H), 7.39 (t, J = 8.71 Hz, 1 H), 6.95 (dd, J = 11.03, 2.87 Hz, 1 H), 6.84 (ddd, J = 8.99, 2.92, 1.32 Hz , 1 H), 4.54 (s, 2
[00323] [00323] For a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazino-carbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (100 mg, 0.31 mmol) and acetic acid (22 mg, 0.37 mmol) in EtOAc (3 mL) were added T3P (388 mg, 0.62 mmol, 50% in EtOAc) and NEt3 (124 mg, 1.22 mmol) at 20 ° C, then the mixture was stirred at 80 ° C for 16 h. The mixture was adjusted to pH = 7-8 with sat. NaHCO3. The aqueous phase was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired product. LC-MS m / z: = 370.1 [M + H] +. Step 2: 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (5-methyl-1,3,4-oxadiazol-2-yl) -3-bicycle [1.1.1] pentanil] acetamide
[00324] [00324] For a mixture of N- [1- (acetamidocarbamoyl) -3-bicyclo [1.1.1] pentanyl] -2- (4-chloro-3-fluoro-phenoxy) acetamide (90 mg, 0.24 mmol) in CH2Cl2 (3 mL) NEt3 (99 mg, 0.97 mmol) and p-TsCl (93 mg, 0.49 mmol) were added at 25 ° C, then the mixture was stirred at 25 ° C for 16 h. The mixture was adjusted to pH = 7-8 with NaHCO3 and concentrated. The aqueous phase was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): 7.34 (t, J = 8.60 Hz, 1 H), 7.01 (s, 1 H), 6.77 (dd, J = 10.14, 2 , 87 Hz, 1 H), 6.69 (dt, J = 8.93, 1.27 Hz, 1 H), 4.43 (s, 2 H), 2.64 (s, 6 H), 2 , 54 (s, 3 H). LC-MS m / z: = 352.3 [M + H] +. EXAMPLE 41
[00325] [00325] To a mixture of methyl 3- (tert-butoxycarbonylamino) bicyclo [1.1.1] pentane-1-carboxylate (500 mg, 2.07 mmol) in THF (10 mL) and water (2 mL) was added LiOH • H2O (173 mg 4.14 mmol) at 25 ° C under N2. The mixture was stirred at 25 ° C for 12 h. To the mixture, water (10 ml) was added. The aqueous phase was extracted with MTBE (5 ml). The combined organic phase was adjusted to pH = 2 by HCl (2M) and extracted with CH2Cl2: MeOH (3 × 10 mL, v: v = 3: 1) and washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product. 1H-NMR (400 MHz, DMSO-d6): δ 7.54 (s, 1 H), 2.05 (s, 6 H), 1.34 (s, 9 H). Step 2: tert-butyl N- [1 - [[[2- (4-Chloro-3-fluoro-phenoxy) acetyl] amino] carbamoyl] -3-bicyclo [1.1.1] pentanil] carbamate
[00326] [00326] For a mixture of 3- (tert-butoxycarbonylamino) bicyclo [1.1.1] pentane-1-carboxylic acid (50 mg, 0.22 mmol) and 2- (4-chloro-3-fluoro-fe - noxy) acetohydrazide (48 mg, 0.22 mmol in EtOAc (5 mL) was added T3P (420 mg, 0.66 mmol, 50% in EtOAc) and NEt3 (89 mg, 0.88 mmol) at 20 ° C under N 2. The mixture was stirred at 80 ° C for 12 h. The mixture was poured into aq. NaHCO3 (10 ml). The aqueous phase was extracted with EtOAc (3 x 5 ml). The combined organic phase was washed brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product Step 3: tert-butyl N- [1- [5 - [(4-chloro-3-fluoro-phenoxy ) methyl] -1,3,4-oxadazole-2-yl] -3-bicycle [1.1.1] pentanyl] carbamate
[00327] [00327] For a mixture of tert-butyl N- [1 - [[[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] carbamoyl] -3-bicycles [1.1.1] pentanyl] carbamate (94 mg, 0.22 mmol) and NEt3 (89 mg, 0.88 mmol) in CH2Cl2 (5 mL) was added p-TsCl (83 mg, 0.44 mmol) at 0 ° C under N2. The mixture was stirred at 25 ° C for 12 h.
[00328] [00328] A mixture of tert-butyl N- [1- [5 - [(4-chloro-3-fluoro-phenoxy) methyl] - 1,3,4-oxadiazol-2-yl] -3-bicycle [1.1 .1] pentanyl] carbamate (64 mg, 0.16 mmol) in HCl / EtOAc (5 mL) was stirred at 25 ° C for 3 h. The mixture was concentrated under reduced pressure at 40 ° C to give the desired product as the HCl salt. Step 6: N- [1- [5 - [(4-chloro-3-fluoro-phenoxy) methyl] -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1] pentanil] - 2-cis- [3- (trifluoromethoxy) cyclobutoxy] acetamide
[00329] [00329] For a mixture of cis-2- [3- (trifluoromethoxy) cyclobutoxy] acetic acid (44 mg, 0.2 mmol) and 1- [5 - [(4-chloro-3-fluoro-phenoxy)) methyl] -1,3, 4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine (53 mg, 0.15 mmol, HCl) in DMF (5 mL) was added HATU (117 mg, 0.31 mmol) and DIEA (132 mg, 1.03 mmol) at 25 ° C under r N2. The mixture was stirred at 25 ° C for 12 h. The mixture was poured into ice water (20 ml). The aqueous phase was extracted with EtOAc (3 x 5 ml). The combined organic phase was washed with brine (4 x 5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3) to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.32 (t, J = 8.66 Hz, 1 H), 6.92 (s, 1 H), 6.86 (dd, J = 10.29 , 2.51 Hz, 1 H), 6.79 (d, J = 8.66 Hz, 1 H), 5.21 (s, 2 H), 4.34 (t, J = 7.03 Hz, 1 H), 3.83 (s, 2 H), 3.65-3.77 (m, 1 H), 2.83 (dd, J = 6.84, 3.20 Hz, 2 H), 2 , 65 (s, 6 H), 2.28 (d, J = 6.53 Hz, 2 H), LC-MS m / z: = 506.4 [M + H] +. EXAMPLE 42
[00330] [00330] To a solution of 4-chloro-3-fluoro-benzoic acid (83 mg, 0.474 mmol) in EtOAc (3 mL) was added Et3N (160 mg, 1.58 mmol), T3P (502 mg, 0, 79 mmol, 50% in EtOAc) and 2- (cyclobutoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (100 mg, 0.395 mmol). After addition, the mixture was stirred at 25 ° C for 12 h. The mixture was concentrated under reduced pressure to give the desired product. LC-MS m / z: = 410.2 [M + H] +. N- [1- [5- (4-chloro-3-fluoro-phenyl) -1,3,4-oxadiazol-2-yl] -3-bicyclo [1.1.1] pentanyl] -2- (cyclobutoxy ) acetamide
[00331] [00331] To a solution of N- [1 - [[(4-chloro-3-fluoro-benzoyl) amino] carbamoyl] -3-bicyclo [1.1.1] pentanil] -2- (cyclobutoxy) acetamide ( 130 mg, 0.317 mmol) in CH2Cl2 (2 mL) Et3N (128.39 mg, 1.27 mmol) and TsCl (121 mg, 0.634 mmol) were added. The mixture was stirred at 20 ° C for 12 h. The mixture was diluted with 10 ml H2O and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with 10 ml brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.77-7.86 (m, 2 H), 7.55 (t, J = 7.78 Hz, 1 H), 7.05 (s, 1 H ), 3.99 (quin, J = 7.25 Hz, 1 H), 3.82 (s, 2 H), 2.68 (s, 6 H), 2.19-2.30 (m, 2 H), 1.90 - 2.05 (m, 4 H), 1.75 (q, J = 10.29 Hz, 1 H), 1.48-1.62 (m, 1 H), LC- MS m / z: = 392.3 [M + H] +. EXAMPLE 43 2- (4-chloro-3-fluorophenoxy) -N- (3- (5 - ((cis) -3- (trifluoromethyl) cyclobutyl) -1,3,4-oxadiazol-2-yl) bicycle [1.1 .1] pentan-1-yl) acetamide
[00332] [00332] To a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicycle [1.1.1] pentanyl] acetamide (100 mg, 0.31 mmol) and cis-3- (trifluoromethyl) cyclobutanecarboxylic acid (62 mg, 0.37 mmol) in EtOAc (3 mL) T3P (388 mg, 0.61 mmol, 50% in EtOAc) and NEt3 (123 mg, 1.22 mmol) in a sealed tube. The mixture was stirred at 80 ° C for 16 h. The reaction mixture was diluted with saturated NaHCO3 (10 ml) at 0 ° C and then extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (3 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2- (4-chloro-3-fluorophenoxy) -N- (3- (2 - ((cis) - 3- (trifluoromethyl) cyclobutanocarbonyl) hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl) acetamide. The crude product was used in the next step without further purification.
[00333] [00333] The mixture of 2- (4-chloro-3-fluorophenoxy) -N- (3- (2 - ((cis) -3- (trifluoromethyl) cyclobutanecarbonyl) hydrazinecarbonyl) bicycles [1.1.1] pentan- 1-yl) acetamide (150 mg, 0.31 mmol), 4-methylbenzenesulfonyl chloride (120 mg, 0.63 mmol), NEt3 (127 mg, 1.26 mmol) in CH2Cl2 (5 mL) was stirred at 25 ° C for 16 h under N2 atmosphere. The reaction mixture was quenched with H2O (10 ml) at 0 ° C and then extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CD3OD): δ 7.38 (t, J = 8.71 Hz, 1 H), 6.94 (dd, J = 11.03, 2.87 Hz, 1 H), 6 , 83 (ddd, J = 8.93, 2.87, 1.21 Hz, 1 H), 4.50 (s, 2 H), 3.78 (quin, J = 9.10 Hz, 1 H) , 3.15 - 3.28 (m, 1 H), 2.46-2.70 (m, 10 H), LC-MS m / z: = 460.4 [M + H] +. EXAMPLE 44. 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5-trans- [3- (trifluoromethyl) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -3 -bicycle [1.1.1] pentanil] acetamide
[00334] [00334] To a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicycle [1.1.1] pentanyl] acetamide (100 mg, 0.31 mmol) and tran-3- (trifluoromethyl) cyclobutanecarboxylic acid (62 mg, 0.37 mmol) in EtOAc (3 mL) were added T3P (388 mg, 0.61 mmol, 50% in EtOAc) and NEt3 (124 mg, 1.22 mmol) at 25 ° C, and the mixture was stirred at 80 ° C for 16 h. The mixture was adjusted to pH = 7-8 with sat. of NaHCO3. The aqueous phase was extracted with EtOAc (4 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2- (4-chloro-3-fluoro-phenoxy) -N- [1 - [[[3- (trifluoromethyl) cyclobutanocarbonyl] amino] carbamoyl] -3-bicyclo [1.1.1] pentanil] acetamide.
[00335] [00335] To a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1 - [[[[trans-3- (trifluoromethyl) cyclobutanocarbonyl] amino] carbamoyl] -3-bicycles [1.1 .1] pentanil] acetamide (130 mg, 0.27 mmol) in CH2Cl2 (5 mL) was added NEt3 (110 mg, 1.09 mmol) and p-TsCl (104 mg, 0.54 mmol) at 25 ° C, then the mixture was stirred at 25 ° C for 16 h. The mixture was adjusted to pH = 7-8 with sat. of NaHCO3. The aqueous phase was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CD3OD): δ 7.38 (t, J = 8.78 Hz, 1 H), 6.94 (dd, J = 10.92, 2.76 Hz, 1 H), 6 , 77-6.86 (m, 1 H), 4.50 (s, 2 H), 3.84 (quin, J = 8.03 Hz, 1 H), 3.16-3.28 (m, 1 H), 2.67 (t, J = 7.91 Hz, 4 H), 2.59 (s, 6 H), LC-MS m / z: = 460.4 [M + H] +. EXAMPLE 45 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- (trifluoromethoxymethyl) -1,3,4-oxadazole-2-yl] -3-bicycle [1.1.1 ] pentanyl] acetamide Step 1: 2- (4-chloro-3-fluoro-phenoxy) N- [1 - [[[2- (trifluoromethoxy) acetyl] amine] carbamoyl] -3-bicycle [1.1.1] pentanil] acetamide
[00336] [00336] To a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1 (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (100 mg, 305.12 µmol ) and 2- (trifluoromethoxy) acetic acid (52 mg, 366.15 µmol) in EtOAc (3 mL) were added T3P (388 mg, 610.24 µmol, 362.93 µL, 50% in EtOAc) and Et3N (123 mg, 1.22 mmol, 169.88 µL) at 25 ° C under N2. The mixture was heated to 80 ° C and stirred for 15 h. The mixture was quenched by sat. NaHCO3 (5 ml). The aqueous phase was extracted with EtOAc (3 x 5 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired product, 1H-NMR (400 MHz, CDCl3): δ 8.46 (br s, 2 H), 7.31-7.37 (m, 1 H), 6.91 (s, 1 H), 6.77 (dd, J = 10.16, 2.76 Hz, 1 H), 6 , 69 (dd, J = 9.03, 1.76 Hz, 1 H), 4.62 (s, 2 H), 4.58 (s,
[00337] [00337] To a mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1 - [[[2- (trifluoromethoxy) acetyl] aminocarbamoyl] -3-bicycle [1.1.1] pentanyl ] acetamide (100 mg, 220.37 µmol) in CH2Cl2 (5 ml) NEt3 (89 mg, 882 µmol) and 4-methylbenzenesulfonyl chloride (84 mg, 441 µmol) were added at 25 ° C under N2, then the reaction was stirred for 15 h. The mixture was quenched by sat. of NaHCO3. The aqueous phase was extracted with EtOAc (3 x 5 ml). The combined organic phase was washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.35 (t, J = 8.53 Hz, 1 H), 6.97 (s, 1 H), 6.78 (dd, J = 10.23, 2.82 Hz, 1 H), 6.70 (dd, J = 8.85, 1.69 Hz, 1 H), 5.16 (s, 2 H), 4.43 (s, 2 H), 2.69 (s, 6 H), LC-MS m / z: = 436.3 [M + H] +. EXAMPLES 46-48
[00338] [00338] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. Example LC / MS (m / z, [M = H] +) 46 422.00 47 391.30 48 404.20 EXAMPLE 49 2- (4-chloro-3-fluorophenoxy) -N- (3- (5- Benzyl (3- (trifluoromethoxy) propyl) -1,3,4-oxadazol-2-yl) bicyclo [1.1.1] pentan-1-yl) acetamide 4- (trifluoromethoxy) butanoate
[00339] [00339] To a solution of AgOTf (2.65 g, 10.30 mmol) in EtOAc (25 mL) was added 1- (chloromethyl) -4-fluoro-1,4-diazon-abicyclo di [tetrafluoroborate [2.2 .2] octane (2.74 g, 7.72 mmol), KF (897 mg, 15.5 mmol), benzyl 4-hydroxybutanoate (1.0 g, 5.15 mmol) in a paper-wrapped flask -
[00340] [00340] To a solution of benzyl 4- (trifluoromethoxy) butanoate (200 mg, 0.76 mmol) in 1,4-dioxane (8 mL) was added hydrazine hydrate (0.38 mL, 7.63 mmol) and the solution was heated to 80 ° C for 12 h. The reaction mixture was cooled to room temperature and was concentrated under reduced pressure to give a residue that was used directly. LC-MS: m / z: 187.1 [M + H] +. 2- (4-chloro-3-fluorophenoxy) -N-3- (2- (4- (trifluoromethoxy) butanoyl) hydrazino-carbonyl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00341] [00341] To a solution of 4- (trifluoromethoxy) butane-hydrazide (120 mg, 0.64 mmol) in THF (5 mL) was added 3 - [[2- (4-chloro-3-fluoro-fe- noxy) acetyl] amino] bicyclo [1.1.1] pentane-1-carboxylic (182 mg, 0.58 mmol), HATU (270 mg, 0.71 mmol) and DIEA (0.34 mL, 1.93 mmol) at 0 ° C. The mixture was stirred at 20 ° C for 2 h. The reaction mixture was poured into cold water (10 ml) and was extracted with EtOAc (3 x 10 ml). The organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep TLC. LC-MS: m / z: 482.3 [M + H] +. 2- (4-chloro-3-fluorophenoxy) -N- (3- (5- (3- (trifluoromethoxy) propyl) -1,3,4-oxadazazol-2-yl) bicycles [1.1.1] pentan -1-yl) acetamide
[00342] [00342] To a mixture of 2- (4-chloro-3-fluorophenoxy) -N- (3- (2- (4- (trifluoro-methoxy) butanoyl) hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl ) acetamide (120 mg 0.25 mmol) in DCM (6 mL) was added NEt3 (0.14 mL, 0.10 mmol) and
[00343] [00343] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. Example LC / MS (m / z, [M = H] +) 50 486.10 51 458.30 52 484.40 53 506.10 55 450.30 56 458.90 57 407.30 58 427.30 40 409 , 3 60 423.3 EXAMPLES 61 AND 62 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [4- [3-cis- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicycle [1.1.1] pentanyl] acetamide and 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [4- [3-trans- (trifluoromethoxy) cyclobutyl] imidazole-1 -yl] -1-bicyclo [1.1.1] pentanil] acetamide cis-3- (trifluoromethoxy) cyclobutane-carbonyl chloride
[00344] [00344] For a solution of 3-cis (trifluoromethoxy) cyclobutanecarboxylic acid (2.0 g, 10.9 mmol; 8: 1 to 10: 1 ratio of cis- to trans-) and DMF (79 mg, 1 , 1 mmol) in DCM (30 mL) (COCl) 2 (4.14 g, 32.6 mmol) was added
[00345] [00345] To a solution of 3-cis- (trifluoromethoxy) cyclobutanocarbonyl chloride (2.5 g, 12.3 mmol) in CH3CN (20 mL) and THF (20 mL) was added TMSCHN2 (2 M, 6 , 17 mL) dropwise at 0 ° C over 10 min. The resulting reaction mixture was stirred at 0 ° C for 20 min and then at 25 ° C for 1 h. HBr (7.5 g, 37.0 mmol, 5.0 mL, 40% in water) was added dropwise at 0 ° C and the mixture was stirred at 25 ° C for 2 h. The reaction mixture was diluted with H2O (50 ml) at 0 ° C and then extracted with EtOAc (3 × 50 ml). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, anhydrous, filtered and concentrated under reduced pressure to provide 2-bromo-1- (3-cis- (trifluoromethoxy) cyclobutyl) ethanone as a mixture of diastereomers in favor of the cis configuration, which was used directly without further purification. 1H-NMR (400 MHz, CDCl3): δ 4.78-4.86 (m, 0.2 H), 4.57-4.70 (m, 1 H), 4.07-4.11 (m , 1 H), 3.86-3.94 (m, 1 H), 3.10-3.26 (m, 1 H), 2.59-2.71 (m, 2 H), 2.43 -2.58 (m, 2 H). 2- (4-chloro-3-fluorophenoxy) -N- (3 - ((2-oxo-2- (3cis- (trifluoromethoxy) cyclobutyl) ethyl) amino) bicyclo [1.1.1] pentan-1-yl ) acetamide
[00346] [00346] To a H- salt solution of N- (1-amino-3-bicyclo [1.1.1] penta-nyl) -2- (4-chloro-3-fluoro-phenoxy) acetamide (1.2 g , 3.74 mmol) and 2-bromo-1- (3-cis- (trifluoromethoxy) cyclobutyl) ethanone (1.95 g, 7.47 mmol) in CH3CN (20 mL) Na2CO3 (1.58 g, 14.95 mmol). The mixture was stirred at 40 ° C for 7 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with H2O (20 ml) and extracted with EtOAc (3 × 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel to provide 2- (4-chloro-3-fluorophenoxy) -N- (3 - ((2-oxo-2- (3-cis- (trifluoromeoxy) cyclobutyl ) ethyl) amino) bicycles [1.1.1] pentan-1-yl) acetamide (as a 5: 1 mixture of diastereomers in favor of the cis configuration). The product was used directly in the next step. LC-MS m / z = 465.3 [M + H] +. 2- (4-chloro-3-fluorophenoxy) -N- (3- (N- (2-oxo-2- (cis-3- (trifluoromethoxy) cyclo-butyl) ethyl) formamide) bicyclo [1.1.1] pentan -1-yl) acetamide
[00347] [00347] To a solution of formic acid (4.88 g, 106 mmol, 4 mL) was added Ac2O (703 mg, 6.88 mmol) at 0 ° C and then a solution of 2- ( 4-chloro-3-fluorophenoxy) -N- (3 - ((2-oxo-2- (cis-3 - ((trifluoromethoxy) cyclobutyl) ethyl) amino) bicyclo [1.1.1] pentan-1-yl ) acetamide (0.8 g, 1.72 mmol) in DCM (4 ml) was added at 0 ° C. The mixture was stirred at 0 ° C for 2 h. The reaction mixture was diluted with H2O (10 ml) and the pH was adjusted to 8-9 with sat. NaHCO3 solution (20 ml) at 0 ° C and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (10 ml), dried on anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 2- (4-chloro-3-fluorophenoxy) -N- (3- (N- (2-oxo-2- (cis - 3 (trifluoromethoxy ) cyclo-butyl) ethyl) formamide) bicyclo [1.1.1] pentan-1-yl) acetamide as a mixture of diastereomers in favor of the cis configuration. The material was used for the next step without further purification. LC-MS m / z = 493.3 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [4- [3-cis- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] acetamide and 2- (4-chloro-3-fluoro-phoxy) - N- [3- [4- [3-trans- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] acetamide
[00348] [00348] To a solution of 2- (4-chloro-3-fluorophenoxy) -N- (3- (N- (2-oxo-2- (3-cis- (trifluoromethoxy) cyclobutyl) ethyl) formamide) bicycles [ 1.1.1] pentan-1-yl) acetamide (0.78 g, 1.58 mmol) in CH3COOH (8 mL) CH3COONH4 (476 mg, 6.17 mmol) was added. The mixture was stirred at 110 ° C for 12 h. The reaction mixture was diluted with NaHCO3 solution (50 ml) at 0 ° C and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Nano-micro Kromasil C18 100 mm x 30 mm, 5 µm; mobile phase: A: 0.1% TFA in water, B: MeCN, gradient: B% in A: 30% - 55% over 10 min) to provide a 3: 1 mixture of diastereomers. This material was further purified by SFC. SFC conditions: Chiralcel OJ 250 mm x 30 mm, 10 µm; mobile phase: A: CO2, B: 0.1% NH4OH in MeOH, gradient: B% in A: 17% -17% over 4 min.
[00349] [00349] 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [4- [3-cis- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicycle [1.1 .1] pentanyl] acetamide: H-NMR (400 MHz, MeOD): δ 7.99 (d, J = 0.88 Hz, 1 H), 7.39 (t, J = 8.71 Hz, 1 H ), 7.18 (d, J = 0.66 Hz, 1 H), 6.95 (dd, J = 11.03, 2.87 Hz, 1 H), 6.84 (ddd, J = 8, 99, 2.81, 1.21 Hz, 1 H), 4.73 (quin, J = 7.50 Hz, 1 H), 4.52 (s, 2 H), 3.10 (tt, J = 10.12, 7.63 Hz, 1 H), 2.71-2.81 (m, 2 H), 2.62 (s, 6 H), 2.30-2.46 (m, 2 H) , LC-MS m / z: = 474.1 [M + H] +
[00350] [00350] 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [4- [3-trans- (trifluoromethoxy) cyclo-1-butyl] imidazol-1-yl] -1-bicycle [1.1 .1] pentanil] acetamide: H-NMR (400 MHz, MeOD): δ 7.92 (d, J = 0.88 Hz, 1 H), 7.39 (t, J = 8.71 Hz, 1 H ), 7.19 (s, 1 H), 6.95 (dd, J = 10.80, 2.87 Hz, 1 H), 6.84 (ddd, J = 8.93, 2.87, 1 , 21 Hz, 1 H), 4.98 (quin, J = 6.78 Hz, 1 H), 4.52 (s, 2 H), 3.48-3.58 (m, 1 H), 2 , 63-2.70 (m, 2 H), 2.62 (s, 6 H), 2.50-2.58 (m, 2 H), LC-MS m / z: = 474.1 [M + H] + EXAMPLE 63 2- [3-cis- (trifluoromethoxy) cyclobutoxy] -N- [3- [4- [3-cis- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicycle [ 1.1.1] pentanyl] tert-butyl acetamide (3- (2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamido) bicyclo [1.1.1] pentan-1-yl) carbamate
[00351] [00351] To a solution of 2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetic acid (1.00 g, 4.67 mmol) in DMF (10 mL) was added tert-butyl N- (1- amino-3-bicyclo [1.1.1] pentanil) carbamate (926 mg, 4.67 mmol), HATU (1.95 g, 5.14 mmol) and DIEA (2.44 mL, 14.0 mmol) at 20 ° C. Then, the mixture was stirred at 20 ° C for 2 h. The reaction mixture was poured into ice water (50 ml) and extracted with EtOAc (3 x 50 ml), the organic phase was washed with brine (50 ml), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue, which was purified by column chromatography on silica gel. 1H-NMR (400 MHz, CDCl3): δ 6.81 (br s, 1H), 4.31 (quin, J = 7.2 Hz, 1H), 3.79 (s, 2H), 3.70 ( quin, J = 6.9 Hz, 1H), 2.90-2.86 (m, 1H), 2.84-2.80 (m, 2H), 2.35 (br s, 6H), 2, 30-2.19 (m, 2H), 1.44 (s, 9H). salt and HCl of N- (3-aminobicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromeotoxy) cyclobutoxy) acetamide
[00352] [00352] To a solution of tert-butyl (3- (2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamido) bicyclo [1.1.1] pentan-1-yl) carbamate (500 mg, 1.27 mmol) in EtOAc (10 mL) EtOAc / HCl (10 mL, 4 M) was added and the reaction mixture was stirred at 25 ° C for 1 h. The reaction mixture was concentrated under reduced pressure to provide a residue, which was used directly. LC-MS: m / z = 295.1 [M + H] +. N- (3 - ((2-oxo-2- (3-cis- (trifluoromethoxy) cyclobutyl) ethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide
[00353] [00353] To a mixture of 2-bromo-1- (3-cis- (trifluoromethoxy) cyclobutyl) ethanone (1.04 g, 3.99 mmol; 8: 1 to 10: 1 ratio of cis- to trans -), H- salt of N- (3-aminobicyclo [1.1.1] pentan-1-yl) -2- (cis-3- (trifluoromethoxy) cyclobutoxy) acetamide (1.2 g, 3.63 mmol ) in CH3CN (10 mL) Na2CO3 (1.54 g, 14.51 mmol) was added and the mixture was stirred at 40 ° C for 15 h. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue, which was purified by column chromatography on silica gel to provide the desired compound. LC-MS: m / z = 475.2 [M + H] +. N- (3- (N- (2-oxo-2- (3-cis- (trifluoromethoxy) cyclobutyl) ethyl) formamide) bicyclo [1.1.1] pentan-1-yl) -2- (cis-3 - (trifluoromethoxy) cyclobutoxy) acetamide
[00354] [00354] Formic acid (3.2 mL, 84 mmol) was added dropwise to Ac2O (630 µL, 6.75 mmol) at 0 ° C. After addition, N- (3 - ((2-oxo-2- (3-cis- (trifluoromethoxy) cyclobutyl) ethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3- cis- (trifluorome-
[00355] [00355] To a solution of N- (3- (N- (2-oxo-2- (3-cis- (trifluoromethoxy) cyclobutyl) ethyl) formamide) bicyclo [1.1.1] pentan-1-yl) -2-3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (800 mg, 1.59 mmol) in AcOH (8 mL) ammonium acetate (491 mg, 6.37 mmol) was added and the reaction mixture was stirred at 120 ° C for 12 h. The reaction mixture was diluted with aqueous NaHCO3 solution (20 ml) at 0 ° C, adjusted to pH = 8-9 and extracted with EtOAc (3 x 12 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue, which was purified by preparative HPLC. 1H-NMR (400 MHz, CDCl3): δ 7.40 (s, 1H), 6.93 (s, 1H), 6.70 (s, 1H), 4.62 (quin, J = 7.6 Hz , 1H), 4.34 (quin, J = 7.2 Hz, 1H), 3.84 (s, 2H), 3.73 (quin, J = 6.9 Hz, 1H), 3.07-2 , 95 (m, 1H), 2.89-2.81 (m, 2H), 2.77-2.69 (m, 2H), 2.59 (s, 6H), 2.47-2.38 (m, 2H), 2.31-2.24 (m, 2H), LC-MS: m / z = 484.4 [M + H] +. EXAMPLES 64 AND 65 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [1- [3-trans- (trifluoromethoxy) cyclobutyl] triazol-4-yl] -1-bicycle [1.1.1 ] pentanyl] acetamide and 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [1- [3-cis- (trifluoromethoxy) cyclobutyl] triazol-4-yl] -1-bicycle [ 1.1.1] pentanyl] acetamide ((3-iodocyclobutoxy) methyl) benzene
[00356] [00356] A mixture of (3-cis-benzyloxycyclobutyl) methanesulfonate (1.0 g, 3.90 mmol) and NaI (1.75 g, 11.7 mmol) in MeCN (10 mL) was stirred at 80 ° C for 40 h. The reaction mixture was diluted with H2O (150 mL) and extracted with
[00357] [00357] A mixture of ((3-iodocyclobutoxy) methyl) benzene (1.0 g, 3.47 mmol) and NaN3 (451 mg, 6.94 mmol) in DMF (10 mL) was stirred at 80 ° C for 15 h. To the reaction mixture was added H2O (60 ml). The mixture was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with H2O (2 x 20 ml) to provide ((3-azidocyclobutoxy) methyl) benzene. EtOAc and the solution were used directly. N- (3- (1- (3- (benzyloxy) cyclobutyl) -1H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) -2- (4-chlorine -3-fluorophenoxy) acetamide
[00358] [00358] A mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanil) acetamide (0.4 g, 1.36 mmol ), sodium ascorbate (5.0 mg, 0.027 mmol), CuSO4 (2 mg, 0.013 mmol), benzoic acid (16 mg, 0.136 mmol) and ((3-azidocyclobutoxy) methyl) benzene (414 mg, 2.04 mmol in EtOAc) in t-BuOH (2 mL) and H2O (4 mL) was stirred at 80 ° C for 15 h in a sealed tube. The mixture was diluted with H2O (30 ml) and was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: MTBE = 1: 0 to 0: 1) to provide N- (3- (1- (3- (benzyloxy) cyclobutyl) -1H-1, 2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) -2- (4-chloro-3-fluorophenoxy) acetamide. LC-MS: m / z: = 497.7 [M + H] +. 2- (4-chloro-3-fluorophenoxy) -N- (3- (1- (3-hydroxycyclobutyl) -1H-1,2,3-triazol-4-yl) bicycles [1.1.1] pentan-1- il) acetamide
[00359] [00359] To a solution of N- (3- (1- (3- (benzyloxy) cyclobutyl) -1H-1,2,3-triazol-4-yl) bicycles [1.1.1] pentan-1-yl) -2- (4-chloro-3-fluorophenoxy) acetamide (0.6 g, 1.21 mmol) in DCM (10 mL) BCl3 (4.8 mL, 4.83 mmol, 1 M in DCM) was added to 0 ° C. The mixture was stirred at 25 ° C for 1 h. The reaction mixture was diluted with H2O (60 mL) and extracted with DCM: i-PrOH (3 × 60 mL, v: v = 3: 1). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (MTBE: MeOH = 1: 0 to 3: 1) to provide 2- (4-chloro-3-fluorophenoxy) -N- (3- (1- (3- hydroxycyclobutyl) -1H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) acetamide. LC-MS: m / z: = 407.2 [M + H] +. S-methyl O- (3- (4- (3- (2- (4-chloro-3-fluorophenoxy) acetamido) bicyclo [1.1.1] pentan-1-yl) -1H-1,2,3 -triazol-1-yl) cyclobutyl) carbonodithioate
[00360] [00360] For a solution of 2- (4-chloro-3-fluorophenoxy) -N- (3- (1- (3-hydro-xicyclobutyl) -1H-1,2,3-triazol-4-yl) bicycle [1.1.1] pentan-1-yl) acetamide (180 mg, 0.44 mmol) in DMF (4.0 mL) DBU (80 mg, 0.53 mmol) was added at 0 ° C. After 0.5 h, CS2 (134 mg, 1.77 mmol) was added to the mixture at 0 ° C. The mixture was stirred at 0 ° C for 0.5 h. To the mixture was added MeI (314 mg, 2.21 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 15 h. The reaction mixture was diluted with H2O (60 ml) and extracted with EtOAc (3 × 20 ml). The combined organic layers were washed with brine (2 x 30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified by prep TLC (PE: EtOAc = 1: 1) to provide the compound of title. LC-MS: m / z: = 497.2 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [1- [3-trans- (trifluoromethoxy) cyclobutyl] triazol-4-yl] -1-bicycle [1.1.1] pentanyl] acetamide and 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [1- [3-cis- (trifluoromethoxy) cyclobutyl] triazol-4-yl] -1-bicycle [1.1.1] pentanil] acetamide
[00361] [00361] To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (103 mg, 0.362 mmol) in DCM (6 mL) was added pyridine; hydrofluoride (683 mg, 4.83 mmol, 70%) at -78 ° C. The mixture was stirred at -78 ° C for 0.5 h. To the mixture was added S-methyl O- (3- (4- (3- (2- (4-chloro-3-fluorophenoxy) ace-
[00362] [00362] 2- (4-chloro-3-fluoro-phenoxy) -N - [3- [1- [3-trans- (trifluoromethoxy) cyclo-1-butyl] triazol-4-yl] -1-bicycle [ 1.1.1] pentanil] acetamide. H-NMR (400 MHz, CDCl3) δ 7.44-7.29 (m, 2H), 6.93 (s, 1H), 6.82-6.64 (m, 2H), 5.20-5 , 03 (m, 2H), 4.42 (s, 2H), 3.13-2.99 (m, 2H), 2.96-2.84 (m, 2H), 2.52 (s, 6H ). LCMS: m / z: = 475.3 [M + H] +.
[00363] [00363] 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [1- [3-cis- (trifluoromethoxy) cyclobutyl] triazol-4-yl] -1-bicycle [1.1. 1] pentanil] acetamide. 1H-NMR (400 MHz, CDCl3): δ 7.43 (s, 1H), 7.34 (t, J = 8.6 Hz, 1H), 6.92 (s, 1H), 6.78 (dd , J = 2.8, 10.2 Hz, 1H), 6.70 (dd, J = 1.8, 8.9 Hz, 1H), 4.73 (quin, J = 8.3 Hz, 1H) , 4.62 (quin, J = 7.2 Hz, 1H), 4.42 (s, 2H), 3.17-3.07 (m, 2H), 3.01-2.81 (m, 2H ), 2.53 (s, 6H), LC-MS: m / z: = 475.3 [M + H] +. EXAMPLE 66 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [3-cis- (difluoromethoxy) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -1- bicycles [1.1.1] pentanil] acetamide methyl 3-cis- (difluoromethoxy) cyclobutanecarboxylate
[00364] [00364] To a solution of methyl 3-cis-hydroxycyclobutanecarboxylate (400 mg, 3.07 mmol) in CH3CN (5 mL) was added CuI (117 mg, 0.61 mmol), the mixture was heated to 50 ° C and a solution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (657 mg, 3.69 mmol) in CH3CN (5 mL) was added dropwise over a period of 5 min. The reaction mixture stirred at 50 ° C for 2 h, was diluted with H2O (10 ml) and then extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide methyl 3- (difluoromethoxy) cyclobutanecarboxylate, which was used directly in the next step. 3-cis- (difluoromethoxy) cyclobutanecarboxylic acid
[00365] [00365] To a solution of methyl 3-cis- (difluoromethoxy) cyclobutanecarboxylate (480 mg, 2.66 mmol) in THF (10 mL) were added LiOH • H2O (447 mg, 10.66 mmol) and H2O ( 2 mL), and the mixture was stirred at 25 ° C for 16 h. The reaction mixture was diluted with MTBE and the layers were separated. The aqueous phase was extracted with MTBE (3 x 5 ml) and the pH of the aqueous layer was adjusted to 3 with HCl (2 N). The acidified mixture was extracted with EtOAc (3 × 5 ml), the organic phase was washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 3-cis- (difluoromethoxy) cyclobutanecarboxylic acid, which was used directly for the next step. 2- (4-chloro-3-fluorophenoxy) -N- (3- (2- (3-cis- (difluoromethoxy) cyclobutanecarbonyl) hydrazinecarbonyl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00366] [00366] To a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-cis-bicyclo [1.1.1] pentanil] acetamide (100 mg, 031 mmol) in THF (10 mL), 3- (difluoromethoxy) cyclobutanecarboxylic acid (61 mg, 0.37 mmol), HATU (139 mg, 0.37 mmol) and DIEA (0.16 mL, 0.92 mmol) were added at 0 ° C and the mixture was stirred at 20 ° C for 2 h. The reaction mixture was poured into ice water (10 ml) and extracted with EtOAc (3 x 10 ml), the organic phase was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to provide title product, which was used directly. LC-MS m / z: = 476.3 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [3-cis- (difluoromethoxy) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -1-bicycle [ 1.1.1] pentanil] acetamide
[00367] [00367] For 2- (4-chloro-3-fluorophenoxy) -N- (3- (2- (3-cis- (difluoromethoxy) cyclobutanocarbonyl) hydrazinecarbonyl) bicycle [1.1.1] pentan-1-yl) acetamide (100 mg, 0.21 mmol) in DCM (6 mL) was added TEA (0.12 mL, 0.84 mmol) and p-TsCl (80 mg, 0.42 mmol) at 25 ° C, and at The mixture was stirred at 25 ° C for 16 h. The reaction mixture was poured into ice water (10 ml) and was extracted with DCM (3 x 10 ml), the organic phase was washed with brine (10 ml), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue, which was purified by HPLC prep (TFA) to provide the desired compound, which was further separated by TLC prep (DCM: MeOH = 10: 1) to provide the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.35 (t, J = 8.60 Hz, 1 H), 6.97 (br s, 1 H), 6.78 (dd, J = 10.23 , 2.82 Hz, 1 H), 6.70 (br d, J = 8.78 Hz, 1 H), 5.99-6.41 (m, 1 H), 4.70 (quin, J = 7.53 Hz, 1 H), 4.44 (s, 2 H), 3.25-3.39 (m, 1 H), 2.78-2.88 (m, 2 H), 2.66 (s, 6 H), 2.57-2.63 (m, 2 H), LC-MS m / z: = 458.3 [M + H] +. EXAMPLE 67 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [4- [1- (2,2,2-trifluoroethyl) azetidin-3-yl] imidazole-1-yl] -1-bicycle [1.1.1] pentanyl] acetamide O1-benzyl O3-ethyl azetidine-1,3-dicarboxylate
[00368] [00368] To a mixture of ethyl azetidine-3-carboxylate hydrochloride (2.0 g, 12.1 mmol) in THF (20 mL) and H2O (20 mL) was added aqueous NaOH solution (4 M, 3, 0 ml) at 0 ° C, followed by CbzCl (2.06 g, 12.1 mmol) dropwise, and then the mixture was stirred at 25 ° C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (30 ml) and water (30 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue, which was purified by silica gel column chromatography (PE: MTBE = 100: 1 to 1: 1) to provide O1-benzyl O3-ethyl azetidine-1,3-dicarboxylate. LC-MS m / z: = 264.1 [M + H] +. 1-Benzyloxycarbonylazetidine-3-carboxylic acid
[00369] [00369] To a mixture of O1-benzyl O3-ethyl azetidine-1,3-dicarboxylate (0.5 g, 1.90 mmol) in THF (2.5 mL) and H2O (2.5 mL) was added LiOH .H2O
[00370] [00370] To a mixture of 1-benzyloxycarbonylazetidine-3-carboxylic acid (0.5 g, 2.13 mmol) and DMF (16 mg, 0.21 mmol) in DCM (10 mL) was added (COCl) 2 ( 809 mg, 6.38 mmol) at 0 ° C, then the mixture was stirred at 25 ° C for 2 h. The reaction mixture was concentrated under reduced pressure to provide benzyl 3-chlorocarbonylazetidine-1-carboxylate. Benzyl 3- (2-diazoacetyl) azetidine-1-carboxylate
[00371] [00371] To a mixture of benzyl 3-chlorocarbonylazetidine-1-carboxylate (640 mg, 2.52 mmol) in THF (5 ml) and MeCN (5 ml) was added TMSCHN2 (2 M, 3.15 ml) at 0 ° C, then the mixture was stirred at 25 ° C for 1 h. The reaction mixture was concentrated under reduced pressure, then diluted with H2O (10 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography over silica gel (PE: EtOAc = 100: 1 to 0: 1) to provide benzyl 3- (2-diazoacetyl-azetidine-1-carboxylate. LC-MS m / z: = 260 , 0 [M + H] + .Benzyl 3- (2-bromoacetyl) azetidine-1-carboxylate
[00372] [00372] To a mixture of benzyl 3- (2-diazoacetyl) azetidine-1-carboxylate (450 mg, 1.74 mmol) in THF (10 mL) was added HBr (421 mg, 2.08 mmol, 40% in H2O) at 0 ° C, and the mixture was stirred at 25 ° C for 0.5 h. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (3 × 20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide benzyl 3- (2-bromoacetyl) azetidine-1-carboxylate. LC-MS m / z: = 312.0, 314.0 [M + H] +. Benzyl 3- [2 - [[3 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -1-bicyclo [1.1.1] pentanyl] amino] acetyl] azetidine-1-carboxylate
[00373] [00373] To a HCl salt mixture of N- (1-amino-3-bicyclo [1.1.1] pentanil) - 2- (4-chloro-3-fluoro-phenoxy) acetamide (0.9 g, 2, 80 mmol) and benzyl 3- (2-bromoacetyl) azetidine-1-carboxylate (1.05 g, 3.36 mmol) in MeCN (50 mL) was added Na2CO3 (1.19 g, 11.21 mmol) and the mixture was stirred at 40 ° C for 2 h. The mixture was filtered and concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE: EtOAc = 100: 1 to 0: 1) to provide benzyl 3- [2 - [[3- [ [2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -1-bicyclo [1.1.1] pentanyl] amino] acetyl] azetidine-1-carboxylate. LC-MS m / z: = 516.2, 518.2 [M + H] +. Benzyl 3- [2 - [[1 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -3-bicyclo [1.1.1] pentanyl] -formyl-amino] acetyl] azetidine-1 -carboxylate
[00374] [00374] To a solution of formic acid (102 mg, 2.13 mmol) was added Ac2O (871 mg, 8.53 mmol) at 0 ° C. To this was added a solution of 3- [2 - [[3 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -1-bicycle [1.1.1] pentanyl] amino] acetyl] azetidine-1-carboxylate (1.1 g, 2.13 mmol) dropwise in DCM (3 ml) and the mixture was stirred at 0 ° C for 2 h. The reaction mixture was adjusted to pH = 7-8 with sat. NaHCO3 solution, the aqueous phase was extracted with EtOAc (3 × 50 mL), the combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 3- [ 2 - [[1 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -3-bicyclo [1.1.1] pentanyl] -formyl-amino] acetyl] azetidine-1-carboxylate. Benzyl 3- [1- [1 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -3-bicyclo [1.1.1] pentanyl] imidazol-4-yl] azetidine-1-carboxylate
[00375] [00375] To a benzyl solution 3- [2 - [[1 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -3-bicyclo [1.1.1] pentanil] - formyl-amino] acetyl] azetidine-1-carboxylate (950 mg, 1.75 mmol) in AcOH (10 mL) ammonium acetate (673 mg, 8.73 mmol) was added and the mixture was stirred at 110 ° C for 16 h. The reaction mixture was adjusted to pH = 7-8 with sat. NaHCO3, the aqueous phase was extracted with EtOAc (3 × 50 mL), the combined organic layers were washed with brine (50 mL), dried over Anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 100: 1 to 10: 1) to provide benzyl 3- [1- [1 - [[2- (4-chloro-3-fluoro-phenoxy ) acetyl] amino] -3-bicyclo [1.1.1] pentanyl] imidazol-4-yl] azetidine-1-carboxylate. LC-MS m / z: = 525.2, 527.2 [M + H] +. N- [3- [4- (azetidin-3-yl) imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] -2- (4-chloro-3-fluoro-phenoxy) acetamide
[00376] [00376] To a solution of 3- [1- [1 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] -3-bicyclo [1.1.1] pentanil] imidazol-4-yl ] azetidine-1-carboxylate (100 mg, 0.19 mmol) in EtOH (5 mL) was added Pd (OH) 2 (10%). The suspension was degassed under vacuum and purged with H2 three times. The reaction mixture was stirred under H2 (30 psi) at 25 ° C for 2.5 h. The reaction mixture was filtered over a pad of celite and the filtrate was concentrated under reduced pressure to provide N- [3- [4- (azetidin-3-yl) imidazol-1-yl] -1-bicycles [1.1.1 ] pentanyl] -2- (4-chloro-3-fluoro-phenoxy) acetamide. LCMS m / z: = 391.1, 393.2 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [4- [1- (2,2,2-trifluoroethyl) azetidin-3-yl] imidazol-1-yl] -1 -bicycle [1.1.1] pentanil] acetamide
[00377] [00377] To a solution of N- [3- [4- (azetidin-3-yl) imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] -2- (4-chloro-3-fluoro -phenoxy) acetamide (80 mg, 0.20 mmol) in THF (2 mL) was added DIEA (106 mg, 0.82 mmol), followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (71 mg, 0.31 mmol ) at 0 ° C. The reaction mixture was stirred at 50 ° C for 4 h and then it was diluted with H2O (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 ml). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified by prep (neutral) HPLC to provide 2- (4-chloro-3- fluoro-phenoxy) -N- [3- [4- [1- (2,2,2-trifluoroethyl) azetidin-3-yl] imidazol-1-yl] -1-bicycle [1.1.1] pentanyl] acetamide. LCMS m / z: = 473.2 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.42 (d, J = 1.13 Hz, 1 H), 7.35 (t, J = 8.60 Hz, 1 H), 6.96 (s, 1 H), 6.75-6.80 (m, 2 H), 6.69 (ddd, J = 8.88, 2.79 , 1.25 Hz, 1 H), 4.41 - 4.49 (m, 2 H), 3.81 - 3.89 (m, 2 H), 3.69-3.81 (m, 1 H ), 3.40-3.50 (m, 2 H), 3.08 (q, J = 9.49 Hz, 2 H), 2.59-2.65 (m, 6 H). EXAMPLES 68 and 69 2- (4-chlorophenoxy) -N- [3- [4- [3-cis- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] - 1-bicycle [1.1.1] pentanyl] acetamide and 2 - (4-chlorophenoxy) -N- [3- [4- [3-trans- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] acetamide 2- (4- chlorophenoxy) -N- (3 - ((2-oxo-2- (3-cis- (trifluoromethoxy) cyclobutyl) ethyl) amino) bicyclo [1.1.1] pentan-1-yl) acetamide
[00378] [00378] To a H- salt solution of N- (1-amino-3-bicyclo [1.1.1] pentanyl) -2- (4-chlorophenoxy) acetamide (0.6 g, 1.98 mmol) and 2-bromo-1- [3-cis- (trifluoromethoxy) cyclobutyl] ethanone (1.03 g, 3.96 mmol; 8: 1 to 10: 1 ratio of cis- to trans-) in CH3CN (20 mL) Na2CO3 (839 mg, 7.92 mmol) was added. The reaction mixture was stirred at 40 ° C for 6 h and then filtered and concentrated under reduced pressure. The residue was diluted with EtOAc (20 ml) and H2O (20 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 10 ml), the combined organic extracts were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography to provide 2- (4-chlorophenoxy) -N- [1 - [[2-oxo-2- [3-cis- (trifluoromethoxy) cyclobutyl]] ethyl] amino] -3-bicyclo [1.1.1] pentanil] acetamide (cis- to trans- 3: 1 ratio). LC-MS m / z: = 446.9 [M + H] +. 2- (4-chlorophenoxy) -N- (3- (N- (2-oxo-2- (3-cis- (trifluoromethoxy) cyclobutyl) ethyl) formamide) bicyclo [1.1.1] pentan-1-yl) acetamide
[00379] [00379] To a solution of formic acid (3.17 g, 68.9 mmol) was added
[00380] [00380] To a solution of 2- (4-chlorophenoxy) -N- [3- [formyl- [2-oxo-2- [3-cis- (trifluoromethoxy) cyclobutyl] ethyl] amino] -1-bicycle [1.1 .1] pentanil] acetamide (360 mg, 0.76 mmol) in AcOH (4 mL) ammonium formate (228 mg, 2.96 mmol) was added and the reaction mixture was stirred at 110 ° C for 12 h. The reaction was diluted with aqueous aHCO3 solution (30 mL) at 0 ° C and adjusted to pH = 8-9. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by preparative HPLC to provide the desired product (3: 1 ratio of cis- to trans-). The individual diastereomers were separated by SFC to give:
[00381] [00381] 2- (4-chlorophenoxy) -N- [3- [4- [3-trans- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] acetamide: 1H-NMR (400 MHz, MeOD): δ 8.48 (s, 1 H), 7.46 (s, 1 H), 7.26-7.33 (m, 2 H), 6.95-7 , 02 (m, 2 H), 4.93-5.01
[00382] [00382] 2- (4-chlorophenoxy) -N- [3- [4- [3-cis- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] acetamide: 1H- NMR (400 MHz, MeOD): δ 7.96 (d, J = 1.13 Hz, 1 H), 7.24-7.33 (m, 2 H), 7.17 (s, 1 H), 6.93-7.02 (m, 2 H), 4.66- 4.78 (m, 1 H), 4.50 (s, 2 H), 2.99-3.15 (m, 1 H ), 2.68-2.81 (m, 2 H), 2.62 (s, 6 H), 2.29-2.44 (m, 2 H), LC-MS m / z: = 456, 3 [M + H] +. EXAMPLE 70 N- [3- [4- (4-chloro-3-fluoro-phenyl) imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] -2- [3-cis- (trifluoromethoxy) cyclobutoxy ] N- (3 - ((2- (4-chloro-3-fluorophenyl) -2-oxoethyl) amino) bicyclo [1.1.1] pentan-1-yl) - 2- (3-cis- (trifluoromethoxy) acetamide) cyclobutoxy) acetamide
[00383] [00383] To a mixture of 2-bromo-1- (4-chloro-3-fluoro-phenyl) ethanone (152 mg, 0.60 mmol) and H- salt of N- (1-amino-3-bicycle) [ 1.1.1] pentanil) -2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetamide (200 mg, 0.60 mmol) in CH3CN (20 mL) Na2CO3 (256 mg, 2.42 mmol) was added and the mixture was stirred at 40 ° C for 1 h. The reaction mixture was diluted with water (5 ml) at 0 ° C and EtOAc (5 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue, which was purified by column chromatography on silica gel to provide the desired product, which was used directly. LC-MS m / z: = 465.1 [M + H] +. N- (3- (N- (2- (4-chloro-3-fluorophenyl) -2-oxoethyl) formamido) bicyclo [1.1.1] pen-tan-1-yl) -2- (3-cis- ( trifluoromethoxy) cyclobutoxy) acetamide
[00384] [00384] Formic acid (0.53 mL, 13.98 mmol) was added dropwise to Ac2O (0.10 mL, 1.12 mmol) at 0 ° C, after which N- (3 - ((2 - (4-chloro-3-fluorophenyl) - 2-oxoethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (130 mg, 0 , 28 mmol) in DCM (5 ml) was added dropwise at 0 ° C and the mixture was stirred at 0 ° C for 2 h. The reaction mixture was diluted with sat. of NaHCO3 (10 ml) and EtOAc (10 ml) at 0 ° C, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 5 ml), the combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the desired compound, which was used directly. LC-MS m / z: = 492.9 [M + H] +. N- [3- [4- (4-chloro-3-fluoro-phenyl) imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] -2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetamide
[00385] [00385] To a solution of N- (3- (N- (2- (4-chloro-3-fluorophenyl) -2-oxoethyl) formed) bicycles [1.1.1] pentan-1-yl) -2 - (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (130 mg, 0.26 mmol) in AcOH (1.0 mL), ammonium formate (81 mg, 1.06 mmol) was added and the mixture it was stirred at 120 ° C for 8 h. The reaction mixture was diluted with sat. of saturated NaHCO3 (10 ml) at 0 ° C and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue, which was purified by prep TLC (EtOAc, 3 times) to provide N- [ 3- [4- (4-chloro-3-fluoro-phenyl) imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] -2- [cis-3- (trifluoromethoxy) cyclobutoxy] aceta- mida. 1H-NMR (400 MHz,, CDCl3): δ 7.62-7.43 (m, 3H), 7.41-7.33 (m, 1H), 7.21 (d, J = 1.3 Hz , 1H), 6.98 (s, 1H), 4.37-4.30 (m, 1H), 3.85 (s, 2H), 3.74 (quin, J = 6.9 Hz, 1H) , 2.87-2.81 (m, 2H), 2.69-2.58 (m, 6H), 2.28 (dtd, J = 3.5, 6.9, 10.1 Hz, 2H) , LC-MS m / z: = 474.3. EXAMPLES 71 and 72 2- (4-fluorophenoxy) -N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadazazol-2-yl] -1-bicycle [ 1.1.1] pentanil] acetamide and 2- (4-fluorophenoxy) -N- [3- [5- [3-trans- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1- bicycle [1.1.1] pentanil] acetamide
[00386] [00386] To a solution of 2- (4-fluorophenoxy) acetic acid (60 mg, 0.35 mmol) in dry DMF (1 mL) was added HATU (161 mg, 0.42 mmol) to
[00387] [00387] 2- (4-fluorophenoxy) -N- [3- [5- [3-trans- (trifluoromethoxy) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1 ] pentanyl] acetamide: 1H-NMR (400 MHz, CDCl3): δ 7.06-7.01 (m, 3H), 6.91-6.87 (m, 2H), 5.00 (quin, J = 6.8 Hz, 1H), 4.75-4.68 (m, 1H), 4.42 (s, 2H), 3.77-3.66 (m, 1H), 3.38-3.28 (m, 1H), 2.91 2.74 (m, 4H), 2.65 (s, 5H), 2.67-2.64 (m, 1H), LC-MS: m / z = 442 , 2 [M + H] +. EXAMPLE 73 N- [1- [5- (5-fluoro-3-pyridyl) -1,3,4-oxadiazol-2-yl] -3-bicyclo [1.1.1] pentanil] - 2- [3-cis - (trifluoromethoxy) cyclobutoxy] acetamide tert-butyl N- [1- [5- (5-fluoro-3-pyridyl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1] pentanyl ] carbamate
[00388] [00388] Terc-butyl N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] carbamate (80.0 mg, 0.33 mmol), 5-fluoropyridine-3-carboxylic acid (70 , 2 mg, 0.50 mmol) and NEt3 (0.23 mL, 1.66 mmol) were dissolved in EtOAC (2.5 mL) and T3P solution (300 µL, 0.99 mmol) was added. The resulting mixture was heated to 100 ° C overnight. The reaction mixture was diluted with saturated NaHCO3 solution (10 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. TFA salt of 1- [5- (5-fluoro-3-pyridyl) -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pen-tan-3-amine
[00389] [00389] Terc-butyl N- [1- [5- (5-fluoro-3-pyridyl) -1,3,4-oxadiazol-2-yl] -3-bicyclo [1.1.1] pentanyl] carbamate (60.0 mg, 0.17 mmol) was dissolved in DCM (2.0 mL), cooled to 0 ° C and TFA (20 mg, 0.17 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 4 h and concentrated under reduced pressure. The crude reaction mixture was used directly. N- [1- [5- (5-fluoro-3-pyridyl) -1,3,4-oxadiazol-2-yl] -3-bicyclo [1.1.1] pentanil] - 2- [3-cis- ( trifluoromethoxy) cyclobutoxy] acetamide
[00390] [00390] 1- [5- (5-fluoro-3-pyridyl) -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine trifluoroacetic acid salt (60.0 mg , 0.17 mmol), [2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetic acid (42.8 mg, 0.20 mmol) and NEt3 (70 µL, 0.50 mmol) were dissolved in EtOAc (1 , 0 mL) and T3P solution (63.6 mg, 0.20 mmol) was added. The resulting mixture was heated to 100 ° C overnight. The reaction mixture was diluted with saturated NaHCO3 solution (10 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 443.6 [M + H] +. EXAMPLE 74. 2- (4-chlorophenoxy) -N-prop-2-ynyl-N- [1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1] pentanil] acetamide
[00391] [00391] To a solution of 2- (4-chlorophenoxy) -N- [1- [5- [3-cis- (trifluoromeotoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -3 -bicycle [1.1.1] pentanil] acetamide (4.2 mg, 0.01 mmol) in THF (0.5 mL) at room temperature NaH was added
[00392] [00392] N-methoxy-N-methyl-3-cis- (trifluoromethoxy) cyclobutanecarboxamide (2.46 g, 10.83 mmol) was dissolved in THF (100 mL) and cooled to -78 ° C. DIBAL-H (3.08 g, 21.6 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was treated with sat. of sodium and potassium tartrate (100 ml) and EtOAc (100 ml) and the resulting emulsion was stirred at room temperature for 8 h. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was used directly. ethyl (E) -3- [3-cis- (trifluoromethoxy) cyclobutyl] prop-2-enoate
[00393] [00393] NaH (534 mg, 13.4 mmol) was suspended in THF (45.0 mL) at 0 ° C. To this, triethyl phosphonoacetate (2.65 ml, 13.4 mmol) in 20 ml of THF was added. The reaction mixture was stirred until a clear solution was formed and 3-cis- (trifluoromethoxy) cyclobutanecarbaldehyde (1.87 g, 11.1 mmol) in 20 ml of THF was added. The reaction mixture was allowed to warm up to room temperature and the TLC (20% EtOAc / hex, KMnO4) did not show initial material and showed it a new less polar point. The reaction mixture was treated with NH4Cl solution (25 ml) and EtOAc (25 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using silica gel column chromatography (0-> 15% EtOAc / hex) to provide the desired product. ethyl 3- [3-cis-trifluoromethoxy) cyclobutyl] propanoate
[00394] [00394] Ethyl (E) -3- [3-cis- (trifluoromethoxy) cyclobutyl] prop-2-e-noate (63.0 mg, 0.26 mmol) was dissolved in EtOH (2.6 mL) and palladium on carbon (6.3 mg, 10% by weight) added. The H2 gas was bubbled into the reaction mixture for 1 hour. TLC (20% EtOAc / hex, KMnO4) did not show initial material and a new stain on the product. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude reaction mixture was used directly. 3- [3-cis- (trifluoromethoxy) cyclobutyl] propanoic acid
[00395] [00395] Ethyl 3- [3-cis- (trifluoromethoxy) cyclobutyl] propanoate (57.0 mg, 0.24 mmol) was dissolved in MeOH (1.0 mL), 1M NaOH (1.0 mL, 0.24 mmol) was added and the reaction mixture was stirred overnight at 65 ° C. The mixture was treated with HCl solution (1M, 10 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was used directly. 3- [3-cis- (trifluoromethoxy) cyclobutyl] -N- [3- [5- [3-cis- (trifluoromethoxy) cyclo-butyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanil] propanamide
[00396] [00396] To a solution of 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxada-diazol-2-yl] bicycles [1.1.1] pentan-3-amine (45 , 0 mg, 0.16 mmol; 8: 1 to 10: 1 ratio of trans-scisa in EtOAc (1.0 mL), N, N-diisopropylethylamine (80 µL, 0.47 mmol) was added ) followed by T3P solution (74.2 mg, 0.23 mmol). The resulting reaction mixture was stirred 10 min and cis-acid was added
[00397] [00397] To a mixture of 2,3-dihydrobenzofuran-2-carboxylic acid (1.0 g, 6.09 mmol) in DMF (10 mL) was added NCS (976 mg, 7.31 mmol) at 25 ° C, and the mixture was heated to 60 ° C for 3 h. The reaction mixture was adjusted to pH = 5-6 by adding 1N HCl, and EtOAc was added (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 5 ml). The combined organic phases were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 5-chloro-2,3-dihydrobenzofuran-2-carboxylic acid. 5-chloro-N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1- bicycle [1.1.1] pentanil] -2.3 -dihydrobenzofuran-2-carboxamide
[00398] [00398] To a HCl salt mixture of 1- [5- [3-cis- (trifluoromethoxy) cyclo-butyl] -1,3,4-oxadiazol-2-yl] bicycle [1.1.1] pentan-3 -amine (120 mg, 0.368 mmol; 8: 1 to 10: 1 ratio of cis- to trans-) and 5-chloro-2,3-dihydrobenzofuran-2-carboxylic acid (80 mg, 0.405 mmol) in DMF (5.0 mL) was added HATU (154 mg, 0.405 mmol) and DIEA (95 mg, 0.736 mmol) at 25 ° C, and the mixture was stirred at 25 ° C for 2 h. The reaction mixture was diluted with water (20 ml) and EtOAc (20 ml) and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 5 ml), the combined organic phases were washed with brine (2 x 5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to provide the title compound. LC-MS m / z: = 470.1 [M + H] +. 1
[00399] [00399] H-NMR (400 MHz, CDCl3) δ 7.17 (s, 1 H), 7.13 (br d, J = 8.41 Hz, 1 H), 7.06 (br s, 1 H ), 6.79 (br d, J = 8.41 Hz, 1 H), 5.12 (br dd, J = 10.67, 6.78 Hz, 1 H), 4.70 (quin, J = 7.50 Hz, 1 H), 3.52-3.63 (m, 1 H), 3.26-3.47 (m, 2 H), 2.81-2.90 (m, 2 H) , 2.65-2.74 (m, 2 H), 2.61 (s, 6 H). EXAMPLE 77 N- [3- [1- (4-chloro-3-fluoro-phenyl) triazol-4-yl] -1-bicyclo [1.1.1] pentanil] -2- [3- cis- (trifluoromethoxy) cyclobutoxy ] Terc-butyl acetamide (3- (1H-1,2,3-triazol-4-yl) bicycles [1.1.1] pentan-1-yl) carbamate
[00400] [00400] A mixture of tert-butyl (3-ethynylbicyclo [1.1.1] pentan-1-yl) carbamate (1.0 g, 4.82 mmol), CuI (45 mg, 0.241 mmol) and TMSN3 ( 833 mg, 7.24 mmol) in DMF (10 ml) and MeOH (2 ml) was stirred at 100 ° C for 15 h. The reaction mixture was diluted with H2O (100 ml) and EtOAc (100 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (60 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified using silica gel column chromatography (PE: MTBE = 1: 0 to 0: 1) to administer tert-butyl (3- (1H-1 1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) carbamate. H-NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 5.15 (br s, 1H), 2.38 (s, 6H), 1.47 (s, 9H). tert-Butyl (3- (1- (4-chloro-3-fluorophenyl) -1H-1,2,3-triazol-4-yl) bicyclo [1,1,1] pentan-1-yl) carbamate
[00401] [00401] A mixture of tert-butyl (3- (1H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) carbamate (0.5 g, 2, 0 mmol), boronic acid (4-chloro - 3-fluoro-phenyl) (696 mg, 4.0 mmol), Cu (OAc) 2 (72 mg, 0.39 mmol) and pyridine (316 mg, 4.0 mmol) in THF (10 mL) was stirred at 60 ° C under O2 for 15 h. The reaction mixture was diluted with H2O (60 ml) and EtOAc (60 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified using silica gel column chromatography (PE: MTBE = 1: 0 to 0: 1) to provide tert-butyl (3- (2- (4-chloro-3-fluorophenyl) -2H-1,2,3-triazol-4-yl) bicycle [1.1.1] pentan-1 -yl) carbamate and tert-butyl (3- (1- (4-chloro-3-fluorophenyl) -1H-1,2,3-triazol-4-yl) bicycles [1.1.1] pentan-1-yl) carbamato. LCMS m / z: = 379.1, 381.1 [M + H] +. 3- (1- (4-chloro-3-fluorophenyl) -1H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-amine
[00402] [00402] A mixture of tert-butyl (3- (1- (4-chloro-3-fluorophenyl) -1H-1,2,3-triazol-4-yl) bicycle [1.1.1] pentan-1-yl ) carbamate (200 mg, 0.527 mmol) in HCl / EtOAc (20 mL) were stirred at 20 ° C for 1 h. The mixture was concentrated under reduced pressure to provide 3- (1- (4-chloro-3-fluorophenyl) -1H-1, 2, 3-triazol-4-yl) bicyclo [1.1.1] pentan-1-amine, HCl salt, which was used directly. LCMS m / z: = 279.1, 281.1 [M + H] +. N- [3- [1- (4-chloro-3-fluoro-phenyl) triazol-4-yl] -1-bicyclo [1.1.1] pentanil] -2- [3- cis- (trifluoromethoxy) cyclobutoxy] acetamide
[00403] [00403] To a solution of 2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetic acid (119 mg, 0.558 mmol) in DMF (3 mL) was added HATU (212 mg, 0.558 mmol) and DIEA (196 mg, 1.52 mmol). The mixture was stirred at 20 ° C for 30 min. To this mixture was added 3- (1- (4-chloro-3-fluorophenyl) -1H- 1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-amine, HCl salt ( 160 mg, 0.507 mmol) and the mixture was stirred at 20 ° C for 15 h. The reaction mixture was diluted with H2O (30 ml) and EtOAc (30 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified by prep HPLC (NH4HCO3) to provide N- [3- [1- ( 4-chloro-3-fluoro-phenyl) triazol-4-yl] -1-bicyclo [1.1.1] pentanil] -2- [cis-3- (trifluoromethoxy) cyclobutoxy] acetamide. 1H-NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.63 (dd, J = 2.3, 9.3 Hz, 1H), 7.60-7.53 (m, 1H), 7.53-7.44 (m, 1H), 6.92 (s, 1H), 4.34
[00404] [00404] A mixture of tert-butyl (3- (2- (4-chloro-3-fluorophenyl) -2H-1,2,3-triazol-4-yl) bicycle [1.1.1] pentan-1-yl ) carbamate (350 mg, 0.923 mmol) in HCl / EtOAc (4 M, 20 mL) was stirred at 20 ° C for 1 h. The mixture was concentrated under reduced pressure to provide a residue that was used directly. N- [3- [2- (4-chloro-3-fluoro-phenyl) triazol-4-yl] -1-bicyclo [1.1.1] pentanil] -2- [3- cis- (trifluoromethoxy) cyclobutoxy] acetamide
[00405] [00405] To a solution of 2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetic acid (74 mg, 0.35 mmol) in DMF (5 mL) was added HATU (132 mg, 0.35 mmol) and DIEA (123 mg, 0.95 mmol). The mixture was stirred at 20 ° C for 0.5 h. To this mixture was added HCl salt of 3- (2- (4-chloro-3-fluorophenyl) -2H- 1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-amine ( 100 mg, 0.317 mmol) and the mixture was stirred at 20 ° C for 15 h. The reaction mixture was diluted with H2O (30 ml) and EtOAc (30 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified by prep (neutral) HPLC to provide N- [3- [2- ( 4-chloro-3-fluoro-phenyl) triazol-4-yl] -1-bicyclo [1.1.1] pentanil] -2- [cis-3-cis- (trifluoromethoxy) cyclobutoxy] acetamide. 1 H-NMR (400 MHz, CDCl3): δ 7.88 (dd, J = 2.4, 9.9 Hz, 1H), 7.85-7.78 (m, 1H), 7.62 (s , 1H), 7.48 (t, J = 8.2 Hz, 1H), 6.91 (s, 1H), 4.34 (quin, J = 7.2 Hz, 1H), 3.84 (s , 2H), 3.74 (quin, J = 6.9 Hz, 1H), 2.89-2.79 (m, 2H), 2.53 (s, 6H), 2.36-2.25 ( m, 2H), LC-MS m / z: = 475.3 [M + H] +. EXAMPLE 79
[00406] [00406] To a solution of methyl 3 - [[2- (4-chloro-3-fluoro-phenoxy) acetyl] amino] bicyclo [1.1.1] pentane-1-carboxylate (4.0 g, 12.2 mmol ) in THF (20 mL) LiBH4 (2.66 g, 122 mmol) was added in three portions at 0 ° C and the reaction mixture was heated to 20 ° C and stirred for 16 h. The reaction was poured into ice and DCM was added. The layers were separated and the aqueous layer was extracted with DCM (3 x 100 ml). The combined organic layers were washed with saline (3x50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the residue, which was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to provide 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydroxymethyl) -3-bicyclo [1.1.1] pentanil] acetamide. LC-MS m / z: = 300.1, 302.1 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- (1-formyl-3-bicyclo [1.1.1] pentanil) acetamide
[00407] [00407] A mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydroxymethyl) -3-bicyclo [1.1.1] pentanil] acetamide (2.0 g, 6.67 mmol ) and Dess-Martin (2.27 ml, 7.34 mmol) in DCM (50 ml) was stirred at 20 ° C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (50 ml) and DCM. The layers were separated and the aqueous layer was extracted with DCM (3 x 50 ml). The combined organic extracts were washed with brine (100 mL), dried over filtered Na2SO4, filtered and concentrated under reduced pressure to provide 2- (4-chloro-3-fluoro-phenoxy) -N- (1-formyl-3-bicycle) [1.1.1] pentanil) acetamide. 2- (4-chloro-3-fluoro-phenoxy) -N- (1-ethynyl-3-bicyclo [1.1.1] pentanil) acetamide
[00408] [00408] To a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- (1-formyl-3-bicyclo [1.1.1] pentanil) acetamide (1.70 g, 5.71 mmol) in MeOH (20 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1.54 g, 7.99 mmol) and K2CO3 (2.37 g, 17.13 mmol) and the mixture was stirred at 20 ° C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (50 ml) and EtOAc (30 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 2- (4-chloro-3-fluoro-phenoxy) -N- (1-ethynyl-3-bicy - clo [1.1.1] pentanil) acetamide. N- (3- (2H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) -2- (4-chloro-3-fluorophenoxy) acetamide
[00409] [00409] A mixture of 2- (4-chloro-3-fluorophenoxy) -N- (3-ethynylbicyclo [1.1.1] pentan-1-yl) acetamide (700 mg, 2.38 mmol), TMSN3 (824 mg , 7.15 mmol), sodium ascorbate (9.44 mg, 0.05 mmol), CuSO4 (7.61 mg, 0.05 mmol) and PhCOOH (58 mg, 0.48 mmol) in t-BuOH ( 3 mL) and H2O (6 mL) were stirred at 80 ° C for 6 h in a sealed tube. The reaction mixture was diluted with H2O (10 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with saturated NaHCO3 solution (5 ml), brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide N- (3- (2H-1,2,3) -triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) -2- (4-chloro-3-fluorophenoxy) acetamide LC-MS m / z: = 337.3, 339.3 [M + H] +. 2- (4-chloro-3-fluorophenoxy) -N- (3- (2- (3-oxocyclobutyl) -2H-1,2,3-triazol-4-yl) bicycle [1.1.1] pentan-1- il) acetamide
[00410] [00410] To a solution of N- (3- (2H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) -2- (4-chloro-3-fluorophenoxy ) acetamide (600 g, 1.78 mmol) in DMF (5 mL) were added Cs2CO3 (581 mg, 1.78 mmol) and 3-bromocyclobutanone (400 mg, 2.67 mmol) at 0 ° C, and the mixture it was stirred at 0 ° C for 2 h. The reaction was poured into ice water (20 ml) and extracted with EtOAc (3 × 20 ml), the combined organic phases were washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 2- (4 -chloro-3-fluorophenoxy) -N- (3- (2- (3-oxocyclobutyl) -2H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) acetamide. LC-MS m / z: = 405.1, 407.1 [M + H] +.
[00411] [00411] For a solution of 2- (4-chloro-3-fluorophenoxy) -N- (3- (2- (3-oxycyclobutyl) -2H-1,2,3-triazol-4-yl) bicycle [1.1.1] pentan-1-yl) acetamide (500 mg, 1.24 mmol) in MeOH (5 mL) NaBH4 (42 mg, 1.11 mmol) was added at -20 ° C, and the mixture was stirred at -20 ° C for 1 h. The reaction mixture was diluted with NH4Cl (5 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide a residue, which was purified by prep TLC (100% EtOAc) to provide 2- (4-chlorine -3-fluorophenoxy) -N- (3- (2- (3-cis-hydroxycyclobutyl) -2H-1,2,3-triazol-4-yl) bicyclo [1.1.1] pentan-1-yl) acetamide. O- (3-cis- (4- (3- (2- (4-chloro-3-fluorophenoxy) acetamido) bicyclo [1.1.1] pentan- 1-yl) -2H-1,2,3-triazole- 2-yl) cyclobutyl) S-methyl carbonodithioate
[00412] [00412] To a solution of 2- (4-chloro-3-fluorophenoxy) -N- (3- (2- (cis-3-hydro-xicyclobutyl) -2H-1,2,3-triazol-4-yl ) bicycle [1.1.1] pentan-1-yl) acetamide (180 mg, 0.44 mmol) in dry DMF (2 mL) DBU (81 mg, 0.53 mmol) was added at 0 ° C. After 30 min CS2 (135 mg, 1.77 mmol) was added at 0 ° C, and the reaction mixture was stirred at 0 ° C for an additional 30 min. At that point, MeI (314 mg, 2.21 mmol) was added at 0 ° C and the reaction was stirred at 20 ° C for 15 h. The reaction mixture was poured into sat. NH4Cl (5 ml), and the aqueous phase was extracted with EtOAc (3 x 5 ml). The combined organic phases were washed with brine (10 ml), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue, which was purified by prep TLC (PE: EtOAc = 2: 1) to provide the desired product. LC / MS m / z: = 497.1, 499.1 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [2- [3-cis- (trifluoromethoxy) cyclobutyl] triazol-4-yl] -1-bicyclo [1.1.1] pentanil ] acetamide
[00413] [00413] To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione
[00414] [00414] To a solution of AgOTf (11.23 g, 43.70 mmol) in EtOAc (80 mL) was added 1- (chloromethyl) -4-fluoro-1,4-diazoniabicyclo [2.2.2] octane; di-tetrafluoroborate (7.74 g, 21.85 mmol), KF (3.39 g, 58.27 mmol) and ethyl 2- (hydroxymethyl) cyclopropanecarboxylate (2.1 g, 14.57 mmol) at 25 ° C. After mixing, 2-fluoropyridine (4.24 g, 43.70 mmol) and trimethyl (trifluoromethyl) silane (6.21 g, 43.70 mmol) were added at 25 ° C and the resulting mixture was stirred at 25 ° C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 100: 1 to 5: 1) to provide 2- (trifluoromethoxymethyl) cyclopropanecarboxylate (ratio of cis- to trans- 1: 3). 2-trans - ((trifluoromethoxy) methyl) cyclopropanecarboxylic acid
[00415] [00415] To a solution of ethyl 2-trans- (trifluoromethoxymethyl) cyclopropane carboxylate (0.86 g, 4.05 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH.H2O (510 mg, 12.16 mmol) at 0 ° C and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with H2O (20 ml) and was extracted with MTBE (3 x 10 ml). The aqueous phase was adjusted to pH = 1-2 by adding 2N HCl at 0 ° C and was extracted with DCM: MeOH (6 x 10 ml, v: v = 10: 1). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide trans-2- (trifluoromethoxymethyl) cyclopropanecarboxylic acid (ratio of cis- to trans- 1: 5). The crude product was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 3.99 (dd, J = 10.80, 6.17 Hz, 1 H), 3.81 (dd, J = 10.80, 7.28 Hz, 1 H), 1.83-1.96 (m, 1 H), 1.68 (dt, J = 8.54, 4.44 Hz, 1 H), 1.34-1.42 (m, 1 H ), 0.98-1.08 (m, 1 H). 2- (4-chloro-3-fluorophenoxy) -N- (3- (2- (2-trans - ((trifluoromethoxy) methyl) cyclopropanecarbonyl) hydrazinecarbonyl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00416] [00416] To a solution of 2-trans- (trifluoromethoxymethyl) cyclopropanecarboxylic acid (0.2 g, 1.09 mmol), 2- (4-chloro-3-fluoro-phenoxy) -N- [1- ( hydrazino-carbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (324 mg, 0.99 mmol) and TEA (400 mg, 3.95 mmol) in DMF (2 mL) T3P (2.51 g) was added , 3.95 mmol, 50% in EtOAc) in a sealed tube. The mixture was stirred at 80 ° C for 12 h. The reaction mixture was diluted with sat. of NaHCO3 (5 ml) at 0 ° C, additional H2O (5 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (3 × 3 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide the desired compound. LC-MS m / z: = 494.2 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [2-trans- (trifluoromethoxymethyl) cyclopropyl] -1,3,4-oxadiazol-2-yl] -1- bicycle [1.1.1] pentanil] acetamide
[00417] [00417] To a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- [1 - [[[2-trans- (trifluoromethoxymethyl) cyclopropanecarbonyl] amino] carbamoyl] -3-bicycle [1.1 .1] penta-nyl] acetamide (300 mg, 0.61 mmol) in 1,4-dioxane (5 mL) POCl3 (466 mg, 3.04 mmol) was added and the mixture was stirred at 100 ° C for 1 H. The reaction mixture was poured into ice water (10 ml) at 0 ° C and adjusted to pH = 8-9 by adding sat. NaHCO3 solution (10 mL). EtOAc (10 ml) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Nano-micro Kromasil C18 100 mm x 30 mm, 5 µm; mobile phase: A: 0.1% TFA in water, B: MeCN, gradient: B% in A: 45% - 65% for 10 min) to provide 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [2-trans- (trifluoromethoxymethyl) cyclopropyl] -1,3,4- 1 oxadiazole- 2-yl] -1-bicycle [1.1.1] pentanil] acetamide (racemic) (80). H-NMR (400 MHz, MeOD): δ 7.38 (t, J = 8.72 Hz, 1 H), 6.94 (dd, J = 10.98, 2.82 Hz, 1 H), 6 , 83 (ddd, J = 8.91, 2.82, 1.19 Hz, 1 H), 4.50 (s, 2 H), 4.14 (dd, J = 10.92, 6.53 Hz , 1 H), 4.00 (dd, J = 10.92, 7.53 Hz, 1 H), 2.57 (s, 6 H), 2.24-2.32 (m, 1 H), 1.92 (dq, J = 13.46, 6.68 Hz, 1 H), 1.42 (dt, J = 8.94, 5.25 Hz, 1 H), 1.28 (dt, J = 8.91, 5.71 Hz, 1 H), LC-MS m / z: = 476.1 [M + H] +, 478.1 [M + H] +.
[00418] [00418] The product was separated by chiral SFC (Chiralcel OD-H 250 mm x 30 mm, 5 µm, 40 ° C; mobile phase: A: CO2, B: 0.1% NH4OH in EtOH, according to: B% in A: 30% -30%, Flow: 65 g / min, pressure 100 bar) to provide:
[00419] [00419] Enantiomer 1 (Peak 1 in the SFC) as the first eluting isomer (81). 1H-NMR (400 MHz, MeOD): δ 8.91 (s, 1 H), 7.38 (t, J = 8.72 Hz, 1 H), 6.94 (dd, J = 10.92, 2.76 Hz, 1 H), 6.83 (ddd, J = 8.91, 2.82, 1.19 Hz, 1 H), 4.50 (s, 2 H), 4.14 (dd, J = 10.92, 6.53 Hz, 1 H), 4.00 (dd, J = 10.92, 7.53 Hz, 1 H), 2.57 (s, 6 H), 2.24- 2.34 (m, 1 H), 1.92 (dq, J = 13.19, 6.69 Hz, 1 H), 1.42 (dt, J = 8.91, 5.27 Hz, 1 H ), 1.28 (dt, J = 8.94, 5.69 Hz, 1 H), LC-MS m / z: =
[00420] [00420] Enantiomer 2 (Peak 2 in SFC) as the second eluting isomer (82). 1H-NMR (400 MHz, MeOD): δ 7.38 (t, J = 8.72 Hz, 1 H), 6.94 (dd, J = 10.92, 2.89 Hz, 1 H), 6 , 83 (ddd, J = 8.97, 2.82, 1.25 Hz, 1 H), 4.50 (s, 2 H), 4.14 (dd, J = 10.92, 6.53 Hz , 1 H), 4.00 (dd, J = 10.92, 7.53 Hz, 1 H), 2.57 (s, 6 H), 2.24-2.33 (m, 1 H), 1.86-2.01 (m, 1 H), 1.42 (dt, J = 8.91, 5.27 Hz, 1 H), 1.28 (dt, J = 8.94, 5.69 Hz, 1 H), LC-MS m / z: = 476.1 [M + H] +, SFC: ee = 100%. EXAMPLE 83 2 - [(6,6-difluoro-3-bicyclo [3.1.0] hexanyl) oxy] -N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3, 4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] acetamide Terc-butyl 2 - [(6,6-difluoro-3-bicyclo [3.1.0] hexanil) oxy] acetate
[00421] [00421] To a mixture of 6,6-difluorobicyclo [3.1.0] hexan-3-ol (100 mg, 0.745 mmol), tert-butyl 2-bromoacetate (218.14 mg, 1.12 mmol), sulfate hydrogen: tetrabutylammonium (12 mg, 0.037 mmol) in toluene (2 mL) eH2O (0.1 mL) a solution of NaOH (447 mg, 11.18 mmol) in H2O (0.5 mL) was added dropwise to 0 ° C, then the mixture was stirred at 20 ° C for 4 h. The reaction mixture was diluted with H2O (10 ml) and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by preparation TLC (SiO2, PE: EtOAc = 5: 1) to provide tert-butyl 2 - [(6,6-difluoro-3-bicyclo [3.1.0] hexanyl) oxy] acetate. 2 - [(6,6-Difluoro-3-bicyclo [3.1.0] hexanyl) oxide] acetic acid
[00422] [00422] To a mixture of tert-butyl 2 - [(6,6-difluoro-3-bicyclo [3.1.0] hexanyl) oxy] acetate (80 mg, 0.322 mmol) in DCM (1 mL) was added TFA (0.2 ml) at 0 ° C, the mixture was stirred at 40 ° C for 2 h. The reaction mixture was concentrated under reduced pressure to provide 2 - [(6,6-difluoro-3-bicyclo [3.1.0] hexanyl) oxy] acetic acid. 2 - [(6,6-difluoro-3-bicyclo [3.1.0] hexanil) oxy] -N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4- oxadiazol-2-yl] -1-bicycle [1.1.1] pentanil] acetamide
[00423] [00423] To a mixture of 2 - [(6,6-difluoro-3-bicyclo [3.1.0] hexanyl) oxy] acetic acid (49.56 mg, 0.257 mmol) in DMF (1 mL) was added HATU (98 mg, 0.257 mmol)), after 20 min, DIEA (103 mg, 0.795 mmol) and HCl salt of 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazole -2-yl] bicyclo [1.1.1] pentan-3-amine (70 mg, 0.214 mmol; 8: 1 to 10: 1 ratio of cis- to trans-) were added to the mixture, then the mixture was stirred at 25 ° C for 12 h. The reaction mixture was diluted with H2O (10 ml) and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by prep (neutral) HPLC to provide 2 - [(6,6-difluoro-3-bicyclo [3.1.0] hexanyl) oxy] -N- [3- [5- [3- cis- (trifluoromethoxy ) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1,1,1] pentanyl] acetamide, LC-MS m / z: = 464.4 [M + H] + , 1H-NMR (400 MHz, CDCl3): δ 6.98 (br s, 1 H), 6.89 (s, 1 H), 4.70 (quin, J = 7.53 Hz, 1 H), 4.23 (quin, J = 6.90 Hz, 1 H), 3.91 - 4.06 (m, 1 H), 3.91 - 4.06 (m, 1 H), 3.85 (d , J = 4.02 Hz, 2 H), 3.24-3.40 (m, 1 H), 2.80-2.94 (m, 2 H), 2.65-2.75 (m, 2 H), 2.61 (d, J = 2.51 Hz, 6 H), 2.26-2.47 (m, 2 H), 1.95-2.06 (m, 2 H), 1 , 85 (br dd, J = 14.12, 5.84 Hz, 1 H). EXAMPLES 84 and 85 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [2-trans- (difluoromethyl) cyclopropyl] - 1,3,4-oxadiazol-2-yl] - 1-bicyclo [1.1.1] pentanil] acetamide and 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [2-cis- (difluoromethyl) cyclopropyl] -1,3,4 -oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] acetamide Ethyl 2- (difluoromethyl) cyclopropanecarboxylate
[00424] [00424] To a solution of ethyl 2-formylcyclopropanecarboxylate (2.0 g, 14.1 mmol) in DCM (6 mL) was added a solution of BAST (5.29 g, 23.92 mmol) in DCM (4 mL ) at 0 ° C and the mixture was stirred at 25 ° C for 12 h. The reaction mixture was diluted with sat. of saturated NaHCO3 (30 ml) at 0 ° C, and then it was extracted with EtOAc (3 × 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide ethyl 2- (difluoromethyl) cyclopropanecarboxylate (cis: trans = 1: 2.). 2- (difluoromethyl) cyclopropanecarboxylic acid
[00425] [00425] To a solution of ethyl 2- (difluoromethyl) cyclopropanecarboxylate (1.8 g, 10.97 mmol) in THF (20 mL) and H2O (20 mL) was added LiOH.H2O (1.38 g, 32, 90 mmol) at 0 ° C and the mixture was stirred at 25 ° C for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with H2O (20 ml) and extracted with MTBE (3 × 10 ml). The aqueous phase was adjusted to pH = 1-2 by adding 2 N HCl at 0 ° C and was extracted with DCM: MeOH (7 x 10 mL, v: v = 10: 1). The combined organic layers were dried over Na2SO4, anhydrous and concentrated under reduced pressure to provide 2- (difluoromethyl) cyclopropanecarboxylic acid (crude, cis: trans = 1: 2). 2- (4-chloro-3-fluorophenoxy) -N- (3- (2- (2- (difluoromethyl) cyclopropanocarbonyl) hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00426] [00426] To a solution of 2- (difluoromethyl) cyclopropanecarboxylic acid (399 mg, 2.93 mmol) and 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicycle [1.1.1] pentanil] acetamide (800 mg, 2.44 mmol) in DMF (10 mL) T3P (6.21 g, 9.76 mmol, 50% in EtOAc) and TEA (988 mg, 9, 76 mmol) and the resulting mixture was stirred at 80 ° C for 12 h in a sealed tube. The reaction mixture was diluted with saturated NaHCO3 (20 ml) at 0 ° C, additional H2O (20 ml) and EtOAc (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with H2O (3 × 10 ml), dried over Na2SO4anhydrous, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 0: 1) to provide 2- (4-chloro-3-fluoro-phenoxy) -N- [1 - [[ [2- (difluoromethyl) cyclopropane-carbonyl] amino] carbamoyl] -3-bicyclo [1.1.1] pentanil] acetamide (cis: trans = 1: 2.). LC-MS m / z: = 446.0 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [2-trans- (difluoromethyl) cyclopropyl] -
[00427] [00427] To a solution of 2- (4-chloro-3-fluoro-phenoxy) -N- [1 - [[[2- (difluoro-methyl) cyclopropanecarbonyl] amino] carbamoyl] -3-bicycle [1.1.1 ] pentanil] acetamide (300 mg, 0.67 mmol) in DCM (5 mL) TEA (136 mg, 1.35 mmol) was added, followed by TsCl (128 mg, 0.67 mmol) and the resulting mixture it was stirred at 25 ° C for 3 h. The reaction mixture was diluted with saturated NaHCO3 solution (10 ml) at 0 ° C, and was extracted with EtOAc (3 × 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep HPLC to provide the desired product (cis: trans = 1: 2 in NMR), which was separated by SFC (mobile phase: A: CO2, B: 0.1% NH4OH in MeOH) to provide :
[00428] [00428] 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [trans-2- (difluoromethyl) cyclopropyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanil] acetamide as the first eluting isomer. 1H-NMR (400 MHz, MeOD): δ 7.38 (t, J = 8.82 Hz, 1 H), 6.94 (dd, J = 11.03, 2.87 Hz, 1 H), 6 , 83 (ddd, J = 8.99, 2.81, 1.21 Hz, 1 H), 5.71 - 6.05 (m, 1 H), 4.50 (s, 2 H), 2, 57 (s, 6 H), 2.49 (dt, J = 8.71, 5.35 Hz, 1 H), 2.01 - 2.17 (m, 1 H), 1.38 - 1.50 (m, 2 H), LC-MS m / z: = 428.1 [M + H] +.
[00429] [00429] 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [cis-2- (difluoromethyl) cyclopropyl] - 1,3,4-oxadiazol-2-yl] -1 -bicycle [1.1.1] pentanil] acetamide as the second eluting isomer. 1H-NMR (400 MHz, MeOD): δ 7.39 (t, J = 8.71 Hz, 1 H), 6.95 (dd, J = 10.91, 2.76 Hz, 1 H), 6 , 83 (ddd, J = 8.93, 2.87, 1.21 Hz, 1 H), 5.52 - 5.87 (m, 1 H), 4.50 (s, 2 H), 2, 58 (s, 6 H), 2.49 - 2.56 (m, 1 H), 1.95 - 2.09 (m, 1 H), 1.48 - 1.60 (m, 2 H), LC-MS m / z: = 428.1 [M + H] +. EXAMPLES 86 and 87 2- (4-chlorophenoxy) -N- [3- [5- [3-cis- (trifluoromethoxymethyl) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1. 1] pentanil] acetamide and 2- (4-chlorophenoxy) -N-
[00430] [00430] A mixture of 3- (hydroxymethyl) cyclobutanocarbonitrile (1.0 g, 9.00 mmol), concentrated HCl (12 M, 6 ml) and MeOH (6 ml) was stirred at 85 ° C for 15 h. The reaction mixture was adjusted to pH = 7 by adding saturated NaHCO3 solution and extracted with EtOAc (3 × 20 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide methyl 3- (hydroxymethyl) cyclobutanecarboxylate. 3 - (((trifluoromethoxy) methyl) methyl cyclobutanecarboxylate
[00431] [00431] To a mixture of AgOTf (4.28 g, 16.65 mmol), 1- (chloromethyl) -4-fluoro-1,4-diazoniabicyclo [2.2.2] octane; ditetrafluoroborate (2.95 g, 8.32 mmol) and KF (1.29 g, 22.20 mmol) in EtOAc (20 mL) was added methyl 3- (hydroxymethyl) cyclobutanecarboxylate (0.8 g, 5 , 55 mmol), 2-fluoropyridine (1.62 g, 16.65 mmol) and TMSCF3 (2.37 g, 16.65 mmol). The mixture was stirred at 25 ° C for 15 h, and was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: MTBE = 1: 0 to 10: 1) to provide methyl 3- (trifluoromethoxymethyl) cyclo-butanecarboxylate. 3 - ((Trifluoromethoxy) methyl) cyclobutanecarboxylic acid
[00432] [00432] To a solution of cis-methyl 3- (trifluoromethoxymethyl) cyclobutanecarboxylate (330 mg, 1.56 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH.H2O (195.79 mg, 4 , 67 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 2 h. The mixture was concentrated under reduced pressure to provide a residue. H2O (60 mL) was added to the residue, then extracted with MTBE (3 × 20 mL). The water layers were adjusted to pH = 1 with HCl (2 M), then extracted with DCM: MeOH (3 × 20 mL, v: v = 10: 1), washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to provide 3- (trifluoromethoxymethyl) cyclobutanecarboxylic acid. 2- (4-chlorophenoxy) -N- (3- (hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00433] [00433] To a mixture of methyl 3 - [[2- (4-chlorophenoxy) acetyl] amino] cycling [1.1.1] pentane-1-carboxylate (1.0 g, 3.23 mmol) in EtOH (30 ml) hydrazine hydrate (1.65 g, 32.3 mmol) was added at 0 ° C and the mixture was stirred at 80 ° C for 5 h. The reaction mixture was concentrated under reduced pressure to provide 2- (4-chlorophenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanyl] acetamide. LC-MS m / z: = 310.1, 312.1 [M + H] +. 2- (4-chlorophenoxy) -N- (3- (2- (3 - ((trifluoromethoxy) methyl) cyclobutanocarbonyl) hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl) acetamide
[00434] [00434] A mixture of 2- (4-chlorophenoxy) -N- [1- (hydrazinocarbonyl) - 3-bicyclo [1.1.1] pentanil] acetamide (200 mg, 0.645 mmol), 3- (trifluoro-methoxymethyl) acid ) cyclobutanecarboxylic (128 mg, 0.645 mmol), T3P (1.64 g, 2.58 mmol, 50% in EtOAc) and TEA (261.35 mg, 2.58 mmol) in EtOAc (3 mL) was stirred at 25 ° C for 15 h. The reaction mixture was diluted with saturated NaHCO3 solution (30 ml) at 0 ° C and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 0: 1) to provide 2- (4-chlorophenoxy) -N- [1 - [[[3- (trifluoromethoxymethyl) cyclobutanocarbonyl] amino] carbamoyl] -3-bicycle [1.1.1] pentanyl] acetamide. LC / MS m / z = 490.1, 492.0 [M + H] +. 2- (4-chlorophenoxy) -N- [3- [5- [3-cis- (trifluoromethoxymethyl) cyclobutyl] -1,3,4- oxadiazol-2-yl] -1-bicycle [1.1.1] pentanil] acetamide and 2- (4-chlorophenoxy) -N- [3- [5- [3-trans- (trifluoromethoxymethyl) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bi-cycle [1.1. 1] pentanil] acetamide
[00435] [00435] A mixture of 2- (4-chlorophenoxy) -N- [1 - [[[3- (trifluoromethoxymethyl) cyclobutanocarbonyl] amino] carbamoyl] -3-bicyclo [1.1.1] pentanyl] acetamide (0, 2 g, 0.408 mmol) and POCl3 (313.00 mg, 2.04 mmol) in 1,4-dioxane (6 mL) was stirred at 100 ° C for 1 h. The reaction mixture was diluted with saturated NH4CO3 (10 ml) and EtOAc (10 ml), the layers were separated and the aqueous layer was extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified by silica gel column chromatography (PE: MTBE = 1: 0 to 0: 1) followed by SFC to provide:
[00436] [00436] 2- (4-chlorophenoxy) -N- [3- [5- [3-cis- (trifluoromethoxymethyl) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1 ] pentanyl] acetamide: 1H-NMR (400 MHz, CDCl3): δ 7.32 - 7.27 (m, 2H), 7.03 (s, 1H), 6.90 - 6.84 (m, 2H) , 4.42 (s, 2H), 3.98 (d, J = 6.2 Hz, 2H), 3.64 (quin, J = 8.9 Hz, 1H), 2.83 - 2.72 ( m, 1H), 2.64 (s, 6H), 2.61 - 2.51 (m, 2H), 2.33 - 2.22 (m, 2H). LC-MS m / z: = 472.3 [M + H] +.
[00437] [00437] 2- (4-chlorophenoxy) -N- [3- [5- [3-trans- (trifluoromethoxymethyl) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1 ] pentanyl] acetamide: 1H-NMR (400 MHz, CDCl3): δ 7.45 - 7.27 (m, 2H), 7.02 (s, 1H), 6.90 - 6.81 (m, 2H) , 4.43 (s, 2H), 4.05 (d, J = 6.2 Hz, 2H), 3.71 (dtt, J = 1.1, 6.5, 9.3 Hz, 1H), 2.96 - 2.82 (m, 1H), 2.66 - 2.63 (m, 6H), 2.63 - 2.55 (m, 2H), 2.42 - 2.33 (m, 2H ), LC-MS m / z: = 472.3 [M + H] +. EXAMPLE 88 N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanyl] carbamate (cis- 3- (trifluoromethoxy) cyclobutyl) [3-cis- (trifluoromethoxy) cyclobutyl] methanol
[00438] [00438] To a solution of LiAlH4 (96 mg, 2.52 mmol) in THF (5 mL) was added methyl 3-cis- (trifluoromethoxy) cyclobutanecarboxylate (0.5 g, 2.52 mmol) at 0 ° C and the mixture was stirred at 0 ° C for 1 h. The mixture was diluted with saturated NH4Cl solution (5 ml) and stirred for 30 min. Was added
[00439] [00439] To a mixture of (3-cis-trifluoromethoxy) cyclobutyl) methanol (300 mg, 1.76 mmol) in DCM (10 mL) was added 4-nitro-phenyl carbonochloride (462 mg, 2.29 mmol) and DMAP (2.15 mg, 0.02 mmol) at 20 ° C. After 30 min, DIPEA (0.31 mL, 1.76 mmol) was added, the mixture was stirred at 20 ° C for 12 h. The reaction mixture was quenched by water (10 ml) and stirred for 30 min and then extracted with DCM (3 x 10 ml), the combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide a residue, which was purified by prep TLC (PE: EtOAc = 5: 1) to provide 4-nitrophenyl ((3-cis- (trifluoromethoxy) cyclobutyl) methyl carbonate). [3-cis N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanyl] carbamate - (trifluoromethoxy) cyclobutyl] methyl
[00440] [00440] To a solution of 3- (5- (3-cis- (trifluoromethoxy) cyclobutyl) -1,3,4-oxada-diazol-2-yl) bicycles [1.1.1] pentan-1-amine (60 mg, 0.21 mmol; 8: 1 to 10: 1 ratio of trans-) in DCM (3 mL) 4-nitrophenyl carbonate ((cis-3- (trifluoromethoxy) cyclobutyl) methyl) ( 70 mg, 0.21 mmol), Et3N (58 µL, 0.41 mmol) and DMAP (0.25 mg, 0.002 mmol) and the mixture was stirred at 25 ° C for 12 h. The reaction mixture was poured into ice water (5 ml) and was extracted with EtOAc (3 x 5 ml). The combined organic phases were washed with brine (5 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide a residue, which was purified by prep (neutral) HPLC to provide [3-cis- (trifluoromethoxy) cyclobutyl] methyl N- [3- [5- [3-cis- (trifluorome-1 toxo) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] carbamate. H- NMR (400 MHz, CDCl3): δ 7.01 (br s, 1H), 4.70 (quin, J = 7.6 Hz, 1H), 3.85 (s, 2H), 3.32 ( tt, J = 7.7, 10.2 Hz, 1H), 2.91 - 2.82 (m, 2H), 2.73 - 2.64 (m,
[00441] [00441] To a mixture of cis-methyl 3-hydroxycyclobutanecarboxylate (10.0 g, 76.84 mmol) in THF (120 mL) was added NaH (3.07 g, 76.84 mmol, 60% in mineral oil ) at 0 ° C. After 30 min, the solution of tert-butyl 2-bromoacetate (14.99 g, 76.84 mmol) in THF (50 mL) was added dropwise at 0 ° C. The reaction mixture was warmed to room temperature and was stirred at 25 ° C for 1.5 h, at which point saturated NH4Cl (150 mL) was added. EtOAc (50 ml) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (40 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: MTBE = 100: 1 to 0: 1) to provide cis-methyl 3- (2- (tert-butoxy) -2-oxoethoxy) cyclobutanecarboxylate. 2- (cis-3- (hydroxymethyl) cyclobutoxy) tert-butyl acetate
[00442] [00442] To a solution of methyl 3- (2-tert-butoxy-2-oxo-ethoxy) cyclobutanocarbon-xylate (2.0 g, 8.19 mmol) in THF (50 mL) was added trihydrate lithium tert-butoxyaluminium (1 M, 20.5 mL) at rt and the mixture was heated to 84 ° C for 6 h. The reaction mixture was diluted with saturated NH4Cl solution (40 ml) at 0 ° C, and extracted with EtOAc (3 × 20 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: MTBE = 100: 1 to 0: 1) to provide tert-butyl 2- (cis-3- (hydroxymethyl) cyclobutoxy) acetate. 2- (cis-3 - ((trifluoromethoxy) methyl) cyclobutoxy) tert-butyl acetate
[00443] [00443] A mixture of AgOTf (2.99 g, 11.65 mmol), 1- (chloromethyl) -4-fluoro-1,4-diazoniabicyclo [2.2.2] octane; di-tetrafluoroborate (2.06 g, 5.83 mmol),
[00444] [00444] To a solution of tert-butyl 2- [3- (trifluoromethoxymethyl) cyclobutoxy] acetate (210 mg, 0.74 mmol) in DCM (5 mL) was added TFA (640 mg, 5.61 mmol) to 25 ° C. The mixture was stirred at 40 ° C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to provide 2- (cis-3 - ((trifluoromethoxy) methyl) cyclobutoxy) acetic acid. N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] -2- [3- cis- (trifluoromethoxymethyl) cyclobutoxy] acetamide
[00445] [00445] To a solution of 2- (cis-3 - ((trifluoromethoxy) methyl) cyclobutoxy) acetic acid (90 mg, 0.39 mmol) in DMF (3 mL) was added HATU (150 mg, 0, 39 mmol) at 0 ° C. The mixture was stirred for 30 min and HCl salt of 3- (5- (3-cis- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadiazol-2-yl) bicyclo [1.1.1] pentan-1- amine (107 mg, 0.33 mmol; 8: 1 to 10: 1 ratio of cis- to trans-) and DIEA (157 mg, 1.22 mmol) were added. The reaction mixture was allowed to warm to rt and was stirred for 6 h, at which time H2O (10 ml) was added followed by EtOAc (5 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with H2O (3 × 3 ml) and brine (3 × 3 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep HPLC (TFA) to provide N- [3- [5- [3-cis- (trifluoromethoxy) cyclo-
[00446] [00446] A mixture of 2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetic acid (1.59 g, 7.43 mmol) and HATU (2.83 g, 7.43 mmol) in DMF (10 mL) it was stirred for 30 minutes at 0 ° C, at which point HCL salt of methyl 3-aminobicyclo [1.1.1] pentane-1-carboxylate (1.1 g, 6.19 mmol) and DIPEA (2, 96 g, 22.91 mmol). The reaction mixture was stirred at 25 ° C for 12 h and was diluted with H2O (50 ml) and EtOAc (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with H2O (3 × 5 ml), brine (3 × 5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtAc = 100: 1 to 0: 1) to provide 3- (2- (cis-3- (trifluoromethoxy) cyclobutoxy) acetamido) bicyclo [ 1.1.1] pentane-1-carboxylate. N- (3- (hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl) -2- (cis-3- (trifluoromeotoxy) cyclobutoxy) acetamide
[00447] [00447] To a solution of 3- (2- (cis-3- (trifluoromethoxy) cyclobutoxy) acetone
[00448] [00448] To a solution of N- (3- (hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl) -2- (cis-3- (trifluoromethoxy) cyclobutoxy) acetamide (100 mg, 0.30 mmol) and trans-2 - ((trifluoromethoxy) methyl) cyclopropanecarboxylic acid (55 mg, 0.30 mmol; 1: 5 ratio of trans-) in EtOAc (3 mL) was added T3P (755 mg, 1.19 mmol, 50% in EtOAc) and TEA (120 mg, 1.19 mmol) and the mixture was stirred at 25 ° C for 12 h. The reaction mixture was diluted with saturated NaHCO3 (10 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 2- (cis-3- (trifluoro-methoxy) cyclobutoxy) -N- (3- (2- (trans-2 - ((trifluoromethoxy) methyl) cyclopropanocarbonyl) hydrazinocarbonyl) bicyclo [1.1.1] pentan-1-yl) acetamide as a mixture of diastereomers. The crude reaction mixture was used in the next step without further purification. LC-MS m / z: = 504.2 [M + H] +. 2- [3-cis- (trifluoromethoxy) cyclobutoxy] -N- [3- [5- [2-trans- (trifluoromethoxy-methyl) cyclopropyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanil] acetamide
[00449] [00449] To a solution of 2- (cis-3- (trifluoromethoxy) cyclobutoxy) -N- (3- (2-
[00450] [00450] 2- [cis-3- (trifluoromethoxy) cyclobutoxy] -N- [3- [5- [cis-2- (trifluoromethoxy-methyl) cyclopropyl] -1,3,4-oxadiazol-2-yl] - 1-bicycle [1.1.1] pentanil] acetamide as the first eluting isomer of SFC. 1H-NMR (400 MHz, MeOD): δ 4.34 - 4.45 (m, 2 H), 3.84 (s, 2 H), 3.72 - 3.82 (m, 2 H), 2 , 81 (dtd, J = 9.62, 6.49, 6.49, 3.20 Hz, 2 H), 2.55 (s, 6 H), 2.49 (td, J = 8.32, 6.06 Hz, 1 H), 2.19 - 2.30 (m, 2 H), 1.88 - 1.99 (m, 1 H), 1.49 (td, J = 8.49, 5 , 51 Hz, 1 H), 1.27 - 1.35 (m, 2 H), LC-MS m / z: = 486.2 [M + H] +.
[00451] [00451] 2- [cis-3- (trifluoromethoxy) cyclobutoxy] -N- [3- [5- [trans-2- (trifluoromethoxymethyl) cyclopropyl] -1,3,4-oxadiazol-2-yl] - 1-bicycle [1.1.1] pentanil] acetamide as the second eluting isomer of SFC. 1H-NMR (400 MHz, MeOD): δ 4.42 (quin, J = 7.17 Hz, 1 H), 4.14 (dd, J = 10.91, 6.50 Hz, 1 H), 4 .00 (dd, J = 11.03, 7.50 Hz, 1 H), 3.84 (s, 2 H), 3.76 (quin, J = 6.89 Hz, 1 H), 2.80 (dtd, J = 9.73, 6.55, 6.55, 3.20 Hz, 2 H), 2.55 (s, 6 H), 2.19 - 2.34 (m, 3 H), 1.92 (dq, J = 13.37, 6.64 Hz, 1 H), 1.42 (dt, J = 8.88, 5.26 Hz, 1 H), 1.24 - 1.33 ( m, 2 H), LC-MS m / z: = 486.2 [M + H] +. EXAMPLE 92
[00452] [00452] To a solution of 2- (3-chlorophenoxy) acetic acid (69 mg, 0.37 mmol) in DMF (2 mL) was added HATU (140 mg, 0.37 mmol) at 0 ° C under N2. The mixture was stirred for 30 minutes at 0 ° C and then HCl salt cis- 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicycles [1.1.1] pentan-3-amine salt (100 mg, 0.31 mmol; 8: 1 to 10: 1 ratio of trans-) and DIEA (147 mg, 1.14 mmol) were added to the solution at 0 ° C. After addition, the mixture was stirred at 16 ° C for 14 h. The reaction mixture was quenched by H2O (8 ml) at 0 ° C and then extracted with EtOAc (3 × 5 ml). The combined organic layers were washed with H2O (3 × 3 ml) and brine (3 × 3 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 458.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 7.05 (dt, J = 7.99, 0.96 Hz, 1H), 7.01-6.94 (m, 2H), 6.83 (dd, J = 8.27, 2.54 Hz, 1H), 4.71 (quin, J = 7 , 61 Hz, 1H), 4.45 (s, 2H), 3.33 (tt, J = 10.17, 7.80 Hz, 1H), 2.94-2.81 (m, 2H), 2 , 74-2.67 (m, 2H), 2.66 (s, 6H). EXAMPLE 93 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [3-fluoro-1- (2,2,2-trifluoroethyl) azetin-din-3-yl] -1 , 3,4-oxadiazol-2-yl] -1-bicycles [1.1.1] pentanyl] acetamide 3- (2- (3- (2- (4-chloro-3-fluorophenoxy) acetamido) bicycles [1.1.1 ] tert-butyl pentane-1-carbonyl) hydrazinocarbonyl) -3-fluoroazetidine-1-carboxylate
[00453] [00453] A solution of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (300 mg, 0.92 mmol ), 1-tert-bu-toxicarbonyl-3-fluoro-azetidine-3-carboxylic acid (200 mg, 0.92 mmol) and NEt3 (370 mg, 3.66 mmol) were suspended in EtOAc (10 mL) and T3P (2.33 g, 3.66 mmol) was added. The resulting reaction mixture was stirred at 16 ° C for 24 h. The reaction mixture was quenched by saturated NaHCO3 (30 ml) and then extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography. LC-MS: m / z = 529.1 [M + H] +. 3- (5- (3- (2- (4-chloro-3-fluorophenoxy) acetamido) bicyclo [1.1.1] pentan-1-yl) -1, 3,4-oxadiazol-2-yl) -3- tert-butyl fluoroazetidine-1-carboxylate
[00454] [00454] To a solution of 3- (2- (3- (2- (4-chloro-3-fluorophenoxy) acetamido) bi-cycle [1.1.1] pentane-1-carbonyl) hydrazinocarbonyl) -3-fluoroazetidine- Tert-butyl 1-carboxylate (100 mg, 0.19 mmol) in MeCN (6 mL) was added DIEA (122 mg, 0.95 mmol) and tosyl chloride (90 mg, 0.472 mmol). The mixture was stirred at 15 ° C for 15 h. The reaction mixture was quenched by the addition of saturated NaHCO3 (30 ml). The mixture was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography. LC-MS: m / z = 511.2 [M + H] +. 2- (4-chloro-3-fluorophenoxy) -N- (3- (5- (3-fluoroazetidin-3-yl) -1,3,4-oxadiazol-2-yl) bicycle [1.1.1] pentan- 1-yl) acetamide
[00455] [00455] To a solution of 3- (5- (3- (2- (4-chloro-3-fluorophenoxy) acetamido) bi-cycle [1.1.1] pentan-1-yl) -1,3,4- tert-butyl oxadiazol-2-yl) -3-fluoroazetidine-1-carboxylate (90 mg, 0.18 mmol) in DCM (2 mL) was added TFA (616 mg, 5.40 mmol) at 0 ° C. The mixture was stirred at 15 ° C for 2 h. The mixture was concentrated under reduced pressure. LC-MS: m / z = 411.1 [M + H] +. 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [3-fluoro-1- (2,2,2-trifluoroethyl) azetin-din-3-yl] -1,3 , 4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanil] acetamide
[00456] [00456] To a mixture of 2- (4-chloro-3-fluorophenoxy) -N- (3- (5- (3-fluoroazetidin-3-yl) -1,3,4-oxadiazol-2-yl ) bicyclo [1.1.1] pentan-1-yl) acetamide, TFA salt (140 mg, 0.27 mmol) in THF (6 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (92 mg, 0, 40 mmol) and DIEA (137 mg, 1.07 mmol) at 0 ° C. The mixture was stirred at 50 ° C for 15 h. The reaction mixture was quenched by the addition of H2O (30 ml). The mixture was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 493.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.34 (t, J = 8.6 Hz, 1H), 6.98 (s , 1H), 6.77 (dd, J = 2.8, 10.2 Hz, 1H), 6.69 (td, J = 1.4, 8.9 Hz, 1H), 4.43 (s, 2H), 4.19 (dd, J = 10.1, 15.6 Hz, 2H), 3.98-3.83 (m, 2H), 3.17 (q, J = 9.0 Hz, 2H ), 2.76-2.64 (m, 6H). EXAMPLE 94 N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] -2- [ 2- (trifluoromethoxy) ethoxy] acetamide 2- (2-benzyloxyethoxy) tert-butyl acetate
[00457] [00457] A mixture of 2-benzyloxyethanol (10.0 g, 65.7 mmol), tert-butyl 2-bromoa-acetate (19.2 g, 98.6 mmol), tetrabutylammonium hydrogen sulfate (1.1 g , 3.3 mmol) and water (5 mL) in toluene (200 mL) NaOH (39.4 g, 985.6 mmol) in water (60 mL) was added. The mixture was stirred at 20 ° C for 2 h. The reaction mixture was quenched with ice water (90 ml) and then extracted with MTBE (3 × 90 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. 2- (2-hydroxyethoxy) tert-butyl acetate
[00458] [00458] To a solution of tert-butyl 2- (2-benzyloxyoxy) acetate (16.3 g, 61.2 mmol) in MeOH (320 mL) was added Pd / C (2 g, 10% carbon) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (50 psi) at 50 ° C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. 2- [2- (trifluoromethoxy) ethoxy] tert-butyl acetate
[00459] [00459] For a reaction flask equipped with a stir bar and covered with aluminum foil in a water bath, AgOTf (21.9 g, 85.1 mmol),
[00460] [00460] To a solution of 2- [2- (trifluoromethoxy) ethoxy] tert-butyl acetate (4.4 g, 17.9 mmol) in DCM (5 mL) was added TFA (10.1 mL, 136, 0 mmol). The mixture was stirred at 40 ° C for 2 h. The reaction mixture was concentrated under reduced pressure. N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] -2- [2- (trifluoromethoxy) ethoxy] acetamide
[00461] [00461] To a solution of 2- [2- (trifluoromethoxy) ethoxy] acetic acid (69.3 mg, 0.37 mmol) in DMF (2 mL) was added HATU (140 mg, 0.37 mmol) at 0 ° C under N2. The mixture was stirred for 30 min at 0 ° C and then DIEA (147 mg, 1.14 mmol) and cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4 hydrochloride - oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine (8: 1 to 10: 1 favoring cis-di-astereomer) (100 mg, 0.31 mmol) was added to the 0 ° solution Ç. The reaction mixture was stirred at 16 ° C for 14 h. The reaction mixture was quenched by H2O (10 ml), and then extracted with EtOAc (3 × 5mL). The combined organic layers were washed with H2O (3 × 3 ml) and brine (3 × 3 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 460.4 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.05 (br s, 1H), 4.70
[00462] [00462] To a mixture of 2- (3-hydroxycyclobutoxy) cis-tert-butyl acetate (2.0 g, 9.9 mmol) and 4-nitrobenzoic acid (1.8 g, 10.9 mmol) in THF (40 ml) PPh3 (3.9 g, 14.8 mmol) was added at 15 ° C under N2. Then DIAD (10.0 g, 49.4 mmol) was added at 0 ° C under N2. The reaction mixture was stirred at 15 ° C for 15 h. The reaction mixture was quenched with water (30 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 2- (3-hydroxycyclobutoxy) trans-tert-butyl acetate;
[00463] [00463] To a solution of trans- [3- (2-tert-butoxy-2-oxo-ethoxy) cyclobutyl 4-nitrobenzoate (1.4 g, 4.0 mmol) in THF (10 mL), H2O (2 ml) and MeOH (20 ml) K2CO3 (559 mg, 4.0 mmol) was added at 15 ° C under N2. The reaction mixture was stirred at 15 ° C for 3 h. The reaction mixture was quenched with water (20 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 2- [3- (trifluoromethoxy) cyclobutoxy] trans-tert-butyl acetate;
[00464] [00464] To a mixture of AgOTf (1.6 g, 6.2 mmol), Selectfluor (1.1 g, 3.1 mmol) and KF (483 mg, 8.3 mmol) in EtOAc (30 mL) was 2- (3-hydroxy-cyclobutoxy) trans-tert-butyl acetate (420 mg, 2.1 mmol) is added at 15 ° C under N2 covered with aluminum foil. Then 2-fluoropyridine (605 mg, 6.2 mmol) was added to the mixture, followed by TMSCF3 (886 mg, 6.2 mmol) at 15 ° C. The reaction mixture was stirred at 15 ° C for 15 h. The reaction mixture was filtered through silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Trans-2- [3- (trifluoromethoxy) cyclobutoxy] acetic acid:
[00465] [00465] To a solution of 2- [3- (trifluoromethoxy) cyclobutoxy] trans-tert-butyl acetate (90 mg, 0.33 mmol) in DCM (5 mL) was added TFA (1.5 g, 13, 5 mmol) at 15 ° C. The mixture was heated to 40 ° C and stirred for 1 h. The mixture was concentrated under reduced pressure. 2- [3 - trans- (trifluoromethoxy) cyclobutoxy] -N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1- bicycle [1.1.1] pentanil] acetamide
[00466] [00466] To a mixture of trans-2- [3- (trifluoromethoxy) cyclobutoxy] acetic acid (72 mg, 0.34 mmol) in DMF (5 mL) was added HATU (128 mg, 0.338 mmol) at 15 ° C under N2. The mixture was stirred for 30 min and then cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pen-tan-3 -amine (8: 1 to 10: 1 favoring the cis-diastereomer) (100 mg, 0.31 mmol) and DIEA (159 mg, 1.2 mmol) was added. The reaction mixture was stirred for 2 h. The reaction mixture was quenched with water (30 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (2 x 5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 486.4 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.00-6.82 (m, 1H), 4.96-4.84 ( m, 1H), 4.71 (quin, J = 7.55 Hz, 1H), 4.28-4.20 (m, 1H), 3.89-3.79 (m, 2H), 3.32 (tt, J = 10.14, 7.72 Hz, 1H), 2.91 2.81 (m, 2H), 2.75-2.64 (m, 2H), 2.63 (s, 6H ), 2.57-2.45 (m, 4H). EXAMPLE 96 N- [3- [2-methyl-4- [3- (trifluoromethoxy) cyclobutyl] imidazol-1-yl] -1-bicyclo [1.1.1] pentanil] -2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetamide (3- (2-3- (trifluoromethoxy) cyclobutoxy) acetamido) bicyclo [1.1.1] pentan-1-yl) cis-tert-butyl carbamate
[00467] [00467] To a solution of cis-2- [3- (trifluoromethoxy) cyclobutoxy] acetic acid (1.0 g, 4.7 mmol) in DMF (10 mL) was added N- (1-amino-3 -bicyclo [1.1.1] pentanyl) tert-butyl carbamate (926 mg, 4.7 mmol), HATU (2.0 g, 5.1 mmol) and DIEA (2.4 mL, 14.0 mmol ) at 20 ° C. The reaction mixture was stirred at 20 ° C for 2 h. The reaction mixture was poured into ice water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. cis-N- (3-aminobicyclo [1.1.1] pentan-1-yl) -2- (3- (trifluoromethoxy) cyclobutoxy) acetamide
[00468] [00468] To a solution of cis-tert-butyl N- [1 - [[2- [3- (trifluoromethoxy) cyclobutoxy] acyl]] -3-bicyclo [1.1.1] pentanyl] carbamate (500 mg, 1.3 mmol) in EtOAc (10 ml) EtOAc / HCl (10 ml) was added. The reaction mixture was stirred at 25 ° C for 1 h. The reaction mixture was concentrated under reduced pressure. LC-MS: m / z = 295.1 [M + H] +. cis-N- (3 - ((2-oxo-2- (3- (trifluoromethoxy) cyclobutyl) ethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3- (trifluoromethoxy) cyclobutoxy) acetamide
[00469] [00469] A mixture of 2-bromo-1- (3- (trifluoromethoxy) cyclobutyl) ethanone (1.0 g, 4.0 mmol), cis-N- (3-aminobicyclo [1.1.1] pentan- 1-yl) -2- (3- (trifluoromethoxy) cyclobutoxy) acetamide (1.2 g, 3.6 mmol) in CH3CN (10 mL) Na2CO3 (1.5 g, 14.5 mmol) was added. The reaction mixture was stirred at 40 ° C for 15 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. LC-MS: m / z = 475.2 [M + H] +. cis-N- (2-oxo-2- (3- (trifluoromethoxy) cyclobutyl) ethyl) -N- (3- (2- (3- (trifluoromethoxy) cyclobutoxy) acetamido) bicyclo [1.1.1] pentan- 1-yl) acetamide
[00470] [00470] Acetyl chloride (66 mg, 0.83 mmol) was added dropwise to cis-N- (3 - ((2-oxo-2- (3- (trifluoromethoxy) cyclobutyl) ethyl) amino) bicycle [ 1.1.1] pen-tan-1-yl) -2- (3- (trifluoromethoxy) cyclobutoxy) acetamide (360 mg, 0.76 mmol) and
[00471] [00471] For a solution of cis-N- (2-oxo-2- (3- (trifluoromethoxy) cyclobutyl) ethyl) -N- (3- (2- (3- (trifluoromethoxy) cyclobutoxy) acetamido) bicycle [1.1.1] pentan-1-yl) acetamide (390 mg, 0.76 mmol) in DMF (0.5 ml) and CH3COOH (4 ml) CH3COONH4 (233 mg, 3.0 mmol) was added. The mixture was stirred at 100 ° C for 24 h. The reaction mixture was quenched by adding NaHCO3 at 0 ° C until pH = 8-9 and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 498.4 [M + H] +, 1 H-NMR (400 MHz, CDCl3): δ 6.91 (s, 1H), 6.58-6.53 (m, 1H ), 4.60 (quin, J = 7.6 Hz, 1H), 4.34 (quin, J = 7.1 Hz, 1H), 3.84 (s, 2H), 3.78-3.70 (m, 1H), 3.00-2.87 (m, 1H), 2.86-2.78 (m, 2H), 2.78-2.66 (m, 2H), 2.66-2 , 59 (m, 6H), 2.45-2.39 (m, 3H), 2.38-2.19 (m, 4H). EXAMPLE 97 2 - [(5-chloro-3-pyridyl) methoxy] -N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -1 -bicycle [1.1.1] pentanil] acetamide
[00472] [00472] To a mixture of (5-chloro-3-pyridyl) methanol (35 mg, 0.24 mmol) in THF (5.0 mL) was added NaH (13.0 mg, 0.33 mmol, 60% in mineral oil) at 0 ° C under N2. The mixture was stirred at 0 ° C for 30 min and then 2- bromo-N- [1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -3 -bicyclo [1.1.1] pentanil] acetamide (90 mg, 0.22 mmol) was added at 0 ° C under N2.
[00473] [00473] To a mixture of 5-cyclopropylisoxazole-3-carboxylic acid (50 mg, 0.32 mmol) in DMF (1 mL) was added HATU (120 mg, 0.32 mmol) under N2, the mixture was stirred for 30 min and then cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine hydrochloride (8: 1 to 10: 1, favoring the cis-diastereomer) (89 mg, 0.27 mmol) and DIEA (140 mg, 1.1 mmol) were added to the solution at 0 ° C. The reaction mixture was stirred at 20 ° C for 12 h. The reaction mixture was quenched by adding H2O (10 ml) at 0 ° C and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, anhydrous, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 425.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 6.32 (s, 1H), 4.71 (quin, J = 7.56 Hz, 1H), 3.40-3.26 (m, 1H), 2.94-2.81 (m, 2H), 2.74-2.69 (m, 2H ), 2.68 (s, 6H), 2.15-2.03 (m, 1H), 1.19-1.08 (m, 2H), 1.03-0.94 (m, 2H). EXAMPLE 99 and 100 (5S) -5-phenyl-N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1. 1] pentanil] -4,5-dihydroisoxazole-3-carboxamide and (5R) -5-
[00474] [00474] To a mixture of 5-phenyl-4,5-dihydroisoxazol-3-carboxylic acid (71 mg, 0.37 mmol) in DMF (5 mL) was added HATU (141 mg, 0.37 mmol) at 15 ° C under N2. The mixture was stirred at 15 ° C for 30 min, then cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadazol-2-yl] bicyclo [1.1 .1] pentan-3-amine (8: 1 to 10: 1, favoring the cis-diastereomer) (110 mg, 0.34 mmol) and DIEA (87 mg, 0.68 mmol). The reaction mixture was stirred for 2.5 h. The reaction mixture was quenched with water (30 ml) and extracted with EtOAc (3 x 10 ml). The combined organic phase was washed with brine (3 x 5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, which was later separated by SFC to provide:
[00475] [00475] cis- (R) -5-phenyl-N- (3- (5- (3- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadazole-2-yl) bicycles [1.1.1] pentan-1-yl) -4,5-dihydroisoxazole-3-carboxamide (99) (peak 1 in SFC). LC-MS: m / z = 463.2 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.48-7.29 (m, 5H), 7.18 (br s, 1H ), 5.77 (br t, J = 9.98 Hz, 1H), 4.81 - 4.63 (m, 1H), 3.79-3.53 (m, 1H), 3.42-3 , 19 (m, 2H), 2.86 (br s, 2H), 2.75-2.68 (m, 2H), 2.65 (br s, 6H).
[00476] [00476] cis- (S) -5-phenyl-N- (3- (5- (3- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadazole-2-yl) bicycle [1.1.1] pentan-1-yl) -4,5-dihydroisoxazole-3-carboxamide (100) (peak 2 in SFC). LC-MS: m / z = 463.2 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.47-7.29 (m, 5H), 7.18 (s, 1H) , 5.77 (dd, J = 11.29, 8.91 Hz, 1H), 4.71 (quin, J = 7.50 Hz, 1H), 3.65 (dd, J = 18.01, 11 , 48 Hz, 1H), 3.42-3.18 (m, 2H), 2.92-2.82 (m, 2H), 2.76-2.68 (m, 2H), 2.66 ( s, 6H). EXAMPLE 101 N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] pyrrole [1, 2-c] pyrimidine-3-carboxamide
[00477] [00477] To a mixture of pyrrole [1,2-c] pyrimidine-3-carboxylic acid (50 mg, 0.31 mmol) in DMF (2 mL) was added HATU (120 mg, 0.31 mmol)
[00478] [00478] To a solution of (2R, 3aR, 6aR) -5-tert-butoxycarbonyl-2,3,3a, 4,6,6a-hexahydrofuro [2,3-c] pyrrole-2-carboxylic (50 mg , 0.19 mmol) in DMF (2 mL) HATU (74 mg, 0.19 mmol) was added at 0 ° C. After addition, the mixture was stirred at 0 ° C for 30 min and then cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [ 1.1.1] pentan-3-amine (8: 1 to 10: 1 favoring the cis-diastereomer) (63 mg, 0.19 mmol) and DIEA (93 mg, 0.72 mmol) was added at 0 ° C. The resulting mixture was stirred at 15 ° C for 12 h. The reaction mixture was quenched by adding H2O (10 ml) at 0 ° C and then extracted with EtOAc (3 × 10 ml). The combined organics were washed with H2O (3 × 5 mL) and brine (5 mL), dried over anhydrous Na2SO4,
[00479] [00479] To a solution of 2 - ((3- (5- (3-cis- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadiazol-2-yl) bicyclo [1.1.1] pentan-1-yl ) carbamoyl) tetrahydro-2H-bore [2,3-c] pyrrole-5 (3H) -carboxylate (2R, 3aR, 6aR) -tert-butyl (140 mg, 0.26 mmol) in DCM (2 ml) TFA (616 mg, 5.4 mmol) was added. The mixture was stirred at 15 ° C for 1 h. The reaction mixture was concentrated under reduced pressure. LC-MS: m / z = 429.2 [M + H] +. (2R, 3aR, 6aR) -5- (2,2,2-trifluoroethyl) -N- [3- [5- [3-cis- (trifluoromethoxy) cyclo-butyl] -1,3,4-oxadiazole-2 -il] -1-bicycle [1.1.1] pentanil] -2,3,3a, 4,6,6a-hexahydrofuro [2,3-c] pyrrole-2-carboxamide
[00480] [00480] For a TFA salt solution of (2R, 3aR, 6aR) -N- (3- (5- (3-cis- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadiazol-2-yl) DI [(1.1.1] pentane-1-yl) hexahydro-2H-bore [2,3-c] pyrrole-2-carboxamide (150 mg, 0.28 mmol) in THF (3 mL) 179 mg, 1.4 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (96 mg, 0.41 mmol) at 0 ° C. The reaction mixture was stirred at 50 ° C for 4 h. The reaction mixture was quenched by adding H2O (10 ml) at 0 ° C and then extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS: m / z = 511.4 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 6.98 (s, 1H), 4.75-4.65 (m, 2H) , 4.55 (dd, J = 8.82, 6.62 Hz, 1H), 3.32 (tt, J = 10.17, 7.80 Hz, 1H), 3.09-2.96 (m , 3H), 2.92-2.82 (m, 4H), 2.74-2.67 (m, 2H), 2.59 (s, 8H), 2.25-2.17 (m, 1H ), 2.17-2.06 (m, 1H). EXAMPLE 103 6-chloro-N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-
[00481] [00481] To a solution of 6-chloroimidazo [1,2-a] pyridine-2-carboxylic acid (100 mg, 0.51 mmol) in DMF (2 mL) was added HATU (193 mg, 0.51 mmol) at 0 ° C under N2. The mixture was stirred for 30 min at 0 ° C and then cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1 .1] pentan-3-amine (8: 1 to 10: 1 favoring the cis-diastereomer) (138 mg, 0.42 mmol) and DIEA (203 mg, 1.6 mmol) was added to the solution at 0 ° C . The reaction mixture was stirred at 16 ° C for 14 h. The reaction mixture was quenched by the addition of H2O (8 ml) at 0 ° C and then extracted with EtOAc (3 x 5 ml). The combined organics were washed with H2O (3 x 3 ml) and brine (3 x 3 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS: m / z = 468.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 8.23 (dd, J = 1.87, 0.77 Hz, 1H), 8 , 11 (s, 1H), 7.81 (s, 1H), 7.52 (d, J = 9.70 Hz, 1H), 7.25 (dd, J = 9.48, 1.98 Hz, 1H), 4.71 (quin, J = 7.55 Hz, 1H), 3.33 (tt, J = 10.14, 7.72 Hz, 1H), 2.93-2.82 (m, 2H ), 2.74-2.68 (m, 8H). EXAMPLE 104 7-chloro-N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1- bicycle [1.1.1] pentanyl] imidazo [ 1,2-a] pyridine-2-carboxamide
[00482] [00482] To a solution of 7-chloroimidazo [1,2-a] pyridine-2-carboxylic acid (50 mg, 0.25 mmol) in DMF (2 mL) was added HATU (97 mg, 0.25 mmol). The mixture was stirred for 30 min at 0 ° C under N2, then cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1 ] penano-3-amine (8: 1 to 10: 1 favoring cis-diastereomer) (69 mg, 0.21 mmol) and DIEA (101 mg, 0.78 mmol) to the solution at 0 ° C. The reaction mixture was stirred at 16 ° C for 14 h. The reaction mixture was quenched by H2O (8 ml) at 0 ° C and then extracted with EtOAc (3 × 5 ml). The combined organics were washed with H2O (3 x 3 ml) and brine (3 x 3 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS: m / z = 468.3
[00483] [00483] To a mixture of 2- (3-fluorophenoxy) acetic acid (100 mg, 0.59 mmol) in DMF (2 mL) was added HATU (270 mg, 0.71 mmol) under N2. After 20 min, cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine (8: 1 to 10: 1 favoring the cis-diastereomer) (170 g, 0.59 mmol) and DIEA (300 mg, 2.4 mmol) was added to the solution at 0 ° C. The reaction mixture was stirred at 20 ° C for 12 H. The reaction mixture was quenched by the addition of H2O (10 ml) at 0 ° C and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS: m / z = 442.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.35-7.28 (m, 1H), 7.02 (s, 1H) , 6.81-6.65 (m, 3H), 4.71 (quin, J = 7.6 Hz, 1H), 4.45 (s, 2H), 3.39-3.26 (m, 1H ), 2.93-2.81 (m, 2H), 2.76-2.68 (m, 2H), 2.66 (s, 6H). Examples 106 and 107 2- [3-cis- (trifluoromethoxy) cyclobutoxy] -N- [3- [5- [3-cis- (trifluoromethoxymethyl) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanyl] acetamide and 2- [3-cis- (trifluoromethoxy) cyclobutoxy] -N- [3- [5- [3-trans- (trifluoromethoxymethyl) cyclobutyl] -1,3 , 4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] acetamide 3-aminobicyclohydrochloride [1.1.1] methyl pentane-1-carboxylate
[00484] [00484] A mixture of methyl 3- (tert-butoxycarbonylamino) bicyclo [1.1.1] pentane-1-carboxylate (500 mg, 2.1 mmol) in EtOAc (15 mL) was added HCl / EtOAc (15 mL, 4 M in EtOAc). The mixture was stirred at 20 ° C for 2 h. The reaction mixture was concentrated under reduced pressure.
[00485] [00485] To a mixture of cis-2- [3- (trifluoromethoxy) cyclobutoxy] acetic acid (530 mg, 2.5 mmol) in DCM (4 mL) was added HATU (1.1 g, 3.0 mmol) under N2. After 30 min, methyl 3-aminobicyclohydrate [1.1.1] pentane-1-carboxylate (440 mg, 2.5 mmol) and DIEA (1.3 g, 9.9 mmol) were added to the solution at 0 ° C. The reaction mixture was stirred at 20 ° C for 12 h. The reaction mixture was quenched by adding H2O 15 ml at 0 ° C, and extracted with EtOAc (3 × 15 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. cis-N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] -2- [3- (trifluoromeotoxy) cyclobutoxy] acetamide
[00486] [00486] To a mixture of 3 - [[2- [3- (trifluoromethoxy) cyclobutoxy] acyl] amino] bicyclo [1.1.1] cis-methyl pentane-1-carboxylate (450 mg, 1.3 mmol ) in EtOH (10 ml) hydrazine hydrate (680 mg, 13.3 mmol) was added under N2. The mixture was stirred at 80 ° C for 2 h. The reaction mixture was concentrated under reduced pressure. cis-2- [3- (trifluoromethoxy) cyclobutoxy] -N- [1 - [[[3- (trifluoromethoxymethyl) cyclobutanocarbonyl] amino] carbamoyl] -3-bicyclo [1.1.1] pentanil] acetamide
[00487] [00487] To a mixture of cis-N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanyl] -2- [3- (trifluoromethoxy) cyclobutoxy] acetamide (200 mg, 0.59 mmol ) in EtOAc (2 mL) 3- (trifluoromethoxymethyl) cyclobutanecarboxylic acid (140 mg, 0.71 mmol), T3P (1.5 g, 2.4 mmol, 50% in EtOAc) and Et3N (0.24 g, 2.36 mmol) at 20 ° C. The reaction mixture was stirred at 20 ° C for 12 h. The reaction mixture was quenched by adding saturated NaHCO3 solution (5 ml) to 0 ° C and extracted with EtOAc (3 × 15 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 2- [3-cis- (trifluoromethoxy) cyclobutoxy] -N- [3- [5- [3-cis- (trifluoromethoxymethyl) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanil] acetamide (106) and 2- [3-cis- (trifluoromethoxy) cyclobutoxy] -N- [3- [5- [3-trans- (trifluoro-methoxymethyl) cyclobutyl] -1,3, 4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] ace-tamide (5: 1 mixture of trans: cis diastereomers, 107)
[00488] [00488] To a mixture of cis-2- [3- (trifluoromethoxy) cyclobutoxy] -N- [1 - [[[3- (trifluoromethoxymethyl) cyclobutanecarbonyl] amino] carbamoyl] -3-bicycle [1.1.1] pentanil] acetamide (20 mg, 0.39 mmol) in CH3CN (2 mL) was added p-TsCl (180 mg, 0.97 mmol) and DIEA (25 mg, 0.19 mmol) under N2. reaction reaction was stirred at 50 ° C for 12 h. The reaction mixture was quenched by adding saturated NaHCO3 (7 ml) and extracted with EtOAc (3 × 7 ml). The combined organic layers were washed with brine (7 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. The main diastereomer was isolated. LC-MS: m / z = 500.4 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 4.34 (quin, J = 7.15 Hz , 1H), 3.98 (d, J = 6.15 Hz, 2H), 3.83 (s, 2H), 3.73 (quin, J = 6.90 Hz, 1H), 3.67-3 .58 (m, 1H), 2.83 (dtd, J = 9.94, 6.67, 6.67, 3.20 Hz, 2H), 2.80-2.70 (m, 1H), 2 , 66-2.59 (m, 6H), 2.59-2.52 (m, 2H), 2.34-2.22 (m, 4H). EXAMPLES 108 and 109 1- [3-cis- (trifluoromethoxy) cyclobutyl] -N- [3- [5- [3-cis- (trifluoromethoxy) cyclo-butyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] pyrazol-3-carboxamide and 2- [3- (trifluoromethoxy) cyclobutyl] -N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl]] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] pyrazol-3-carboxamide 1- (3-oxocyclobutyl) -1H-pyrazol-3-carboxylate
[00489] [00489] To a solution of ethyl 1H-pyrazol-5-carboxylate (940 mg, 6.7 mmol) in DMF (50 mL) was added Cs2CO3 (2.2 g, 6.71 mmol) and 3-bro- mocyclobutanone (1.0 g, 6.7 mmol) at -10 ° C. The reaction mixture was stirred at -10 ° C for 1 h. The reaction mixture was quenched by H2O (90 ml) and extracted with EtOAc (3 × 30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Mixture of regioisomers. LC-MS: m / z = 209.1 [M + H] +. Ethyl 1- (3-hydroxycyclobutyl) -1H-pyrazol-3-carboxylate
[00490] [00490] A mixture of ethyl 1- (3-oxocyclobutyl) -1H-pyrazol-3-carboxylate (770 mg, 3.7 mmol) in MeOH (10 mL) was added NaBH4 (139 mg, 3.7 mmol) at -30 ° C under N2. The reaction mixture was stirred at -30 ° C for 0.5 h. The mixture was quenched by the addition of NH4Cl (30 ml) at 0 ° C over 30 min. The mixture was concentrated under reduced pressure to remove MeOH and then extracted with EtOAc (3 x 10 ml). The combined organics were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated. Mixture of regioisomers. LC-MS: m / z = 211.1 [M + H] +. Ethyl 1- (3- (trifluoromethoxy) cyclobutyl) -1H-pyrazol-3-carboxylate
[00491] [00491] To a mixture of AgOTf (2.4 g, 9.4 mmol), Selectfluor (1.7 g, 4.7 mmol) and KF (729 mg, 12.6 mmol) in EtOAc (20 mL) was Ethyl 1- (3-hydroxycyclobutyl) -1H-pyrazol-3-carboxylate (660 mg, 3.1 mmol) is added followed by 2-fluoropyridine (914 mg, 9.4 mmol) and TMSCF3 (1.34 g , 9.42 mmol) under N2. The reaction mixture was stirred at 20 ° C for 15 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Mixture of regioisomers. LC-MS: m / z = 279.1 [M + H] +. 1- (3- (trifluoromethoxy) cyclobutyl) -1H-pyrazole-3-carboxylic acid
[00492] [00492] To a solution of ethyl 1- [3- (trifluoromethoxy) cyclobutyl] -1H-pyrazol-3-carboxylate (460 mg, 1.7 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH • H2O (208 mg 5.0 mmol) at 0 ° C. The reaction mixture was stirred
[00493] [00493] To a solution of 1- [3- (trifluoromethoxy) cyclobutyl] pyrazole-3-carboxylic acid (60 mg, 0.24 mmol) in DMF (3 mL) was added HATU (91 mg, 0.24 mmol) , DIEA (84 mg, 0.65 mmol) and cis-1- [5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine (8: 1 to 10: 1 favoring cis-diastereomer) (71 mg, 0.22 mmol) at 0 ° C. The reaction mixture was stirred at 15 ° C for 15 h. The reaction mixture was quenched by H2O (30 ml) and extracted with EtOAc (3 x 10 ml). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC to provide:
[00494] [00494] 1- [cis-3- (trifluoromethoxy) cyclobutyl] -N- [3- [5- [cis-3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] - 1-bicycle [1.1.1] pentanil] pyrazole-3-carboxamide (HPLC peak 1, main diastereomer of the main constitutional isomer) LC-MS: m / z = 522.4 [M + H] +, 1H- NMR (400 MHz, CDCl3): δ 7.43 (d, J = 2.3 Hz, 1H), 7.40 (s, 1H), 6.80 (d, J = 2.1 Hz, 1H), 4.71 (quin, J = 7.5 Hz, 1H), 4.57 (quin, J = 7.3 Hz, 1H), 4.48-4.37 (m, 1H), 3.39-3 , 27 (m, 1H), 3.05-2.83 (m, 6H), 2.70 (s, 8H).
[00495] [00495] 2- [3- (trifluoromethoxy) cyclobutyl] -N- [3- [5- [cis-3- (trifluoromethoxy) cyclo-butyl] -1,3,4-oxadiazol-2-yl] -1- bicycles [1.1.1] pentanyl] pyrazol-3-carboxamide (HPLC peak 2, mixture of diastereomers minor constitutional isomer) LC-MS: m / z = 522.4 [M + H] + EXAMPLES 110 and 111 (4- chlorophenyl) methyl-N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadazol-2-yl] -1-bicyclo [1.1.1] pentanil] carbamate and (4-chlorophenyl) methyl-N- [3- [5- [3-trans- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil ] (4-chlorophenyl) methyl carbonate (4-nitrophenyl) carbamate
[00496] [00496] To a solution of (4-chlorophenyl) methanol (3.7 g, 25.6 mmol) in DCM (35 mL) was added (4-nitrophenyl) carbonochloridate (6.7 g, 33.2 mmol) and DMAP (31 mg, 0.26 mmol). After 30 min, DIEA (4.3 g, 33.2 mmol) was added. The reaction mixture was stirred at 25 ° C for 12 h. The reaction mixture was quenched by adding H2O (35 ml) 0 ° C and extracted with DCM (35 ml), followed by EtOAc (3 × 35 ml). The combined organics were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. (4-chlorophenyl) methyl-N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadazazol-2-yl] -1-bicyclo [1.1.1] pentanil ] carbamate and (4-chlorophenyl) methyl-N- [3- [5- [3-trans- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1. 1] pentanil] carbamate
[00497] [00497] To a mixture of (4-nitrophenyl) methyl (4-chlorophenyl) carbonate (213 mg, 0.69 mmol) in DCM (1 mL) was added 1- [5- [3- (trifluorome-taxi) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine (8: 1 to 10: 1 favoring cis-diastereomer) (100 mg, 0.35 mmol), Et3N (0.10 mL, 0.69 mmol) and DMAP (4 mg, 0.003 mmol) under N2. The reaction mixture was stirred at 25 ° C for 12 h. The reaction mixture was quenched by adding H2O (5 ml) at 0 ° C and extracted with EtOAc (3 x 5 ml). The combined organics were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC to provide: cis- (3- (5- (3- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadiazol-2-yl) bicyclo [1.1.1 ] pentan-1-yl) carbamate.
[00498] [00498] LC-MS: m / z = 458.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.39- 7.32 (m, 2H), 7.32-7 , 28 (m, 2H), 5.33 (br s, 1H), 5.07 (br s, 2H), 4.70 (quin, J = 7.5 Hz, 1H), 3.40-3, 25 (m, 1H), 2.92-2.81 (m, 2H), 2.68 (q, J = 10.0 Hz, 2H), 2.61-2.45 (m, 6H). trans- (3- (5- (3- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadiazol-2-yl) bicyclo [1.1.1] pentan-1-yl) 4-chlorobenzyl carbamate.
[00499] [00499] LC-MS: m / z = 458.1 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.30-7.25 (m, 2H), 7.24-7 , 20 (m, 2H), 5.22 (br s, 1H), 5.00 (br s, 2H), 4.91 (quin, J = 7.0 Hz, 1H), 3.69-3, 56 (m, 1H), 2.85-2.64 (m, 4H), 2.46 (br s, 6H). EXAMPLES 112 and 113 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [2-trans-methylcyclopropyl] -1,3,4-oxadazole-2-yl] -1 -bicycle [1.1.1] pentanil] acetamide
[00500] [00500] The racemic mixture of 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- (2-methyl-cyclopropyl) -1,3,4-oxadiazol-2-yl] - 3-bicycle [1.1.1] pentanil] acetamide was separated by chiral SFC to provide:
[00501] [00501] 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- [2-methylcyclopropyl] -1,3,4-oxadazole-2-yl] -3-bicycle [ 1.1.1] pentanil] acetamide (Peak 1 in SFC, enantiomer 1). LC-MS: m / z = 392.3 [M + H] +. 1H-NMR (400 MHz, CDCl3): δ 7.34 (t, J = 8.6 Hz, 1H), 6.95 (br s, 1H), 6.77 (dd, J = 2.9, 10 , 3 Hz, 1H), 6.72-6.63 (m, 1H), 4.45-4.39 (m, 1H), 4.42 (s, 1H), 2.61 (s, 6H) , 1.85-1.79 (m, 1H), 1.53-1.43 (m, 1H), 1.34-1.24 (m, 1H), 1.21 (d, J = 6, 0 Hz, 3H), 0.93 (ddd, J = 4.8, 6.1, 8.5 Hz, 1H).
[00502] [00502] 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5- [2-methylcyclopropyl] -1,3,4-oxadazole-2-yl] -3-bicycle [ 1.1.1] pentanil] acetamide (Peak 2 in SFC, enantiomer 2). LC-MS: m / z = 392.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.34 (t, J = 8.6 Hz, 1H), 6.95 (s , 1H), 6.77 (dd, J = 2.8, 10.2 Hz, 1H), 6.69 (ddd, J = 1.3, 2.9,
[00503] [00503] To a mixture of cyclopent-3-en-1-ol (3.0 g, 35.7 mmol), tert-butyl 2-brominoacetate (10.4 g, 53.5 mmol), hydrogen sulfate of tetrabutylammonium (600 mg, 1.8 mmol) and H2O (1.5 mL) in toluene (60 mL) NaOH (21.4 g, 535.0 mmol) in H2O (20 mL) was added. The reaction mixture was stirred at 25 ° C for 4 h. The reaction mixture was quenched by adding ice water (30 ml) at 0 ° C and extracted with MTBE (3 x 30 ml). The combined organics were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 2- tert-butyl (3-hydroxycyclopentoxy) acetate
[00504] [00504] To a solution of tert-butyl 2-cyclopent-3-en-1-yloxyacetate (1.0 g, 5.0 mmol) in THF (40 mL) was added dropwise 9-BBN (0, 5 M in THF, 12.1 ml) at 0 ° C more than 50 min under N2. The reaction mixture was stirred at 0 ° C for 10 min and then heated to 20 ° C and stirred for 4 h. A suspension of sodium perborate monohydrate (1.5 g, 15.1 mmol) in water (56 ml) was then added. The reaction mixture was stirred at 20 ° C for 12 h and then filtered and extracted with EtOAc (3 x 30 ml). The combined organics were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Cis- [3- (2-tert-butoxy-2-oxo-ethoxy) cyclopentyl 4-nitrobenzoate]
[00505] [00505] To a mixture of 2- [3-hydroxycyclopentoxy] tert-butyl acetate (2.8 g, 13.0 mmol) and 4-nitrobenzoic acid (2.4 g, 14.2 mmol) in THF (40 ml) PPh3 (5.1 g, 19.4 mmol) was added at 20 ° C under N2. Then DIAD (13.1 g, 64.7 mmol) was added at 0 ° C under N2. The reaction mixture was stirred at 20 ° C for 15 h. The reaction mixture was diluted with H2O (30 ml) and extracted with EtOAc (3 × 30 ml). The combined organics were washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 2- (3-hydroxycyclopentoxy) cis-tert-butyl acetate
[00506] [00506] To a mixture of cis- [3- (2-tert-butoxy-2-oxo-ethoxy) cyclopentyl 4-nitrobenzoate (3.8 g, 10.4 mmol) in THF (15 mL), H2O (3 ml) and MeOH (30 ml) K2CO3 (1.4 g, 10.4 mmol) was added at 20 ° C under N2. The reaction mixture was stirred at 25 ° C for 16 h. The reaction mixture was diluted with H2O (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organics were washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 2- [3- (trifluoromethoxy) cyclopentoxy] cis-tert-butyl acetate
[00507] [00507] To a mixture of AgOTf (2.1 g, 8.3 mmol) in EtOAc (20 mL) was added Selectfluor (1.5 g, 4.2 mmol), KF (0.6 g, 11.1 mmol) and cis-tert-butyl 2- (3-hydroxy-cyclopentoxy) acetate (0.6 g, 2.8 mmol) under N2 followed by 2-fluoropyridine (0.8 g, 8.3 mmol) and TMSCF3 (1.2 g, 8.3 mmol). The reaction mixture was stirred at 25 ° C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by a silica gel column. Cis-2- [3- (trifluoromethoxy) cyclopentoxy] acetic acid
[00508] [00508] To a mixture of 2- [3- (trifluoromethoxy) cyclopentoxy] cis-tert-butyl acetate (100 mg, 0.35 mmol) in DCM (3 mL) was added TFA (1.6 g, 14, 1 mmol) in a portion under N2. The mixture was stirred at 40 ° C for 2 h. The reaction mixture was concentrated under reduced pressure. N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -1-bicyclo [1.1.1] pentanil] -2- [3- cis- (trifluoromethoxy) cyclopentoxy] acetamide
[00509] [00509] To a mixture of cis-2- [3- (trifluoromethoxy) cyclopentoxy] acetic acid (60 mg, 0.26 mmol) in DMF (1 mL) was added HATU (120 mg, 0.32 mmol) under N2. The mixture was stirred for 20 min, then the HCl salt of 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan- 3-amine (86 mg, 0.26 mmol; 8: 1 to 10: 1 ratio of cis- to trans-) and DIEA (136 mg, 1.05 mmol) were added to the solution at 0 ° C. The reaction mixture was stirred at 20 ° C for 12 h. The reaction mixture was quenched by the addition of H2O (5 ml) and extracted with EtOAc (3 × 5 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS: m / z = 500.4 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.06 (br s, 1H), 4.80-4.73 (m, 1H ), 4.73-4.63 (m, 1H), 4.08-3.99 (m, 1H), 3.95-3.83 (m, 2H), 3.31 (tt, J = 10 , 12, 7.76 Hz, 1H), 2.86 (dtd, J = 9.76, 7.26, 7.26, 2.82 Hz, 2H), 2.73-2.63 (m, 2H ), 2.60 (s, 6H), 2.14-2.05 (m, 3H), 2.05-1.91 (m, 2H), 1.89-1.79 (m, 1H), EXAMPLE 115 2-Spiro [2,3] hexan-5-yloxy-N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] - 1,3,4-oxadiazol-2-yl] -1- bicycle [1.1.1] pentanil] acetamide
[00510] [00510] Prepared using General Procedure A using HCl 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan salt -3-amine (50 mg, 0.15 mmol; 8: 1 to 10: 1 ratio of cis- to trans-), 2-spiro [2,3] hexan-5-yloxyacetic (36 mg, 0.23 mmol), NEt3 (0.07 mL, 0.49 mmol) and T3P (0.27 mL, 0.46 mmol, 50% in EtOAc) in EtOAc (1.5 mL). The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 428.2 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.05 (s, 1H), 4.72 (t, J = 7.5 Hz , 1H), 4.27 (t, J = 6.8 Hz, 1H), 3.85 (d, J = 4.3 Hz, 2H), 3.33 (d, J = 10.2 Hz, 1H ), 2.88 (dt, J = 7.4, 2.5 Hz, 2H), 2.71-2.69 (m, 2H), 2.64 (s, 6H), 2.32-2, 28 (m, 2H), 2.21 (td, J = 7.5, 3.8 Hz, 2H), 0.50-0.43 (m, 4H). EXAMPLE 116
[00511] [00511] Prepared using General Procedure A, using HCl salt of 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicycle [1.1.1] pentan -3-amine (75 mg, 0.23 mmol; 8: 1 to 10: 1 ratio of cis- to trans-), 2- [1- (2,2,2-trifluoroethyl) azetidin-3-yl ] oxyacetic (74 mg, 0.35 mmol), NEt3 (0.16 mL, 1.15 mmol) and T3P (0.41 mL, 0.69 mmol, 50% in EtOAc) in EtOAc (2.3 mL) . The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 485.4 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.01 (s, 1H), 4.71 (q, J = 7.5 Hz , 1H), 4.26 (quintet, J = 5.4 Hz, 1H), 3.86 (s, 2H), 3.77-3.72 (m, 2H), 3.38-3.28 ( m, 3H), 3.07 (q, J = 9.3 Hz, 2H), 2.87 (dtt, J = 11.2, 6.0, 2.9 Hz, 2H), 2.74-2 , 66 (m, 2H), 2.66 (d, J = 2.0 Hz, 6H). EXAMPLE 117 2 - [[3-cis- (trifluoromethoxy) cyclobutyl] methoxy] -N- [3- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl ] -1-bicycle [1.1.1] pentanil] acetamide
[00512] [00512] Prepared using General Procedure A using HCl salt of 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan- 3-amine (50 mg, 0.15 mmol; ratio 8: 1 to 10: 1 cis- to trans-), cis-2 - [[3- (trifluoromethoxy) cyclobutyl] methoxy] acetic acid (53 mg, 0 , 23 mmol), NEt3 (0.11 mL, 0.77 mmol), and T3P (0.27 mL, 0.46 mmol, 50% in EtOAc) in EtOAc (1.5 mL). The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 500.3 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 6.94 (s, 1H), 4.71 (t, J = 7.5 Hz , 1H), 4.60 (t, J = 7.4 Hz, 1H), 3.93 (d, J = 6.8 Hz, 2H), 3.54 (d, J = 5.8 Hz, 2H ), 3.36-3.31 (m, 1H), 2.87 (qq, J = 6.4, 2.6 Hz, 2H), 2.73-2.65 (m, 2H), 2, 65 (d, J = 0.5 Hz, 6H), 2.54 (dtd, J = 12.9, 7.3, 3.0 Hz, 2H), 2.23 (dd, J = 8.6, 6.6 Hz, 1H), 2.07 (td, J = 8.8, 2.2 Hz, 2H). EXAMPLE 118 N- [3- [5- [1- (2,2,2-trifluoroethyl) pyrazol-4-yl] -1,3,4-oxadiazol-2-yl] -1-bicycle [1.1. 1] pentanil] -2- [3-cis- (trifluoromethoxy) cyclobutoxy] acetamide
[00513] [00513] cis-N- [1- [5- (1H-pyrazol-4-yl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1]
[00514] [00514] cis-N- [1- [5- (1H-pyrazol-3-yl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1] pentanyl] -2- [ 3-cis- (trifluoromethoxy) cyclobutoxy] acetamide (48 mg, 0.12 mmol) was dissolved in DMF (1.2 ml). Cs2CO3 (76 mg, 0.23 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.02 mL, 0.14 mmol) were then added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 solution (5 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with water (2 x 20 ml) and brine (1 x 20 ml) and then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 496.4 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.67 (d, J = 2.5 Hz, 1H), 7.07 (d , J = 2.5 Hz, 1H), 6.95 (s, 1H), 4.86 (q, J = 8.2 Hz, 2H), 4.35 (t, J = 7.2 Hz, 1H ), 3.85 (s, 2H), 3.75 (t, J = 6.9 Hz, 1H), 2.85 (dtd, J = 9.9, 6.7, 3.2
[00515] [00515] Prepared using General Procedure A using 1- [5- [3- cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan-3-amine ( 50 mg, 0.17 mmol; 8: 1 to 10: 1 ratio of cis- to trans-), 2- (4-cyclopropylphenoxy) acetic acid (50 mg, 0.26 mmol), NEt3 (0.12 mL , 0.86 mmol) and T3P (0.3 mL, 0.52 mmol, 50% in EtOAc) in EtOAc (1.7 mL). The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 464.3 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.10-7.05 (m, 3H), 6.87-6.83 ( m, 2H), 4.72 (t, J = 7.5 Hz, 1H), 4.44 (s, 2H), 3.34 (td, J = 9.0, 2.4 Hz, 1H), 2.92-2.85 (m, 2H), 2.75-2.67 (m, 2H), 2.67 (s, 6H), 1.89 (dt, J = 9.3, 4.2 Hz, 1H), 0.98-0.93 (m, 2H), 0.67-0.63 (m, 2H). EXAMPLE 121 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [2-methyl-1- (2,2,2-trifluoroethyl) azetidin-3-yl] -1,3 , 4-oxadiazol-2-yl] -1-bicycle [1.1.1] pentanil] acetamide
[00516] [00516] 2- (4-Chloro-3-fluoro-phenoxy) -N- [1- [5- (2-methylazetidin-3-yl) - 1,3,4-oxadiazol-2-yl] -3 acid -bicycle [1.1.1] pentanil] acetamide; 2,2,2-trifluoroacetic (13 mg, 0.03 mmol) was dissolved in EtOAc (0.5 ml). Water (0.5 mL), NaHCO3 (11 mg, 0.13 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.01 mL, 0.05 mmol) were then added. The reaction mixture was stirred at 50 ° C overnight. The reaction mixture was cooled to room temperature and diluted with saturated NaHCO3 solution (5 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 489.3 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.97 (s , 1H), 6.79 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.7, 1.1 Hz, 1H), 4, 44 (s,
[00517] [00517] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (60 mg , 0.18 mmol), 1-tert-butoxycarbonyl-2-methyl-azetidine-3-carboxylic acid (59 mg, 0.27 mmol), NEt3 (0.13 mL, 0.92 mmol) and T3P ( 0.65 ml, 0.55 mmol, 50% in EtOAc) in EtOAc (1.8 ml). LC-MS, m / z = 451.3 [M – C4H7] +, 1 H-NMR (400 MHz; CDCl3): δ 7.37 (t, J = 8.6 Hz, 1H), 6.96 ( s, 1H), 6.80 (dd, J = 10.2, 2.8 Hz, 1H), 6.72 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4 , 54 (t, J = 6.3 Hz, 1H), 4.45 (s, 2H), 4.19 (d, J = 8.7 Hz, 1H), 4.15 (d, J = 7, 2 Hz, 1H), 3.53 (dd, J = 6.6, 1.9 Hz, 1H), 2.68 (s, 6H), 1.55 (d, J = 6.3 Hz, 3H) , 1.49 (s, 9H). EXAMPLE 123 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [1- (2,2,2-trifluoro-1-methyl-ethyl) azetidin-3-yl] -1 , 3,4-oxadiazol-2-yl] -1-bicycles [1.1.1] pentanil] acetamide
[00518] [00518] N- [1- [5- (azetidin-3-yl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1] pentanyl] -2- (4- chloro-3-fluoro-phenoxy) acetamide; 2,2,2-trifluoroacetic acid (45 mg, 0.09 mmol) was dissolved in CHCl3 (0.9 mL) followed by the addition of 1,1,1-trifluoropropan-2-one (1.6 mL, 17, 76 mmol). NaCNBH3 (17 mg, 0.27 mmol) was then added as a solid in one portion followed by MeOH (0.9 mL) at room temperature. After 1 h, an additional 1,1,1-trifluoropropan-2-one (1.6 mL, 17.76 mmol) was added. After an additional 11 h, another portion of NaCNBH3 (17 mg, 0.27 mmol) was added. After a combined 20 h, the reaction mixture was diluted with saturated NaHCO3 solution (15 ml) and EtOAc (40 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 489.4 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.99 (s , 1H), 6.79 (dd, J = 10.2, 2.8 Hz, 1H), 6.72-6.69 (m, 1H), 4.44 (s, 2H), 3.95 ( dd, J = 13.1, 6.2 Hz, 2H), 3.81 (ddd, J = 8.2, 5.9, 2.3 Hz, 1H), 3.62 - 3.58 (m, 2H), 2.97 (t, J = 6.6 Hz, 1H), 2.67 (s, 6H), 1.18 (d, J = 6.6 Hz, 3H). EXAMPLE 124 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [5-cis- (trifluoromethoxymethyl) tetrahydrofuran-2-yl] -1,3,4-oxadiazole -2-yl] -1-bicycle [1.1.1] pentanil] acetamide
[00519] [00519] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicycles [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), cis-5- (trifluoromethoxymethyl) tetrahydrofuran-2-carboxylic acid (39 mg, 0.18 mmol), NEt3 (0.09 mL, 0.61 mmol) and T3P (0.44 mL, 0.37 mmol, 50% in EtOAc) in EtOAc (1.2 mL). LC-MS, m / z = 506.3 [M + H] +, 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.95 ( s, 1H), 6.80 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 5 , 23 (dd, J = 7.5, 5.3 Hz, 1H), 4.44 (s, 2H), 4.41 (d, J = 5.0 Hz, 1H), 4.07 (dd, J = 10.3, 4.2 Hz, 1H), 4.01 (dd, J = 10.3, 5.4 Hz, 1H), 2.67 (s, 6H), 2.52-2.39 (m, 2H), 2.25 (d, J = 7.7 Hz, 1H), 2.09 (t, J = 6.4 Hz, 1H). EXAMPLE 125 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5 - [(3,3-difluoropyrrolidin-1-yl) methyl] - 1,3,4-oxadiazol-2-yl ] -1-bicycle [1.1.1] pentanil] acetamide
[00520] [00520] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), TFA salt of 2- (3,3-difluoropyrrolidin-1-yl) acetic acid (51 mg, 0.18 mmol), NEt3 (0.09 mL, 0.61 mmol), and T3P (0.44 ml, 0.37 mmol, 50% in EtOAc) in EtOAc (1.2 ml). LC-MS, m / z = 457.2 [M + H] +, 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.96 ( s, 1H), 6.80 (dd, J = 10.2, 2.9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4 , 44 (s, 2H), 3.94 (s, 2H), 3.10 (t, J = 13.1 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H), 2 . 68 (s, 6H), 2.35
[00521] [00521] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 2,2,2-trifluoroacetic acid; 2- [3- (trifluoromethyl) azetidin-1-yl] acetic acid (54 mg, 0.18 mmol), NEt3 (0.09 mL, 0.61 mmol), and T3P (0.22 mL, 0 , 37 mmol, 50% in EtOAc) in EtOAc (1.2 mL). LC-MS, m / z = 475.3 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.39-7.34 (m, 1H), 6.95 (d, J = 0.6 Hz, 1H), 6.79 (dd, J = 10.3, 2.9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H ), 4.44 (d, J = 3.0 Hz, 2H), 3.86 (s, 2H), 3.69 (t, J = 8.3 Hz, 2H), 3.45 (t, J = 7.7 Hz, 2H), 3.28-3.22 (m, 1H), 2.67 (s, 6H). EXAMPLE 127 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [4- (2,2,2-trifluoroethyl) morpholin-2-yl] - 1,3,4-oxadiazole -2-yl] -1-bicycle [1.1.1] pentanil] acetamide
[00522] [00522] 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [5-morpholin-2-yl-1,3,4-oxadiazol-2-yl) -3-bicycle [1.1. 1] pentanil] acetamide; 2,2,2-trifluoroacetic acid (12 mg, 0.02 mmol) was dissolved in EtOAc (0.5 ml). Water (0.5 mL), NaHCO3 (10 mg, 0.11 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.01 mL, 0.03 mmol) were then added in sequence. The resulting reaction mixture was heated to 50 ºC for 6 h, followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.01 mL, 0.03 mmol). The resulting reaction mixture was stirred at 50 ° C overnight. The reaction mixture was cooled to room temperature and diluted with saturated NaHCO3 solution (5 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 505.3 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.39-7.35 (m, 1H),
[00523] [00523] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicyclo [1.1.1] pentanil] acetamide acid (48 mg, 0.15 mmol), 4- (tert-butoxycarbonyl) morpholine-2-carboxylic (51 mg, 0.22 mmol), NEt3 (0.10 mL, 0.73 mmol) and T3P (0.52 mL, 0.44 mmol, 50% in EtOAc) in EtOAc (1.5 mL). LC-MS, m / z = 467.2 [M – C4H7] +, 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.96 (s , 1H), 6.79 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4, 74 (dd, J = 10.1, 2.9 Hz, 1H), 4.44 (s, 2H), 4.28-4.25 (m, 1H), 4.07-4.03 (m, 1H), 3.97-3.92 (m, 1H), 3.75-3.69 (m, 1H), 3.41-3.33 (m, 1H), 3.19-3.12 ( m, 1H), 2.64 (s, 6H), 1.47 (s, 9H). EXAMPLE 129 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5 - [(3,3-difluoroazetidin-1-yl) methyl] -1,3,4-oxadiazol-2-yl ] -1-bicycle [1.1.1] pentanil] acetamide
[00524] [00524] Prepared using General Procedure C, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicycles [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 2- (3,3-difluoroazetidin-1-yl) acetic acid; 2,2,2-trifluoroacetic acid (49 mg, 0.18 mmol), NEt3 (0.09 mL, 0.61 mmol), and T3P (0.44 mL, 0.37 mmol, 50% in EtOAc) in EtOAc (1.2 ml). LC-MS, m / z = 443.3 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.39-7.33 (m, 1H), 6.97-6.95 ( m, 1H), 6.81-6.78 (m, 1H), 6.73-6.70 (m, 1H), 4.44-4.43 (m, 2H), 3.98 (dt, J = 2.1, 1.0 Hz, 2H), 3.86-3.79 (m, 4H), 2.68 (s, 6H). EXAMPLE 130 2- (4-chloro-3-fluoro-phenoxy) -N- [3- [5- [1- (2,2-difluoroethyl) azetidin-3-yl] -1,3,4-oxadiazole-2 -il] -1-bicycle [1.1.1] pentanil] acetamide
[00525] [00525] N- [1- [5- (azetidin-3-yl) -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1] pentanyl] -2- (4- chloro-3-fluoro-phenoxy) acetamide (45 mg, 0.11 mmol) was dissolved in EtOAc (1.8 ml). Water (1.0 mL), NaHCO3 (49 mg, 0.57 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (0.02 mL, 0.14 mmol) were then added sequentially at 0 ° C. The resulting reaction mixture was stirred at 50 ° C overnight. The reaction mixture was cooled to room temperature and diluted with saturated NaHCO3 solution (5 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 457.3 [M + H] +, 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.96 (s , 1H), 6.80 (dd, J = 10.2, 2.9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 5, 80 (tt, J = 55.8, 4.3 Hz, 1H), 4.44 (s, 2H), 3.98-3.93 (m, 1H), 3.87 (t, J = 7, 6 Hz, 2H), 3.62-3.59 (m, 2H), 2.95-2.86 (m, 2H), 2.65 (d, J = 5.3 Hz, 6H). EXAMPLE 131 2- (4-chloro-3-fluoro-phenoxy) -N - [3- [5- (2,2-difluoro-1,1-dimethyl-ethyl) -1,3,4-oxadiazole-2 -il] -1-bicycle [1.1.1] pentanil] acetamide
[00526] [00526] Prepared using General Procedure A, using 2- (4-chloro-3-fluoro-phenoxy) -N- [1- (hydrazinocarbonyl) -3-bicycles [1.1.1] pentanil] acetamide (40 mg , 0.12 mmol), 3,3-difluoro-2,2-dimethyl-propanoic acid (25 mg, 0.18 mmol), NEt3 (0.09 mL, 0.61 mmol), and T3P (0.22 mL, 0.37 mmol, 50% in EtOAc) in EtOAc (1.2 mL). The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 430.2 [M + H] +. 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.80 (dd, J = 10.2, 2, 8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 5.95 (t, J = 56.0 Hz, 1H), 4.45 ( s, 2H), 2.68 (s, 6H), 1.54 (s, 6H). EXAMPLE 132
[00527] [00527] The title compound was produced through similar procedures described throughout the text. LC-MS, m / z = 481.4, 483.4 [M + H] +. EXAMPLE 133 2- (4-chloro-3-fluoro-phenoxy) -N- [1- [2- [cis-3- (trifluoromethoxy) cyclobutoxy] ethylamino] -3-bicycle [1.1.1] pentanyl] acetamide
[00528] [00528] N- (1-amino-3-bicyclo [1.1.1] pentanil) -2- (4-chloro-3-fluoro-phenoxy) acetamide (258.64 mg, 0.91 mmol), 2- [ 3-cis- (trifluoromethoxy) cyclobutoxy] acetaldehyde (120 mg, 0.61 mmol) and acetic acid (200 mg, 3.33 mmol) were dissolved in DCE (5 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with aqueous 1N NaOH (50 ml) and DCM (50 ml). The layers were separated and the aqueous layer was extracted with DCM (3  150 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material mixture was purified by preparative HPLC. 1H-NMR (400 MHz; CDCl3): δ 7.38-7.33 (m, 1H), 6.89-6.87 (m, 1H), 6.80-6.77 (m, 1H), 6.70 (dtd, J = 8.9, 2.6, 1.3 Hz, 1H), 4.35-4.28 (m, 1H), 3.72-3.61 (m, 2H), 3.57-3.46 (m, 2H), 2.91-2.88 (m, 1H), 2.83-2.76 (m, 2H), 2.63-2.44 (m, 5H ), 2.33-2.19 (m, 7H), LC-MS m / z = 467.36 [M + H] +.
[00529] [00529] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 134-138 Example LC-MS (m / z, [M + H] +) General Procedure 134 490.3 Procedure H 135 458.3 Procedure H 136 440.4 Procedure H 137 440.3 Procedure H 138 458.3 Procedure H
[00530] [00530] Prepared using General Procedure F, using 2- bromo-1- [3- (trifluoromethyl) phenyl] ethanone (403 mg, 1.51 mmol) and H- N- (3-aminobicyclo salt [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (500 mg, 1.36 mmol) in MeCN (5 mL). Purified by silica gel column chromatography. LC-MS: m / z: 447.2 [M + H] +. N- (3- (N- (2- (4-chlorophenyl) -2-oxoethyl) formamide) bicyclo [1.1.1] pentan-1-yl) - 2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide
[00531] [00531] Prepared using General Procedure G, using N- (3- ((2- (4-chlorophenyl) -2-oxoethyl) amino) bicycles [1.1.1] pentan-1-yl) -2- (3- cis- (trifluoro-methoxy) cyclobutoxy) acetamide (235 mg, 0.53 mmol) in DCM (0.9 mL). LC-MS: m / z: 475.2 [M + H] +. N- (3- (4- (4-chlorophenyl) -1H-imidazol-1-yl) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide
[00532] [00532] Prepared using General Procedure H, using N- (3- (N- (2- (4-chlorophenyl) -2-oxoethyl) formamide) bicyclo [1.1.1] pentan-1-yl) -2- ( 3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (100 mg, 0.21 mmol) in AcOH (3 mL). LC-MS: m / z: 456.2 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.71-7.68 (m, 2H), 7.51 (s, 1H) , 7.35-7.33 (m, 2H), 7.19 (s, 1H), 6.94 (s, 1H), 4.35 (quin, J = 7.09 Hz, 1H), 3, 86 (s, 2H), 3.75 (quin, J = 6.88 Hz, 1H), 2.85 (dtd, J = 9.86, 6.56, 6.56, 3.30 Hz, 2H) , 2.67 (s, 6H), 2.24-2.37 (m, 2H).
[00533] [00533] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 140-145
[00534] [00534] N- (3 - ((2- (4-chloro-2-fluorophenyl) -2-oxoethyl) amino) bicyclo [1.1.1] pen-tan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide was prepared using General Procedure F, using H- salt of N- (3-aminobicyclo [1.1.1] pentan-1-yl) -2- (3cis (trifluoromethoxy) cyclobutoxy) acetamide (1, 0 g, 3.02 mmol) and 2-bromo-1- (4-chloro-2-fluoro-phenyl) ethanone (760 mg, 3.02 mmol) in MeCN (40 mL). Purified by silica gel column chromatography to obtain the desired product. LC-MS: m / z: 465.2 [M + H] +. N- (3- (N (2- (4-chloro-2-fluorophenyl) -2-oxoethyl) amino) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy ) acetamide
[00535] [00535] N- (3- (N- (2- (4-chloro-2-fluorophenyl) -2-oxoethyl) formamide) bicyclo [1.1.1] pentan-1-yl) -2- (3- cis- (trifluoromethoxy) cyclobutoxy) acetamide was prepared using General Procedure G employing N- (3 - ((2- (4- (chloro-2-fluorophenyl) -2-oxoethyl) amino) bicycles [1.1. 1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (750 mg, 1.61 mmol) in DCM (8.0 mL). LC-MS: m / z: 493.2 [M + H] +. N- (3- (4- (4-chloro-2-fluorophenyl) -1H-imidazol-1-yl) bicycles [1.1.1] pentan-1-yl) - 2 - (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide
[00536] [00536] N- (3- (4- (4-chloro-2-fluorophenyl) -1H-imidazol-1-yl) bicycle [1.1.1] pen-tan-1-yl) -2- (3-cis - (trifluoromethoxy) cyclobutoxy) acetamide was prepared using General Procedure H employing N- (3- (N- (2- (4-chloro-2-fluorophenyl) -2-oxoethyl) formamide) bicycles [1.1.1] pentan- 1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (700 mg, 1.42 mmol) in AcOH (10 mL). LC-MS: m / z: 474.1 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 8.08 (t, J = 8.4 Hz, 1H), 7.53 (s , 1H), 7.38-7.35 (m, 1H), 7.20 (dd, J = 1.8, 8.6 Hz, 1H), 7.14 (dd, J = 1.9, 11 , 1 Hz, 1H), 6.95 (s, 1H), 4.35 (quin, J = 7.2 Hz, 1H), 3.86 (s, 2H), 3.75 (quin, J = 6 , 9 Hz, 1H), 2.85 (dtd, J = 3.3, 6.6, 9.9 Hz, 2H), 2.66 (s, 6H), 2.39-2.23 (m, 2H).
[00537] [00537] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 147-156 Example LC-MS (m / z, [M + H] +) General Procedure 147 454.4 Procedure H 148 508.1 Procedure H 149 508.1 Procedure H 150 490.1 Procedure H 151 491.4 Procedure H 152 448.2 Procedure A 153 444.3 Procedure A 154 486.2 Procedure A 155 471.0 Procedure A 156 458.3 Procedure A EXAMPLES 157 and 158 6-chloro-N- (3- (5- (3 -cis- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadiazol-2-yl) bi- cycle [1.1.1] pentan-1-yl) croman-2-carboxamide
[00538] [00538] Prepared using General Procedure A, using HCl salt 3- (5- (3-cis- (trifluoromethoxy) cyclobutyl) -1,3,4-oxadiazol-2-yl) bicycles [1.1.1] pentan- 1-amine (77 mg, 0.23 mmol; 8: 1 to 10: 1 ratio of cis- to trans-) and 6-
[00539] [00539] Example 157, first elution peak in SFC: 1H-NMR (400 MHz, CDCl3): δ 7.12 - 7.07 (m, 2H), 7.06 (s, 1H), 6.84 ( d, J = 8.6 Hz, 1H), 4.71 (quin, J = 7.5 Hz, 1H), 4.45 (dd, J = 2.8, 10.0 Hz, 1H), 3, 33 (tt, J = 7.7, 10.2 Hz, 1H), 2.90 - 2.78 (m, 4H), 2.69 (br d, J = 10.5 Hz, 2H), 2, 65 (s, 6H), 2.47 - 2.40 (m, 1H), 1.98 (dtd, J = 5.4, 10.4, 13.8 Hz, 1H), LC-MS: m / z: 484.2 [M + H] +.
[00540] [00540] Example 158, second elution peak in SFC: 1H-NMR (400 MHz, CDCl3): δ 7.12 - 7.07 (m, 2H), 7.06 (s, 1H), 6.84 ( d, J = 8.6 Hz, 1H), 4.71 (quin, J = 7.6 Hz, 1H), 4.45 (dd, J = 2.8, 10.1 Hz, 1H), 3, 38 - 3.28 (m, 1H), 2.92 - 2.76 (m, 4H), 2.73 - 2.66 (m, 2H), 2.65 (s, 6H), 2.48 - 2.39 (m, 1H), 1.98 (tdd, J = 5.3, 10.3, 19.0 Hz, 1H), LC-MS: m / z: 484.2 [M + H] + .
[00541] [00541] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 159-161 Example LC-MS (m / z, [M + H] +) General Procedure 159 468.2 Procedure A 160 468.2 Procedure A 161 465.2 Procedure A EXAMPLE 162 N- [1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -3-bicyclo [1.1.1] pentanil] -2- [4- (trifluoromethyl) phenoxy] acetamide
[00542] [00542] Prepared using General Procedure A, using salt of
[00543] [00543] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 163-165 Example LC-MS (m / z, [M + H] +) General Procedure 163 502.24 Procedure A 164 479.58 Procedure A 165 469.2 Procedure A EXAMPLE 166 N- [1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -3-bicyclo [1.1.1] pentanil] -6- (trifluoromethyl) quinoline-2-carboxamide
[00544] [00544] Prepared using General Procedure A, using HCl salt of 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan -3-amine (8: 1 to 10: 1 favoring cis-diastereomer) (50 mg, 0.15 mmol), 6- (trifluoromethyl) quinoline-2-carboxylic acid (44 mg, 0.18 mmol), NEt3 (0.11 mL, 0.77 mmol) and T3P (58 mg, 0.18 mmol, 50% in EtOAc) in EtOAc (0.77 mL). Purified by reverse phase prep HPLC. LC-MS: m / z: 513.8 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.47 (d, J = 8.4 Hz , 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.29-8.25 (m, 2H), 7.98 (dd, J = 8.9, 2.1 Hz, 1H), 4.78-4.70 (m, 1H), 3.37 (tt, J = 10.2, 7.8 Hz, 1H), 2.94-2.86 (m, 2H), 2 , 80 (s, 6H), 2.78-2.69 (m, 2H). EXAMPLE 167 3-chloro-N- [1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] -3-bicycle [1.1.1] pentanyl] quinoline- 7-carboxamide
[00545] [00545] Prepared using General Procedure A, using HCl 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo [1.1.1] pentan- 3-amine (8: 1 to 10: 1 favoring the cis-diastereomer) (50 mg, 0.15 mmol) and 3-chloroquinoline-7-carboxylic acid (38 mg, 0.18 mmol), NEt3 (0.11 mL, 0.77 mmol) and T3P solution (58 mg, 0.18 mmol, 50% in EtOAc) in EtOAc (0.77 mL). Purified by reverse phase prep HPLC. LC-MS: m / z: 479.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 8.89 (d, J = 2.4 Hz, 1H), 8.45 (t , J = 0.8 Hz, 1H), 8.20-8.19 (m, 1H), 8.06 (dd, J = 8.5, 1.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 4.77-4.67 (m, 1H), 3.34 (qt, J = 10.2, 7.8 Hz, 1H ), 2.93-2.83 (m, 2H), 2.79-2.65 (m, 8H).
[00546] [00546] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 168-188 Example LC-MS (m / z, [M + H] +) General Procedure 168 479.4 Procedure A 169 479.3 Procedure A 170 452.4 Procedure A 171 468.3 Procedure A 172 469.7 Procedure A 173 508.7 Procedure A 174 493.7 Procedure A 175 485.2 Procedure A 176 469.2 Procedure A 177 469.1 Procedure A 178 453.3 Procedure A 179 512.3 Procedure A 180 452.4 Procedure A 181 468.3 Procedure A 182 479.3 Procedure A 183 480.2, 482.0 Procedure A
[00547] [00547] Prepared according to General Procedure A, using HCl 1- [5- [3-cis- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl] bicyclo salt [1.1. 1] pentan-3-amine (8: 1 to 10: 1 favoring cis-diastereomer) (45 mg, 0.14 mmol) and 6-fluoroquinoline-2-carboxylic acid (40 mg, 0.21 mmol) in EtOAc (1.4 mL). Purified by reverse phase prep HPLC. LC-MS: m / z: 463.5 [M + H] +, 1H-NMR (400 MHz, CDCl3): 8.68 (s, 1H), 8.34-8.29 (m, 2H), 8.15 (dd, J = 9.2, 5.3 Hz, 1H), 7.59 (ddd, J = 9.2, 8.2, 2.8 Hz, 1H), 7.55-7, 52 (m, 1H), 4.77-4.70 (m, 1H), 3.36 (tt, J = 10.2, 7.8 Hz, 1H), 2.94-2.86 (m, 2H), 2.80 (s, 6H), 2.77-2.69 (m, 2H).
[00548] [00548] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 190-235 Example LC-MS (m / z, [M + H] +) General Procedure 190 523.2 Procedure A 191 446.8 Procedure A 192 485.3 Procedure A 193 513.2 Procedure A 194 486.2 Procedure A 195 480.3 Procedure A 196 497.3 Procedure A 197 450.2 198 473.2 199 493.3 200 338.1
[00549] [00549] To a solution of 4-chloro-3-fluoroaniline (5.0 g, 34.4 mmol) and 2-
[00550] [00550] To a solution of 2 - ((4-chloro-3-fluorophenyl) amino) tert-butyl a (4.0 g, 15.4 mmol) in 1,4-dioxane (20 ml) was added TFA (5 mL) and the mixture was heated to 80 ºC for 16 h. The mixture was concentrated under reduced pressure. The residue was dispersed in aqueous HCl (20 ml, 6 N) and the mixture was concentrated under reduced pressure. The residue was coevaporated with toluene (50 ml) twice, triturated in PE: EtOAc (50 ml, v: v 1: 1) and then filtered. The filter cake was dried under reduced pressure to obtain the title compound. LC-MS: m / z: 204.1 [M + H] +. 2- (4-chloro-3-fluoro-N-nitrous-anilino) acetic acid
[00551] [00551] To a solution of 2- (4-chloro-3-fluoro-anilino) acetic acid (2.4 g, 10.0 mmol) in H2O (20 mL) and MeCN (10 mL) was added NaNO2 (690 mg, 10.0 mmol) and the mixture was stirred for 16 h at 15 ° C. The mixture was concentrated under reduced pressure to remove MeCN and the remaining aqueous mixture was filtered. The filter cake was washed with H2O (2 × 10 mL) and then dried under reduced pressure to provide the desired product. 1H-NMR (400 MHz, CDCl3): δ 13.23 (br s, 1H), 7.84-7.71 (m, 2H), 7.55 (dd, J = 1.6, 8.8 Hz , 1H), 4.78 (s, 2H). 3- (4-chloro-3-fluorophenyl) -1,2,3-oxadiazole-3-io-5-olate
[00552] [00552] A solution of 2- (4-chloro-3-fluoro-N-nitroso-anilino) acetic acid (1.5 g, 6.45 mmol) in Ac2O (15 mL) was heated to 100 ° C for 2 h. The mixture was concentrated under reduced pressure, the residue was dispersed in water (20 ml) and then filtered. The filter cake was washed with water (2 x 10 ml) and then dried under reduced pressure to obtain the desired compound. LC-MS: m / z: 215.0 [M + H] +. N- (3- (1- (4-chloro-3-fluorophenyl) -1H-pyrazol-4-yl) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy ) acetamide
[00553] [00553] To a solution of 3- (4-chloro-3-fluorophenyl) -1,2,3-oxadiazole-3-io-5-olate (50 mg, 0.23 mmol), N- (3-ethynylbicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (71 mg, 0.23 mmol) and NEt3 (70 mg, 0.70 mmol) in t- BuOH (1 mL) was added 4- [7- (4-sulfonatophenyl) -1,10-phenanthro-lin-4-yl] benzenesulfonate disodium (25 mg, 0.046 mmol) followed by a solution of CuSO4 (7.0 mg , 0.046 mmol) in H2O (0.5 mL) and a solution of sodium ascorbate (92 mg, 0.46 mmol) in H2O (0.5 mL). The mixture was heated to 60 ºC for 3 h. The mixture was cooled to 15 ° C and diluted with water (5 ml). The aqueous phase was extracted with EtOAc (2 x 5 ml), the combined organic layers were washed with brine (5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep TLC and then purified by prep HPLC to obtain the desired compound. LC-MS: m / z: 474.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.56 (s, 1H), 7.55 -7.51 (m, 1H), 7.47-7.36 (m, 2H), 6.87 (s, 1H), 4.37-4.30 (m, 1H), 3.83 (s , 2H), 3.76-3.69 (m, 1H), 2.86-2.80 (m, 2H), 2.40 (s, 6H), 2.32-2.25 (m, 2H ).
[00554] [00554] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 237-247 Example LC-MS (m / z, [M + H] +) General Procedure 237 458.4 238 481.3 239 475.1 Procedure A
[00555] [00555] To a solution of 4-chloro-3-fluorobenzaldehyde (2.0 g, 12.6 mmol) and NH2OH • HCl (1.05 g, 15.1 mmol) in EtOH (20 mL) at 0 ºC was A solution of NaOH (757 mg, 18.9 mmol) in H2O (5 ml) was added dropwise, and the mixture was heated to 15 ° C and was stirred for 3 h. The mixture was diluted with water (20 ml) and was concentrated under reduced pressure to remove EtOH. The aqueous phase was extracted with EtOAc (2 x 10 ml), the combined organic layers were washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue that was used directly. 1H-NMR (400 MHz, CDCl3): δ 8.07 (br d, J = 8.8 Hz, 1H), 7.83 (br s, 1H), 7.41 (q, J = 8.0 Hz , 2H), 7.31-7.22 (m, 1H). (Z) -4-chloro-3-fluoro-N-hydroxybenzimidoyl chloride
[00556] [00556] To a solution of (E) -4-chloro-3-fluorobenzaldehyde oxime (500 mg, 2.88 mmol) in DMF (5.0 mL) was added a solution of NCS (423 mg, 3.17 mmol) in DMF (3.0 mL) dropwise at 0 ° C, and the mixture was heated to 15 ° C and was stirred for 4 h. The mixture was diluted with saturated aqueous NH4Cl solution (20 ml) and was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (3 x 20 ml), dried over
[00557] [00557] To a solution of N- (3-ethynylbicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (50 mg, 0.16 mmol) and (Z) -4-chloro-3-fluoro-N-hydroxybenzimidoyl chloride (69 mg, 0.33 mmol) in DMF (2 mL) NEt3 (25 mg, 0.25 mmol) was added, and the mixture was heated at 60 ° C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep HPLC. LC-MS: m / z: 475.3 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.59 (br d, J = 9.6 Hz, 1H), 7.54- 7.43 (m, 2H), 6.93 (br s, 1H), 6.33 (s, 1H), 4.38-4.31 (m, 1H), 3.83 (s, 2H), 3.79-3.71 (m, 1H), 2.83 (br dd, J = 3.2, 6.4 Hz, 2H), 2.57 (s, 6H), 2.28 (br d, J = 7.2 Hz, 2H).
[00558] [00558] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 249-253 Example LC-MS (m / z, [M + H] +) 249 472.1 250 415.0 251 457.0 252 475.1 253 472.2 EXAMPLE 254 N- (3- (4- (2-hydroxy-4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide N- ( Tert-butyl 3-imidazol-1-yl-1-bicycles [1.1.1] pentanyl) carbamate
[00559] [00559] To a mixture of formaldehyde (4.09 g, 50.4 mmol, 37%) in MeOH (20 mL) was added tert N- (1-amino-3-bicycle [1.1.1] pentanyl) carbamate -butyl (2.0 g, 10.1 mmol) and ammonium acetate (3.89 g, 50.4 mmol). Oxaldehyde (2.93 g, 50.4 mmol) was added dropwise and the mixture was stirred at 20 ° C for 12 h. The reaction mixture was adjusted to pH = 7-8 with saturated aqueous NaHCO3 solution, and the aqueous phase was extracted with DCM: MeOH (v: v 3: 1, 3 × 50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the title compound. LC-MS: m / z: 250.2 [M + H] +. N- [3- (4,5-diiodoimidazol-1-yl) -1-bicycles [1.1.1] pentanyl] tert-butyl carbamate
[00560] [00560] To a mixture of N- (3-imidazol-1-yl-1-bicycles [1.1.1] pentanyl) tert-butyl carbamate (1.0 g, 4.01 mmol) in DMF (10 ml) NIS (2.71 g, 12.03 mmol) was added and the mixture was heated to 50 ° C for 7 h. The reaction mixture was poured into a mixture of water (30 ml) and saturated aqueous Na2S2O3 (20 ml) and then extracted with EtOAc (3 × 40 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography. 1H-NMR (400 MHz, CDCl3): δ 7.54 (s, 1H), 5.10 (br s, 1H), 2.68 (s, 6H), 1.54-1.42 (m, 9H ). Tert-butyl N- [3- (4-iodoimidazol-1-yl) -1-bicyclo [1.1.1] pentanyl] carbamate
[00561] [00561] To a mixture of tert-butyl N- [3- (4,5-diiodoimidazol-1-yl) -1-bicyclo [1.1.1] pentanyl] carbamate (300 mg, 0.60 mmol) in THF (5.0 mL) at - 78 ° C i-PrMgCl (2 M, 0.45 mL) was added, and the reaction mixture was stirred at -78 ° C for 1 h. The reaction mixture was diluted with saturated aqueous NH4Cl (10 ml) and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired product. LC-MS: m / z: 376.0 [M + H] +. N- [3- [4- [2-hydroxy-4- (trifluoromethyl) phenyl] imidazol-1-yl] -1-bicycles [1.1.1]
[00562] [00562] A mixture of tert-butyl N- [3- (4-iodoimidazol-1-yl) -1-bicycles [1.1.1] pentanyl] carbamate (100 mg, 0.27 mmol), acid [ 2-hydroxy-4- (trifluoromethyl) phenyl] boronic (110 mg, 0.53 mmol), CsF (121 mg, 0.80 mmol), Pd (dppf) Cl2 (20 mg, 0.027 mmol) and chloride benzyl (triethyl) ammonium (6 mg, 0.027 mmol) in a microwave tube in toluene (1 mL) and H2O (1 mL) was sealed and heated to 110 ° C for 2 h under microwave irradiation. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC to obtain the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.55 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.22 (s , 1H), 7.07 (d, J = 7.5 Hz, 1H), 5.07 (br s, 1H), 2.57 (s, 6H), 1.49 (s, 9H). HCl salt of 2- [1- (1-amino-3-bicyclo [1.1.1] pentanyl) imidazol-4-yl] -5- (trifluoromethyl) phenol
[00563] [00563] tert-butyl N- [3- [4- [2-hydroxy-4- (trifluoromethyl) phenyl] imidazol-1-yl] -1-bicyclo [1.1.1] pentanyl] carbamate (60 mg , 0.15 mmol) in HCl / EtOAc (4 M, 2 mL) was stirred at 25 ° C for 10 min. The reaction mixture was concentrated under reduced pressure to obtain a residue that was used directly. N- (3- (4- (2-hydroxy-4- (trifluoromethyl) phenyl) -1H-imidazol-1-yl) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis - (trifluoromethoxy) cyclobutoxy) acetamide
[00564] [00564] To a mixture of 2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetic acid (19 mg, 0.086 mmol) in DMF (1.0 mL) at 0 ° C were added HATU (36 mg, 0, 10 mmol), HCl 2- [1- (1-amino-3-bicyclo [1.1.1] pentanyl) imidazol-4-yl] -5- (trifluoromethyl) phenol salt (30 mg, 0.087 mmol) and N-methyl morpholine (26 mg, 0.26 mmol). The reaction mixture was heated to rt and was stirred for 40 min. The mixture was diluted with H2O (10 ml) and was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep. LC-MS: m / z: 506.2 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 12.32 (br s, 1H), 7.57 (d, J = 1.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 1.1 Hz, 1H), 7.22 (d, J = 1.0 Hz,
[00565] [00565] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 255-269 Example LC-MS (m / z, [M + H] +) 255 515.1 256 488.2 257 472.2 258 503.0 259 474.1 260 504.2 261 390.2 262 462 , 1 263 456.1 264 474.1 265 491.1 266 511.1 267 483.1 268 483.1 269 492.1 EXAMPLE 270 N- (3- (4- (4-chloro-2,3-difluorophenyl ) -1H-imidazol-1-yl) bicyclo [1.1.1] pentan- 1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide 4-chloro-2,3-difluorobenzoyl chloride
[00566] [00566] Prepared using General Procedure D, using 4-chloro-2,3-difluorobenzoic acid (1.0 g, 5.19 mmol) (COCl) 2 (725 mg, 5.71 mmol) and DMF (2 mL ) in THF (20 mL) at 0 oC under N2. The mixture was stirred for 1 h. The reaction mixture was used directly. 2-bromo-1- (4-chloro-2,3-difluorophenyl) ethanone
[00567] [00567] Prepared using General Procedure E employing 4-chloro-2,3-difluorobenzoyl chloride, TMSCHN2 (2 M, 5.19 mL) and HBr (2.10 g, 10.4 mmol, 40%). The mixture was stirred for 1 h. The crude product (0.8 g, 57%)
[00568] [00568] Prepared using General Procedure F, using 2-bromo-1- (4-chloro-2,3-difluorophenyl) ethanone (200 mg, 0.74 mmol), H- N- (3-aminobicyclo salt) [1.1 .1] pentan-1-yl) - 2 - (- 3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (245 mg, 0.74 mmol) and Na2CO3 (315 mg, 2.97 mmol) in MeCN (5 mL ) at 40 oC for 1 h. The residue was concentrated under reduced pressure to obtain the title compound. LC-M: m / z = 483.2 [M + H] +. N- (3- (N- (2- (4-chloro-2,3-difluorophenyl) -2-oxoethyl) formamide) bicyclo [1.1.1] pentan-1-yl) -2 - (- 3-cis- (trifluoromethoxy) cyclobutoxy) acetamide
[00569] [00569] Prepared using General Procedure G, using N- (3- ((2- (4-chloro-2,3-difluorophenyl) -2-oxoethyl) amino) bicycles [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy) cyclobutoxy) acetamide (400 mg, 0.83 mmol), Ac2O (483 mg, 3.31 mmol) and HCOOH (1.5 mL) in DCM (2 mL) at 1 ha 0 oC. The residue was purified by prep TLC (PE: EtOAc = 1: 1) to obtain the desired product. LC-MS: m / z = 511.2 [M + H] +. N- (3- (4- (4-chloro-2,3-difluorophenyl) -1H-imidazol-1-yl) bicyclo [1.1.1] pentan-1-yl) -2- (3-cis- (trifluoromethoxy ) cyclobutoxy) acetamide
[00570] [00570] Prepared using General Procedure H, using N- (3- (N- (2- (4-chloro-2,3-difluorophenyl) -2-oxoethyl) formamide) bicyclo [1.1.1] pentan-1- il) -2- (3-cis - (trifluoromethoxy) cyclobutoxy) acetamide (150 mg, 0.29 mmol) and NH4OAc (113 mg, 1.47 mmol) in AcOH (10 mL) at 110 oC for 16 h under N2. The residue was purified by prep (neutral) HPLC under the following conditions: column: Waxers Xbridge 150 x 25 mm, 5 µM; mobile phase: [water (10 mM NH4HCO3) -ACN]; B%: 45% -75%, 10 min to obtain the desired product. LC-MS: m / z = 492.1 [M + H] +, 1H-NMR (400 MHz, CDCl3): δ 7.85 (ddd, J = 2.0, 7.2, 8.8 Hz, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.40 (dd, J = 1.2, 4.0 Hz, 1H), 7.21 (ddd, J = 2.0 , 6.8, 8.8 Hz, 1H), 6.95 (s, 1H), 4.35 (quin, J = 7.2 Hz, 1H), 3.86 (s, 2H), 3.75 (quin,
[00571] [00571] The following Examples, as shown in Table 1, were synthesized through procedures similar to those described throughout the text. EXAMPLES 271-277 Example LC-MS (m / z, [M + H] +) 271 492.1 272 520.1 273 548.2 274 462.1 275 422.4 276 476.3 277 496.4
[00572] [00572] Proton NMR data for selected compounds is provided in Table 3. Table 3 Ex, Proton NMR data 1 H-NMR (400 MHz, CDCl3): δ 7.09 (s, 1 H), 6 , 84 (dd, J = 6.30, 1.53 Hz, 2 H), 6.80 (br d, J = 8.56 Hz, 1 H), 4.71 (quin, J = 7.55 Hz , 1 H), 4.43 (dd, J = 10.21, 159 2.75 Hz, 1 H), 3.33 (tt, J = 10.18, 7.73 Hz, 1 H), 2, 76 - 2.93 (m, 4 H), 2.66 - 2.73 (m, 2 H), 2.65 (s, 6 H), 2.40 - 2.48 (m, 1 H), 1.92 - 2.04 (m, 1 H), LC-MS: m / z: 468.2 [M + H] + 1 H-NMR (400 MHz, CDCl3): δ 7.09 (s, 1 H), 6.84 (dd, J = 6.30, 1.53 Hz, 2 H), 6.80 (br d, J = 8.44 Hz, 1 H), 4.71 (quin, J = 7.55 Hz, 1 H), 4.43 (dd, J = 10.21, 160 2.75 Hz, 1 H), 3.33 (tt, J = 10.18, 7.73 Hz, 1 H ), 2.78 - 2.96 (m, 4 H), 2.68 - 2.77 (m, 2 H), 2.64 (s, 6 H), 2.39 - 2.48 (m, 1 H), 1.92 - 2.03 (m, 1 H) 1 H-NMR (400 MHz, CDCl3): δ 7.34 (t, J = 8.60 Hz, 1 H), 6.89 ( s, 1 H), 6.77 (dd, J = 10.14, 2.87 Hz, 1 H), 6.69 (ddd, J = 8.99, 2.81, 1.21 Hz, 1 H ), 4.53 - 4.63 207 (m, 1 H), 4.45 - 4.52 (m, 1 H), 4.41 (s, 2 H), 3.60 (t, J = 8.49 Hz, 1 H), 3.11 (dd, J = 8.49, 6.95 Hz, 1 H), 2.41 - 2.58 (m, 8 H ), 2.10 - 2.25 (m, 3 H)
[00573] [00573] The separation conditions for selected compounds were as follows.
[00574] [00574] Compounds 157 and 158 were separated by SFC under the following conditions: column: Chiralpak AD-3 150 mm x 4.6 mm, 3 µm; mobile phase: mobile phase: A for SFC CO2 and B for MeOH (0.05% IPA), Gradient: B in A from 10% to 40% in 6 minutes. Flow rate: 2.5 mL / min Wavelength: 220 nm System Return Pressure: 1500 psi.
[00575] [00575] Compounds 159 and 160 were separated by SFC under the following conditions: column: DAICEL Chiralpak AD-H (250 mm x 30 mm, 5 µm); mobile phase: A: CO2. B: 0.1% NH4OH in MeOH; gradient: B% at A: 25% -25%
[00576] [00576] Compounds 208 and 209 were separated by SFC under the following conditions: The residue was purified by reverse phase prep HPLC (Nano-micro Kromasil C18 100 mm x 30 mm, 5 µm; mobile phase: A: 0.1% TFA in water, B: MeCN, gradient: B% in A: 45% -65% over 10 min) and then by chiral SFC (Chiralpak IC-H 250 mm x 30 mm, 5 µm; mobile phase: A: CO2, B: 0.1% NH4OH in IPA, gradient: B% in A: 45% -45% over 6 min).
[00577] [00577] Compounds 217 and 218 were separated by SFC under the following conditions: The residue was purified by SFC (Chiralpak AD-H 250 mm x 30 mm, 5 m, 40 ° C; mobile phase: A: CO2 , B: 0.1% NH4OH in MeOH, gradient: B% in A: 35% -35% over 6 min, Flow: 70 g / min, Pressure 100 bar). BIOCHEMICAL EXAMPLE 1 Biochemical Assay of Compounds
[00578] [00578] Cellular stress leads to activation of the integrated stress response pathway through one of the four kinases of eukaryotic initiation factor 2 and interrupts the global translation, allowing the translation of transcripts selected as ATF4 (transcription factor activator 4) that are important for the response to cellular stress. During normal conditions, small open reading frames (ORFs) in the ATF4 5 'RTU occupy the ribosome and prevent the translation of the ATF4 coding sequence. However, during stressful conditions, the ribosome examines these ORFs upstream and preferably begins the translation in the ATF4 coding sequence. In this way, the translation and, therefore, the ATF4 protein level is a reading of the activation of the ISR pathway. Thus, a fusion of the uORFs and the beginning of the ATF coding sequence with a common cell reporter such as nanoluciferase allows a sensitive and high-performance reading of the activity of the ISR pathway.
[00579] [00579] The compounds as provided in this document have been tested in the following test. The ATF4 reporter Nano Luciferase was constructed by fusing the 5 'full-length human (5'-RTU) untranslated region and a small portion of the ATF4 gene coding sequence upstream of the Nano Luciferase (NLuc) coding sequence without its codon from start. Specifically, nucleotides +1 to +364 (relative to the transcription start site) of variant 2 of the ATF4 transcript (NCBI NM_182810.2) flanked 5 'by EcoRI and 3' by BamHI restriction enzyme sites were synthesized and cloned at the EcoRI / BamHI cloning sites of the pLVX-EF1a-IRES-Pure lentivirus vector (Clontech). The lentiviral particles were produced with single doses of Lenti-X (VSV-G, Clontech) according to the manufacturer's instructions and used to transduce a human neuroglioma cell line H4 (ATCC HTB-148). H4 cells were selected with 1.25 µg / mL of puromycin and clonal cell lines generated by limiting dilution. This cell line was used to generate an integrated stress response (ISR) assay to assess the activity of ISR pathway inhibitors via luminescence reading. The H4 ATF4-NLuc cell line (clone 17) is plated at a density of
[00580] [00580] In the table below, the activity of the tested compounds is provided in Table 4 as follows: +++ = IC50 <1 µM; ++ = IC50 1-10 µM; + = IC50> 10 µM.
[00581] [00581] Specific data for certain compounds are shown below in Table 5. Table 5 Ex. IC50 3 0.0092 6 0.0025 15 0.0171 49 0.0182 51 0.0137 61 0.0019 70 0.0028 81 0 .0118 133 0.0181 136 0.0220 139 0.0043 146 0.0037 148 0.0026 151 0.0355 152 0.0382 157 0.0092 161 0.0134 162 0.0149 163 0.0085 166 0.0081 167 0.0439 169 0.0038 179 0.1025 189 0.0285 236 0.0215 248 0.0282 254 0.0053 269 0.0075 270 0.0011 BIOLOGICAL EXAMPLE 2 Permeability MDCKII-MDR1
[00582] [00582] The blood-brain barrier (BBB) separates the circulating blood from the extracellular fluid of the central nervous system (CNS). The passive membrane permeability (Papp) and the efflux potential of the substrate P-gp (P-glycoprotein) were determined using the cell line MDCKII-MDR1 as a model of the effective in vitro permeability of a compound through BBB. A bidirectional (Apical to Basolateral (AB) and Basolateral to Apical (BA)) assay, in the absence and presence of GF120918 (a P-gp inhibitor) was conducted using pre-plated MDCKII-MDR1 cells (Corning HTS Transwell-96) obtained from SOLVO Biotechnology. The test was performed at 3 µM for 90 min (minutes) in triplicate using a HBSS + HEPES 12.5 mM pH 7.4 transport buffer. After incubating the donor and recipient samples, the wells were removed and measured by LC-MS / MS. The samples were extracted by protein precipitation with acetonitrile containing an appropriate internal standard (IS) having a known mass and molecular weight. The precipitate was centrifuged for 10 min at 3000 rpm (revolutions per minute). The supernatants were then collected, diluted, if necessary, and injected into the LC-MS / MS system. Specific ion / origin ion pairs for the test article and IS were used to selectively measure the test articles. Papp values (apparent permeability expressed in nm / s [nanometer / second]) were calculated according to the following equation:  dQ   1   1  Papp (nm / sec)    x  x   dt   C 0   A 
[00583] [00583] Where dQ / dt is the permeability rate, C0 is the initial concentration in the donor solution (expressed as IS ratio), A and B are the surface areas of the filter (the surface area of the cell monolayer).
[00584] [00584] Monolayer efflux ratios (ER) were derived using the following equation:  B  APapp (nm / sec)  efflux o   EffluxRati ratios   A  BPapp (nm / sec) 
[00585] [00585] It is likely that compounds with an efflux rate of MDCKII-MDR1 less than or equal to 2.5 demonstrate the ability to cross the blood-brain barrier.
[00586] [00586] It was found that the following compounds have an efflux ratio MDCKII-MDR1 less than or equal to 2.5: Example 3, Example 6, Example 49, Example 61, Example 70, Example 81, Example 133, Example 139, Example 146, Example 166, Example 169, Example 189, Example 236, Example 248, Example 254 and Example 270.
[00587] [00587] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by a person of common knowledge in the technique to which this invention belongs.
[00588] [00588] The inventions described illustratively in this document, can conveniently be practiced in the absence of any element or elements, limitations or limitations, not specifically disclosed in this document. Thus, for example, the terms "comprising", "including", "containing", etc. should be read expansively and without limitation. In addition, the terms and expressions used in this document have been used as terms of description and not of limitation, and there is no intention in using such terms and expressions to exclude any equivalents of the features shown and described, or parts of them, but it is recognized that several modifications are possible in the scope of the claimed invention.
[00589] [00589] All publications, patent applications, patents and other references mentioned in this document are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In the event of a conflict, this descriptive report, including definitions, will serve as a basis for control. It should be understood that, although the description has been described in conjunction with the above modalities, the description and the previous examples are intended to illustrate and not to limit the scope of the description. Other aspects, advantages and changes in the scope of the description will be evident to those skilled in the art to which the description belongs.

权利要求:
Claims (49)
[1]
1. Compound, characterized by the fact that it presents Formula I:
I or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, where: L is a heteroalkylene optionally substituted by one to six R10, or L is optionally substituted heterocyclyl or optionally substituted heteroaryl , provided that when L is optionally substituted heterocyclyl and bridged to the cycloalkyl bridged through a nitrogen atom in the ring, a carbon atom in L adjacent to the point of attachment will not be replaced by = O or = S; x is 1 or 2; z is 0 or 1, provided that when z is 0 and X1 is O, then R3 will not be alkyl; X1 is O, NR9 or a bond; R1 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl or heterocyclyl, each of which, except hydrogen, is optionally substituted by one or more halo, oxo, acetyl, amino, hydroxyl or C1-12 alkyl, or R1 and R5 together form a heterocyclyl ring; R2 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkoxy, heterocyclyl, aryl or heteroaryl, each of which, except hydrogen , is optionally substituted by one or more R11, provided that when L is a heteroalkyl, R2 will be C3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by one or more R11;
R3 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which, except hydrogen, is optionally substituted by one or more R11; each of R4 and R5 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, each of which, except hydrogen, is optionally independently substituted by one or more halo, oxo, acetyl, amino or hydroxyl; or R3 and R4, together with the atoms to which they are attached, come together to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R11; or R4 and R5, together with the atoms to which they are attached, come together to form a C3-10 cycloalkyl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more R11; each of R6, R7 and R8 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R20, -C (O) OR20, -C (O) NR20R21, -S (O) 1-2R20 or -S (O) 1-2NR20, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R6, R7 and R8 is optionally replaced with one or more R12; or two of R6, R7 and R8 are taken together with the atoms to which they are attached to form heterocyclyl optionally independently substituted by one or more halo, oxo or C1-12 alkyl optionally independently substituted by one or more oxo, halo, hydroxyl or amino; R9 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl or heterocyclyl, each of which, except hydrogen, is optionally substituted by one or more halo, oxo, acetyl, amino, hydroxyl or C1-12 alkyl;
each R10 is independently halo, C1-12 alkyl or C1-12 haloalkyl; y is 1, 2, 3, 4, 5, 6, 7 or 8; each R11 is independently halo, cyano, nitro, oxo, -OR6, -SR6, -SF5, -NR6R7, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R6, -C (O) OR6, - OC (O) OR6, -OC (O) R6, -C (O) NR6R7, -OC (O) NR6R7, -NR6C (O) NR7R8 , - S (O) 1-2R6, -S (O) 1-2NR6, -NR6S (O) 1-2R7, -NR6S (O) 1-2NR7R8, -NR6C (O) R7 or –NR6C (O) OR7 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R11 is optionally independently substituted by one or more R12; each R12 is independently halo, cyano, nitro, oxo, -OR30, -SR30, -SF5, -NR30R31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R30, -C (O) OR30, -OC (O) OR30, -OC (O) R30, - C (O) NR30R31, -OC (O) NR30R31, -NR30C (O) NR30R31, - S (O) 1-2R30, -S (O) 1- 30 2NR, -NR30S (O) 1-2R31, -NR30S (O) 1-2NR30R31, -NR30C (O) R31 or - NR30C (= O) OR31 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R12 is optionally substituted independently by one or more halo or C1-12 alkyl optionally independently substituted by one or more oxo, halo, hydroxyl or amino; each R20 and R21 is independently hydrogen or C1-12 alkyl optionally independently substituted by one or more oxo, halo, hydroxyl or amino; or R20 and R21 are taken together with the atoms to which they are attached to form heterocyclyl optionally independently substituted by one or more halo or C1-12 alkyl optionally independently substituted by one or more oxo, halo, hydroxyl or amino; and each R30 and R31 is independently hydrogen or C1-12 alkyl optionally independently substituted by one or more oxo, halo, hydroxyl or amino; or R30 and R31 are taken together with the atoms to which they are attached to form heterocyclyl optionally independently substituted by one or more halo or C1-12 alkyl optionally independently substituted by one or more oxo, halo, hydroxyl or amino.
[2]
2. Compound according to claim 1, characterized by the fact that z is 0 and X1 is a bond.
[3]
3. Compound according to claim 1, characterized by the fact that the compound is represented by Formula II: A R2
(R 10) y X1 R3 N x 4 5 RR R1 II or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, in which ring A is optionally substituted or heteroaryl heterocyclyl optionally substituted, provided that when ring A is optionally substituted heterocyclyl and bridged to the cycloalkyl bridged through a ring nitrogen atom, a carbon atom in ring A adjacent to the attachment point will not be replaced by = O or = S .
[4]
4. Compound according to claim 1 or 3, characterized by the fact that X1 is O.
[5]
5. Compound according to any one of the preceding claims, characterized by the fact that x is 1.
[6]
6. A compound according to any one of the preceding claims, characterized by the fact that L or ring A is an optionally substituted heteroaryl ring.
[7]
7. A compound according to any one of the preceding claims, characterized by the fact that L or ring A is an optionally substituted five-membered heteroaryl C2-4 ring.
[8]
8. A compound according to any one of the preceding claims, characterized by the fact that L or ring A is an optionally substituted five-membered heteroaryl C2-4 ring having 1 to 3 atoms in the nitrogen ring and optionally 1 or 2 atoms of oxygen and / or sulfur.
[9]
Compound according to any one of the preceding claims, characterized by the fact that L or ring A is an optionally substituted triazole, oxazole, imidazole, oxadiazole, benzoxazole, pyrazole, triazole, thiadiazole, tetrazole or isoxazole.
[10]
10. Compound according to any one of claims 1 to 5, characterized in that L or ring A is an optionally substituted heterocyclyl ring.
[11]
A compound according to any one of claims 1 to 5, characterized by the fact that L or ring A is an optionally substituted five-membered C2-4 heterocyclyl.
[12]
12. A compound according to any one of claims 1 to 5, characterized by the fact that L or ring A is an optionally substituted five-membered C2-4 heterocyclyl ring having 1 to 3 atoms in the nitrogen ring and optionally 1 or 2 oxygen and / or sulfur atoms.
[13]
13. A compound according to any one of claims 1 to 5, characterized in that the L or ring A is an optionally substituted pyrrolidine, imidazolidine, dihydropyrrole, oxathiazolidine, dihydroisoxazole or oxazolidine.
[14]
14. Compound according to any one of claims 3 to 13, characterized by the fact that ring A can still be replaced by one to five R13, in which R13 is independently selected from halo, cyan, oxo, thioxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy.
[15]
15. A compound according to any one of claims 3 to 13, characterized by the fact that ring A is not yet replaced and R2 is C3-10 cycloalkyl optionally substituted by one or more R11.
[16]
16. A compound according to any one of the preceding claims, characterized by the fact that R2 is hydrogen or halo.
[17]
17. A compound according to any one of the preceding claims, characterized by the fact that R2 is C1-12 alkyl, C1-12 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkoxy, heterocyclyl or aryl, each of which is optionally replaced by one to six R11.
[18]
18. A compound according to any one of the preceding claims, characterized by the fact that R2 is C3-10 cycloalkyl optionally substituted by one or more R11.
[19]
19. A compound according to any one of the preceding claims, characterized by the fact that R2 is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, methyl, ethyl, propyl, methoxy or cyclobutoxy, each of which is optionally replaced by one to six R11.
[20]
20. Compound according to claim 19, characterized by the fact that R2 is replaced by at least one R11.
[21]
21. Compound according to any one of the preceding claims, characterized by the fact that R11 is hydroxyl, halo (C1-6 alkoxy), halo, cycloalkyl, cycloalkoxy, phenyl, C1-6 alkoxycarbonyl, cyano, halo (C1-6 alkyl), halo (C1-6 alkoxy) cycloalkoxy, halo (C1-6 alkoxy) alkyl, halo (heterocyclyl) or halophenoxy.
[22]
22. A compound according to claim 3, characterized by the fact that R2 is (4-chloro-3-fluoro-phenoxy) methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl , 2,2-difluorocyclopropyl, 3- (difluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) cyclobutoxymethyl, 3- (trifluoromethoxy) cyclobutyl, 3- (trifluoromethoxy) propyl, 3- (trifluoromethyl) cyclobutyl, 3-cyanocyclobutyl, 3-cyanocyclobutyl, 3,3-difluoro-1-methyl-propyl, 4-chloro-3-fluoro-phenyl, phenyl, 3- (trifluoromethyl) phenyl, 2-hydroxymethyl-4- (trifluoromethyl) phenyl, 2-fluoro-4- (trifluoromethyl) phenyl, 3-fluoro-4- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 2,4-difluorophenyl, 4-chloro-2,6-difluorophenyl, 4-chloro-2,3-di - fluorophenyl, 4-chloro-2,5-difluorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-2-methyl-phenyl , 4-fluoro-3-methylphenyl, 4-chloro-2-fluoro-phenyl, 5- (trifluoromethyl) -2-pyridyl, 6- (trifluoromethyl) -2-pyridyl, 2- (trifluoromethyl) pyrimidin-5-yl a, 5-fluoropyridin-3-yl, 1,2,3-triazol-2-yl) cyclobut-3-yl, 1,2,3-triazol-2-yl) cyclobut-1-yl, 2- hydroxy-4- (trifluoromethyl) phenyl, 2-cyano-4- (trifluoromethyl) phenyl, 2,2-difluorobenzo [d] [1,3] dioxol-5-yl, 3 - (((tert-butyldimethylsilyl) oxy) cyclobutyl , 5- (trifluoromethyl) -4,5-dihydrooxazol-2-yl, 2-methoxycarbonyl-4- (trifluoromethyl) phenyl, 2- (trifluoromethoxy) ethoxy, 4-chlorophenyl, benzyl, 2-cyanocyclobutyl, 2 -hydroxycyclobutyl, cyclobutoxymethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopropyl, cyclopropylethyl, cyclopropylmethyl, hydroxycyclobutyl, methyl, N-tert-butoxy (carbonyl) azetidin-3-yl, N-tert-butyl-pyrrolidinyl-pyrrolidone -3-yl, tetrahydrofuranyl, trifluoroethyl, trifluoromethoxy, (trifluoromethoxy) cyclobutoxy, trifluoromethoxyethyl, trifluoromethoxymethyl, 3- (1,1-di-fluoroethyl) cyclobutyl, 3- (1,1,1-trifluoroethyl) azetid, 3- (triazol-2-yl) cyclo-butyl, 3- (trifluoromethylthio) cyclobutyl, 3- (cyclopropyl) cyclobutyl, (3,3-difluo-roazetidin-1-yl) methyl, (3 3-difluoropyrrolidin-1-yl) methyl, 1- (2,2,2-trifluoro-1-methyl-ethyl) azetidin-3-yl, 1- (2,2,2-trifluoroethyl) azetidin-3-yl, 1- (2,2,2-trifluoroethyl) pyrazol-3-yl, 1- (2,2,2-trifluoroethyl) pyrazol-4-yl, 1- (2,2-difluoroethyl) azetidin-3 -yl, 1-tert-butoxycarbonyl-2-methylazetidin-3-yl, 2- (4-chloro-
3-fluoro-phenyl, 2- (difluoromethyl) cyclopropyl, 2- (trifluoromethoxymethyl) cyclopropyl, 2,2-difluoro-1,1-dimethyl-ethyl, 2-methyl-1- (2,2,2-trifluoroethyl ) azetidin-3-yl, 3- (trifluoromethoxymethyl) cyclobutyl, 3- (trifluoromethyl) azetidin-1-yl, 3-fluoro-1- (2,2,2-trifluoroethyl) azetidin-3-yl, 4- (2,2,2-trifluoroethyl) morpholin-2-yl, 4-tert-butoxycarbonyl-morpholin-2-yl, 5- (trifluoromethoxymethyl) tetrahydrofuran-2-yl, 2 - ((trifluoromethoxy) methyl) cyclopropyl or 5-fluoro-3-pyridyl.
[23]
23. Compound according to claim 3, characterized by the fact that the fraction is (4-chloro-3-fluoro-phenoxy) methyl] -1,3,4-oxadiazol-2-yl, 1 - (3-cyanocyclobutyl) triazol-4-yl, 1- (3-hydroxycyclobutyl) triazol-4-yl, 1- (4-chlorophenyl) triazol-4-yl, 1-benzyltriazole-4-yl, 1- cyclobutyltriazole-4-yl, 1H-1,2,3-triazol-4-yl, 2- (3-cyanocyclobutyl) triazol-4-yl, 2- (trifluoromethoxy) ethyl] -1,3,4-oxadiazole -2-yl, 2-cyclobutyltriazol-4-yl, 3 - [(trifluoromethoxy) cyclobutoxy] -imidazol-1-yl, 3-cyanocyclobutyl) triazol-4-yl, 3-cyclobutyloxyol-5-yl, 4- (cyclobutylmethyl) ) imidazol-1-yl, 4- [3- (trifluoromethoxy) cyclobutyl] imidazol-1-yl, 4-cyclobutylimidazol-1-yl, 4-cyclobutyloxazol-2-yl, 5 - ((4-chlorine -3-fluorophenoxy) methyl) -4H-1,2,4-triazol-3-yl, 5- (1-fluorocyclopropyl) -1,3,4-oxadiazol-2-yl, 5- (2-cyclopropylethyl) - 1,3,4-oxadazole-2-yl, 5- (2,2-difluorocyclopropyl) -1,3,4-oxadiazole-2-yl, 5- (2,2,2-trifluoro-ethyl) - 1,3,4-oxadiazol-2-yl, 5- (3-cyanocyclobutyl) -1,3,4-oxadiazol-2-yl, 5- (3 , 3-difluoro-1-methyl-propyl) -1,3,4-oxadiazol-2-yl, 5- (4-chloro-3-fluoro-phenyl) -1,3,4-oxadiazol-2-yl, 5- (cyclobutoxymethyl) -1,3,4-oxadiazol-2-yl, 5- (cyclobutylmethyl) -1,3,4-oxadiazol-2-yl, 5- (cyclopropylmethyl) -1,3,4-oxadi- azol-2-yl, 5- (trifluoromethoxymethyl) -1,3,4-oxadiazol-2-yl, 5 - [(4-chloro-3-fluoro-phenoxy) methyl] -1,3,4-oxadiazole -2-yl, 5 - [[3- (trifluoromethoxy) cyclobutoxy] methyl] -1,3,4-oxadiazol-2-yl, 5- [2-methylcyclopropyl] -1,3,4-oxadiazole-2 - ila, 5- [3- (trifluoromethoxy) cyclobutyl] -1,3,4-oxadiazol-2-yl, 5- [3- (trifluoro-methoxy) propyl] -1,3,4-oxadiazol-2-yl , 5- [3- (trifluoromethyl) cyclobutyl] -1,3,4-oxadiazol-2-yl, 5- [N- (1,1,1-trifluoroethyl) azetidin-3-yl] -1,3,4 -oxadiazole-2-
ila, 5- [N- (1,1,1-trifluoroethyl) pyrrolidin-3-yl] -1,3,4-oxadiazol-2-yl, 5- [N-tert-butoxy (carbonyl) azetidin-3- yl] -1,3,4-oxadiazol-2-yl, 5- [N-tert-butoxy (carbonyl) pyrrolidin-3-yl] -1,3,4-oxadiazol-2-yl, 5-cyclobutyl -1,3,4-oxadiazol-2-yl, 5-cyclobutyl-4,5-dihydroisoxazol-3-yl, 5-cyclobutyloxyol-3-yl, 5-cyclobutyloxazol-2-yl, 5-cyclopentyl-4 , 5-dihydroisoxazol-3-yl or oxazolidin-2-one-5-yl.
[24]
24. A compound according to any one of the preceding claims, characterized by the fact that R3 is C1-12 alkyl, which is optionally substituted by one or more R11.
[25]
25. A compound according to any one of the preceding claims, characterized by the fact that R3 is C3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by one or more R11.
[26]
26. A compound according to any one of the preceding claims, characterized by the fact that R3 is C3-10 cycloalkyl, aryl or heteroaryl, each of which is optionally substituted by one or more R11.
[27]
27. A compound according to any one of the preceding claims, characterized by the fact that R3 is cyclobutyl, triazolyl or phenyl, each of which is optionally substituted by one or more R11.
[28]
28. Compound according to any one of the preceding claims, characterized by the fact that R3 is optionally substituted phenyl.
[29]
29. A compound according to claim 28, characterized by the fact that R3 is phenyl optionally substituted by one or more substituents independently selected from halo, cyano, C1-12 alkyl optionally substituted by one or more halo and C1-12 alkoxy optionally substituted by one or more halo.
[30]
30. A compound according to any one of the preceding claims, characterized by the fact that R3 is phenyl substituted by chlorine, fluoro or a combination thereof.
[31]
31. Compound according to any one of the preceding claims, characterized by the fact that R3 is 3,4-difluorophenyl, 2- (trifluoromethyl) pyridin-5-yl, 4- (trifluoromethyl) phenyl, 2- (4 -fluoro-1H-pyrazol-1-yl) ethyl, 2- (trifluoromethoxy) ethyl, 1- (2,2,2-trifluoroethyl) piperidin-4-yl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl , 6-chlorochroman-2-yl, 6-fluoro-rochroman-2-yl, 5-chlorobenzo [d] oxazol-2-yl, 6- (trifluoromethyl) quinolin-2-yl, 3-chloroquinolin-7-yl, 7-chloroquinolin-3-yl, 6-chloroquinolin-2-yl, 7-fluoroimidazo [1,2-a] pyridin-2-yl, 6-fluoropyrazolo [1,5-a] pyridin-2-yl, 3- (2H-1,2,3-triazol-2-yl) cyclobutyl, 3- (trifluoromethoxy) phenyl, 5-chloro-benzo [d] thiazol-2-yl, 7-chloro- [1,2,4] triazole [1,5-a] pyridin-2-yl, 7-chloroimidium [1,2-b] pyridazin-2-yl, 5-fluorobenzo [d] oxazol-2-yl, 7-bromoimide [1 , 2-a] pyridin-2-yl, 6-fluoroimidazo [1,2-a] pyridin-2-yl, 7-chloropyrrolo [1,2-c] pyrimidin-3-yl, 7-chloroisoquinolin-3 -ila, 7-chlorocinnolin-3-yl, 7-bromoisoquinolin-3-yl, 7 - (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl, 6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl, quinolin-2-yl, quinoxalin-2-yl , 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, quinazolin-2-yl, 6-chloro-benzo [d] thiazol-2-yl, 5-bromobenzo [d] oxazol-2-yl, 7 -chloro-6-fluoroimidium [1,2-a] pyridin-2-yl, 6-chloroquinazolin-2-yl, 6-chloro-7-fluoroquinolin-2-yl, 5- (trifluoromethyl) pyridin-2- ila, 1- (2- (trifluoromethoxy) ethyl) -1H-pyrazol-3-yl, 3- (trifluoromethoxy) cyclobutylmethyl, 3- (2- (trifluoromethoxy) ethoxy) cyclo-butyl, 4 - ((trifluoromethoxy) methyl) cyclohexanil, 1- (2,2,2-trifluoroethyl) azetidinyl, 3-ethoxycyclobutanyl, 3-cyanocyclobutyl, 2- (4-chlorophenyl) -1-hydroxyethyl, 4-chloro-3- (hydroxymethyl) phenyl, 2- (4-chlorophenyl) -2-hydroxyethyl, 3- (4-fluoro-1H-pyrazol-1-yl) cyclobutyl, 1- (trifluoromethoxy) propan-2-yl, 6-chloro-3,4- dihydroisoquinolin-2 (1H) -yl, 2- (trifluoromethoxy) propyl, 1- (2- (trifluoro-methoxy) ethyl) -1H-imidazol-4-yl, 4-chloro-3-fluorophenyl or trifluoromethoxy-clobut-2 -ila.
[32]
32. Compound according to any one of the preceding claims, characterized by the fact that R4 and R5 are H.
[33]
33. A compound according to any one of the preceding claims, characterized by the fact that R4 and R5 are each independently H, alkyl optionally substituted by hydroxy.
[34]
34. Compound according to any one of the preceding claims, characterized by the fact that R1 is H.
[35]
35. Compound or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers or prodrug thereof, characterized by the fact that they are selected from Table 1.
[36]
36. Compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, characterized by the fact that they are selected from Table 2.
[37]
37. Pharmaceutical composition characterized by the fact that it comprises a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier.
[38]
38. Method for treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B, characterized by the fact that it comprises administering an effective amount of the pharmaceutical composition as defined in claim 37 to a subject in need her.
[39]
39. Method according to claim 38, characterized by the fact that the disease or condition is a neurodegenerative disease.
[40]
40. Method, according to claim 39, characterized by the fact that the disease is Alexander disease, Alper disease,
Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasis, Batten's disease (also known as Spielmeyer-Vogt-Sjogren-Batten's disease), bovine spongiform encephalopathy (BSE), Canavan's disease, Cockayne syndrome, corticobasal degeneration , Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, dementia with Lewy corpuscles, Machado's disease -Joseph (pinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Peliza-Merzbacher's disease, Pick's disease, primary lateral sclerosis, Prion's disease, Refsum's disease , Sandhoffs disease, Schilder disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with varying characteristics), muscular atrophy and s pine forest, Steele-Richardson-Olszewski's disease, insulin resistance or Tabes dorsalis.
[41]
41. Method according to claim 40, characterized by the fact that the neurodegenerative disease is Alzheimer's disease, ALS, Parkinson's disease or dementia.
[42]
42. Method for improving cognitive memory, characterized by the fact that it comprises the administration of an effective amount of the pharmaceutical composition as defined in claim 37 to a subject who needs it.
[43]
43. A compound according to any one of claims 1 to 36, characterized in that it is for use in therapy.
[44]
44. A compound according to any one of claims 1 to 36, characterized in that it is for use in the treatment of a neurodegenerative disease.
[45]
45. A compound according to claim 44, characterized
due to the fact that the disease is Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten's disease (also known as Spi- elmeyer-Vogt-Sjogren-Batten disease) , bovine spongiform encephalopathy (BSE), Canavan's disease, Cockayne's syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia , Kennedy's disease, Krabbe's disease, kuru, dementia with Lewy corpuscles, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, disease Pelizaeus-Merzbacher's disease, Pick's disease, primary lateral sclerosis, Prion's disease, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined degeneration of the secondary spinal cord of pernicious anemia, schizophrenia, ataxia and pinocerebellar (various types with varied characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski's disease, insulin resistance or Tabes dorsalis.
[46]
46. A compound according to any one of claims 1 to 36, characterized in that it is for use in the treatment of Alzheimer's disease, ALS, Parkinson's disease or dementia.
[47]
47. Use of a compound according to any one of claims 1 to 36, characterized in that it is for the manufacture of a medicament for the treatment of a neurodegenerative disease.
[48]
48. Use according to claim 47, characterized by the fact that the disease is Alexander disease, Alper disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasis, Batten's disease (also known as Spielmeyer disease -
Vogt-Sjogren-Batten), bovine spongiform encephalopathy (BSE), Canavan's disease, Cockayne's syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, dementia - associated with HIV, Kennedy's disease, Krabbe's disease, kuru, dementia with Lewy bodies, Machado-Joseph disease (pinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, disease Parkinson's disease, Pellizaeus-Merzbacher's disease, Pick's disease, primary lateral sclerosis, Prion's disease, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined spinal cord degeneration of pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski's disease, insulin resistance or Tabes dorsalis.
[49]
49. Use of a compound according to any one of claims 1 to 36, characterized in that it is for the manufacture of a medicament to treat Alzheimer's disease, ALS, Parkinson's disease or dementia.

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法律状态:
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优先权:

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