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WO2025096660A1 - Compositions et inhibiteurs de polrmt - Google Patents

Compositions et inhibiteurs de polrmt Download PDF

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Publication number
WO2025096660A1
WO2025096660A1 PCT/US2024/053724 US2024053724W WO2025096660A1 WO 2025096660 A1 WO2025096660 A1 WO 2025096660A1 US 2024053724 W US2024053724 W US 2024053724W WO 2025096660 A1 WO2025096660 A1 WO 2025096660A1
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compound
pharmaceutically acceptable
acceptable salt
cyclopropyl
mmol
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Andrew Griffin
Simon Giroux
Paul Charifson
Jeremy Green
Andrew Mckenzie
Gabriel Martinez Botella
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Pretzel Therapeutics Inc
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Pretzel Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present disclosure relates to POLRMT modulators, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof.
  • the present disclosure also relates to novel oxadiazole compositions, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof.
  • the present disclosure also relates to methods of making the modulator compounds and/or oxadiazole compositions.
  • the present disclosure further relates to methods of using such compounds and compositions, including to inhibit or promote POLRMT.
  • POLRMT Human mitochondrial RNA polymerase
  • CTD C- terminal polymerase domain
  • NTD N-terminal domain
  • NTE N- terminal extension
  • POLRMT biochemistry While aspects of POLRMT biochemistry are known, its full physiological role in mitochondrial gene expression and homeostasis, as well as its underlying impact in the etiology of various disease states, remains unclear. Its dysfunction and/or deregulation impacts mitochondrial metabolism, sometimes through the OXPHOS system, which ultimately contributes to many metabolic, degenerative and age-related diseases such as cancer, diabetes, obesity, and Alzheimer's disease. Pharmacological inhibition of POLRMT is one means by which to gain a further understanding of the role of this polymerase in cell physiology and the development of disease. Regulation of metabolic mechanisms, including oxidative phosphorylation, with POLRMT modulators affords an opportunity for intervention in complex disorders.
  • the present disclosure is directed to compounds, pharmaceutically acceptable salts of the compounds, and methods of using the compounds, salts of the compounds to treat various neurodegenerative and metabolic disorders, cancer, and also disorders related to aging and mitochondrial diseases.
  • the present disclosure provides a compound, which, according to an embodiment of the present disclosure is a compound represented by Formula (I), [0007]
  • X 1 -X 5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , - C(O)NHY 1 , -C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1 OY 2 .
  • Y 1 and Y 2 are each independently a C 1 -C 6 alkyl optionally substituted with one or more halogen or hydroxy.
  • X6-X8 are each independently a C, N, S, or O.
  • R 3 is a halogen, a hydrogen, a C 1 -C 6 alkyl, a C 1 -C 6 alkyl substituted with one or more halogen, or a C 3 -C 6 cycloalkyl.
  • R 4 is a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkyl substituted with one or more halogen.
  • R 3 and R 4 are optionally interconnected they form a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, 5-membered heterocyclic ring, a substituted 5- membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.
  • A1 and A2 are each independently a hydrogen, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, an aryl, substituted aryl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C3-C6 heterocyclyl, substituted C 3 -C 6 heterocyclyl, or absent.
  • A1 and A2 may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH 2 , -CS(O) 2 Y 3 , a -CY 1 S(O) 2 Y 3 .
  • Y 3 is independently hydrogen or C 1 -C 4 alkyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, C 1 -C 4 haloalkoxyl, and C 1 -C 4 alkoxyl.
  • Some aspects of the present disclosure include compounds described above, wherein the compound has a POLRMT IC 50 of 200 nM or less. [0017] Some aspects of the present disclosure include a pharmaceutical composition comprising a compound according to any of the previous claims. [0018] Some aspects of the present disclosure are directed towards a method of inhibiting the activity of POLRMT comprising administering a compound of any of the previous claims to a subject in need thereof. [0019] Other aspects and iterations of the present disclosure are detailed below. DETAILED DESCRIPTION OF THE INVENTION [0020] Modulators of POLRMT are useful in compositions and methods suitable for treating many disorders, such as cancer, neurodegenerative disorders, metabolic disorders, as well as diseases related to aging and mitochondrial diseases.
  • novel compositions their pharmaceutically acceptable salts, and pharmaceutical compositions thereof.
  • compounds of Formulae (I), (IIa), (IIa-2), (IIb-1), (IIb-2)a, (IIc), (IIc-1), (IIc-2a), (IIc-2b), (IId), (IIe), (IIf), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (Va), (Va-1), (Vb), and (Vb-1) pharmaceutically acceptable salts thereof, prodrugs thereof, and pharmaceutical compositions comprising such compounds, their salts, or their prodrugs that are useful as inhibitors of POLRMT.
  • alkyl refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in a specified range.
  • C 1 -C 6 alkyl means linear or branched chain alkyl groups, including all possible isomers, having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl groups allow for substituents to be located on any of the carbon atoms.
  • a substituted C 3 alkyl group allows for the substituent to be located on any of the three carbon atoms.
  • alkoxy or “alkoxyl” as used herein refers to an -O-alkyl group.
  • C 1 -C 4 alkoxyl means -O- C 1 -C 4 alkyl.
  • alkoxyl include methoxyl, ethoxyl, propoxyl (e.g., n-propoxyl and isopropoxyl), and the like.
  • haloalkoxy or “haloalkoxyl” as used herein refers to an -O-alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced with a halogen atom.
  • haloalkoxyl examples include trifluoromethoxyl, 2,2,2-trifluoroethoxyl, and the like.0027
  • alkanoyl or “acyl” as used herein refers to an -C(O)-alkyl group.
  • C 1 -C 6 alkanoyl means -C(O)-C 1 -C 6 alkyl.
  • alkanoyl include acetyl, propionyl, butyryl, and the like.
  • bicyclic refers to a saturated or unsaturated 6- to 12- membered ring consisting of two joined cyclic substructures, and includes fused, bridged, and spiro bicyclic rings.
  • heterocyclic refers to a bicyclic ring that contains 1 or more heteroatom(s) in one or more rings that are optionally substituted or oxidized, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • heterobicyclic rings include, but are not limited to, 8-azabicyclo[3.2.1]octan-8- yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3- azabicyclo[3.2.1]octan-3-yl, and 5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl.
  • cycloalkyl refers to a cyclized alkyl ring having the indicated number of carbon atoms in a specified range.
  • C 3 -C 6 cycloalkyl encompasses each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to a monocyclic or fused bicyclic ring system having the characteristics of aromaticity, wherein at least one ring contains a completely conjugated pi-electron system.
  • aryl groups contain 6 to 14 carbon atoms (“C 6 - C 14 aryl”) or preferably, 6 to 12 carbon atoms (“C 6 -C 12 aryl”).
  • Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring.
  • the point of attachment to the base molecule on such fused aryl ring systems may be a C atom of the aromatic portion or a C or N atom of the non-aromatic portion of the ring system.
  • Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, indanyl, indenyl, and tetrahydronaphthyl.
  • cycloaryl herein refers to a polycyclic group wherein an aryl group is fused to a 5- or 6-membered aliphatic or heterocyclic ring.
  • C 6 -C 12 cycloaryl means a C 6 - C 12 aryl fused to a 5- or 6-membered aliphatic or heterocyclic ring.
  • C 6 cycloaryl is 2,3-dihydrobenzo[b][1,4]dioxine.
  • heteroaryl refers to (i) a 5- or 6-membered ring having the characteristics of aromaticity containing at least one heteroatom selected from N, O and S, wherein each N is optionally in the form of an oxide, and (ii) a 9- or 10- membered bicyclic fused ring system, wherein the fused ring system of (ii) contains at least one heteroatom independently selected from N, O and S, wherein each ring in the fused ring system contains zero, one or more than one heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O) 2 .
  • heteroaryl groups typically contain 5 to 14 ring atoms (“5-14 membered heteroaryl”), and preferably 5 to 12 ring atoms (“5-12 membered heteroaryl”).
  • Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring, such that aromaticity is maintained.
  • Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, 3-fluroropyridyl, 4-fluoropyridyl, 3- methoxypyridyl, 4-methoxypyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl or 1,2,4- triazolyl), tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl (i.e., the 1,2,3-, 1,2,4-, 1,2,5- (furazanyl), or 1,3,4- isomer), oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • pyridyl
  • Suitable 9- and 10-membered heterobicyclic, fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, chromenyl, quinolinyl, isoquinolinyl, benzopiperidinyl, benzofuranyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, indazolyl, indolinyl, and isoindolinyl.
  • heteroaryloxy refers to an -O- heteroaryl group.0035
  • heterocycle refers to a stable 3- to 10-membered monocyclic, non-aromatic ring that is either saturated or unsaturated, and that consists of carbon atoms and from one to two heteroatoms selected from the group consisting of N, O, and S.
  • Examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, and oxazepanyl.
  • oxo refers to a group which consists of oxygen which is double bonded to carbon or any other element.
  • the term “imine” as used herein refers to a group containing a carbon-nitrogen double bond.
  • deuterium refers to an isotope of hydrogen that has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen. Deuterium herein is represented by the symbol “D”.
  • deuterated by itself or used to modify a compound or group as used herein refers to the presence of at least one deuterium atom attached to carbon.
  • deuterated compound refers to a compound which contains one or more carbon-bound deuterium(s).
  • a deuterated compound of the present invention when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015 %.
  • the term “undeuterated” or “non-deuterated” as used herein refers to the ratio of deuterium atoms of which is not more than the natural isotopic deuterium content, which is about 0.015 %; in other words, all hydrogen are present at their natural isotopic percentages. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • isotopic enrichment factor refers to the ratio between the isotope abundance and the natural abundance of a specified isotope.
  • isotopologue refers to a species in which the chemical structure differs from a specific compound of the invention only in the isotopic composition thereof.
  • substantially free of other stereoisomers means less than 10 % of other stereoisomers, preferably less than 5 % of other stereoisomers, more preferably less than 2 % of other stereoisomers and most preferably less than 1 % of other stereoisomers are present.
  • salt refers to a salt that is not biologically or otherwise undesirable (e.g., not toxic or otherwise harmful).
  • a salt of a compound of the invention is formed between an acid and a basic group of the compound, or a base and an acidic group of the compound.
  • the invention when the compounds of the invention contain at least one basic group (i.e., groups that may be protonated), the invention includes the compounds in the form of their acid addition salts with organic or inorganic acids such as, for example, but not limited to salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, citric acid, glutamic acid, lactic acid, and methanesulfonic acid.
  • organic or inorganic acids such as, for example, but not limited to salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, citric acid, glutamic acid, lactic acid, and methanesulfonic acid.
  • the invention when compounds of the invention contain one or more acidic groups (e.g., a carboxylic acid), the invention includes the pharmaceutically acceptable salts of the compounds formed with but not limited to
  • salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Additional examples of such salts may be found in Stahl, P. H. et al. Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, Wiley, 2011. [0042]
  • the term “prodrug” as used herein refers to derivatives of compounds of the invention which may have reduced pharmacological activity, but can, when administered to a patient, be converted into the inventive compounds.
  • prodrugs Design and use of prodrugs may be found in “Pro- drugs as Novel Delivery Systems,” Vol.14, ACS Symposium Series (T Higuchi and W Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.
  • treatment include their generally accepted meanings, i.e., the management and care of a patient for the purpose of preventing, reducing the risk in incurring or developing a given condition or disease, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, delaying, or reversing the progression or severity, and holding in check existing characteristics of a disease, disorder, or pathological condition, including the alleviation or relief of symptoms or complications, or the cure or elimination of the disease, disorder, or condition.
  • terapéuticaally effective amount refers to that amount of compound of the invention that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
  • a therapeutically effective amount of the compounds of the invention will vary and will depend on the diseases treated, the severity of the disease, the route of administration, and the gender, age, and general health condition of the subject to whom the compound is being administered.
  • the therapeutically effective amount may be administered as a single dose once a day, or as split doses administered multiple (e.g., two, three or four) times a day.
  • the therapeutically effective amount may also be administered through continuous dosing, such as through infusion or with an implant.
  • X 1 -X 5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1 OY 2 , wherein Y 1 and Y 2 are each independently a C 1 -C 6 alkyl optionally substituted with one or more halogen or hydroxy.
  • R3 and R4 may optionally be interconnected to form a C 3 -C 6 cycloalkyl, a substituted C3-C6 cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.
  • A1 and A2 are each independently be one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH 2 , -CS(O) 2 Y 3 , a - CY 1 S(O) 2 Y 3 , wherein Y 3 may be independently a hydrogen or a C 1 -C 4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C 1 -C 4 haloalkoxyl, and a C 1 -C 4 alkoxyl.
  • a 1 and A 2 may each independently be -C(O)NY 3 Y 4 , -CY1(O)NY 3 Y 4 , or - NY 3 Y 4 .
  • Y 3 is independently a hydrogen or a C 1 -C 4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C 1 -C 4 haloalkoxyl, and a C 1 -C 4 alkoxyl.
  • Y 4 is independently Y 3 , cyano, C 3 -C 6 cycloheteroalkyl, C 1 -C 6 amide, C 1 -C 6 amine, C 1 -C 6 carboxyl, aryl, C 1 -C 6 alkyl optionally substituted with one or more halogen groups, 5- or 6-membered heterocyclyl, or C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxy, or -C(O)C 1 -C 4 alkyl optionally substituted with one or more halogen groups.
  • Y 3 and Y 4 are attached to the same nitrogen atom, Y 3 and Y 4 together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing one or more heteroatoms that is N, O, S, S(O), SO 2 , or S(O)NY 3 , and such heterocyclic ring is optionally substituted with one or more groups, each group independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, C 1 -C 4 haloalkoxyl, carboxyl, oxo, and C1-C4 ⁇ alkylcarboxylate.
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1 OY 2 , wherein
  • R 3 may be a halogen, a hydrogen, a C 1 -C 6 alkyl, a C 1 -C 6 alkyl substituted with one or more halogen, or a C 3 -C 6 cycloalkyl.
  • R4 may be a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkyl substituted with one or more halogen.
  • R 3 and R 4 may optionally be interconnected to form a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.
  • R 10 -R 15 may each independently be a hydrogen, an alkoxy, a halogen, a C 1 -C 6 alkyl, or a carboxylic acid.
  • X 1 may be a C 1 -C 6 alkyl or a halogen.
  • X 2 may be a hydrogen or a halogen.
  • X 3 may be a hydrogen, a halogen, or a C 1 -C 6 alkyl.
  • X 4 may be hydrogen.
  • X 5 may be a hydrogen or a C 1 -C 6 alkyl.
  • at least two of X 2 - X 5 are hydrogen.
  • at least three of X 2 - X 5 are hydrogen.
  • X 2 - X 5 may be hydrogen.
  • X 1 may be methyl or Cl.
  • X 2 may be Cl or hydrogen and X 3 may be methyl, F, Cl, or hydrogen.
  • R 3 may be a hydrogen, a methyl or -CHF 2 .
  • R 4 may be hydrogen.
  • R 10 -R 15 may each independently be a hydrogen, a methyl, a methoxy, a halogen, a carboxylic acid, or an amide.
  • R 3 may be -CHF 2 , methyl, or hydrogen, and R 4 is hydrogen.
  • the X 1 may be halogen or methyl and R 3 may be methyl, -CHF 2 , or - CF 3 .
  • the X 2 may be hydrogen or halogen and R 3 may be methyl, -CHF 2 , or -CF 3 .
  • the X 3 may be hydrogen or halogen and R 3 may be methyl, -CHF 2 , or -CF 3 .
  • X 1 -X 3 may each be independently hydrogen, halogen, or methyl, and R 3 may be methyl, -CHF 2 , or -CF 3 .
  • X 1 -X 3 may each be independently hydrogen, halogen, or methyl, and R 3 -R 4 are independently hydrogen, methyl, -CHF 2 , or -CF 3 .
  • at least one of R 10 -R 15 is carboxylic acid.
  • R 10 -R 11 is carboxylic acid
  • at least one of R 12 -R 13 is carboxylic acid
  • at least one of R 14 -R 15 is carboxylic acid.
  • R 12 -R 13 may each independently be hydrogen, fluorine, methyl, methoxy, or carboxylic acid.
  • R 10 -R 11 and R 14 -R 15 may be hydrogen and the compound may be represented by Formula (IIa-2): [0084] In some embodiments of Formula (IIa-2), X 1 -X 5 may each independently be hydrogen, halogen, or C 1 -C 6 alkyl.
  • R 3 may be halogen, hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl.
  • R4 may be hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl.
  • R 12 and R 13 are each independently a C 1 -C 6 alkyl, a hydrogen, a halogen, a carboxylic acid, an alkoxy, or an amide.
  • X 1 may be methyl.
  • X 3 may be a halogen or a hydrogen.
  • X 2 , X 4 , and X 5 may be hydrogen.
  • R 3 may be hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl.
  • R 4 may be hydrogen.
  • R 12 and R 13 may each independently be hydrogen, carboxylic acid, alkoxy, or amide.
  • X 1 may be methyl
  • X 2 , X 4 , and X 5 are hydrogen
  • X 3 may be a halogen or a hydrogen
  • R 3 may be hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl
  • R 4 may be hydrogen
  • R 12 and R 13 may each independently be hydrogen, carboxylic acid, alkoxy, or amide.
  • R3 may be difluoromethyl.
  • R 10 may be carboxylic acid and R 11 may be hydrogen.
  • R 10 may be amide and R 11 may be hydrogen.
  • X 1 may be a halogen.
  • X 2 may be hydrogen or halogen.
  • X 3 may be methyl, halogen, or hydrogen.
  • X 4 and X 5 may be hydrogen
  • X 1 may be a halogen
  • X 2 is hydrogen or halogen
  • X 3 is methyl, halogen, or hydrogen
  • X 4 and X 5 are hydrogen
  • R 3 may be difluoromethyl
  • R 4 may be hydrogen
  • R 12 and R 13 are each independently hydrogen or carboxylic acid.
  • R 10 may be carboxylic acid and R 11 may be methoxy.
  • R 10 may be carboxylic acid and R 11 may be methyl.
  • C. Compounds with Formulae (IIb-1) & (IIb-2) [0107] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formulae (IIb-1) & (IIb-2): Formula (IIb-1); or
  • X 1 -X 5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1 OY 2 , wherein Y 1 and Y 2 are each independently a C 1 -C 6 alkyl optionally substituted with one or more halogen or hydroxy.
  • R 3 may be a halogen, a hydrogen, a C 1 -C 6 alkyl, a C 1 -C 6 alkyl substituted with one or more halogen, or a C 3 -C 6 cycloalkyl.
  • R4 may be a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkyl substituted with one or more halogen.
  • R3 and R4 may optionally be interconnected to form a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.
  • R 20 -R 29 may each independently be a hydrogen, a C 1 -C 6 alkyl, a carboxylic acid, an amide, a substituted amide, an alkoxy, or a halogen.
  • X 1 may be a C 1 -C 6 alkyl.
  • X 1 may be a methyl.
  • X 2 and X 4 may be hydrogen.
  • X 3 may be a hydrogen or halogen.
  • X 5 may be a hydrogen or a C 1 -C 6 alkyl.
  • at least two of X 2 - X 5 may be hydrogen.
  • at least three of X 2 - X 5 may be hydrogen.
  • X 2 -X 5 may be hydrogen.
  • R 3 may be a hydrogen, a methyl, or -CHF 2 .
  • R 4 may be hydrogen.
  • R 20 -R 29 are each independently a hydrogen, a C 1 -C 6 alkyl, an alkoxy, a halogen, a carboxylic acid, amide, or a substituted amide.
  • the substituted amide may be substituted with one or more C 1 -C 6 alkyl.
  • at least one of R20-R29 may be carboxylic acid, amide, or substituted amide.
  • At least one of R20-R21 may be carboxylic acid, amide, or substituted amide.
  • at least one of R22-R23 may be carboxylic acid, amide, or substituted amide.
  • at least one of R24-R25 may be carboxylic acid, amide, or substituted amide.
  • at least one of R26-R27 may be carboxylic acid, amide, or substituted amide.
  • at least one of R28-R29 may be carboxylic acid, amide, or substituted amide.
  • X1 may be halogen or methyl and R3 may be hydrogen, methyl, CHF 2 , or CF 3 .
  • X2 may be hydrogen or halogen and R3 may be hydrogen, methyl, CHF 2 , or CF 3 .
  • X3 may be hydrogen or halogen and R3 may be hydrogen, methyl, CHF 2 , or CF 3 .
  • X1-X3 may each independently be hydrogen, halogen, or methyl, and R 3 is H, methyl, CHF 2 , or CF 3 .
  • X 1 -X 3 may each independently be hydrogen, halogen, or methyl
  • X 4 - X 5 may each independently be hydrogen or halogen
  • R 3 -R 4 may independently be hydrogen, methyl, CHF 2 , or CF 3
  • X 1 -X 3 may each independently be hydrogen, fluorine, chlorine, bromine, or methyl
  • X 4 -X 5 are each independently hydrogen or halogen
  • R 3 -R 4 are independently hydrogen, methyl, CHF 2 , or CF 3 .
  • at least one of R 20 -R 29 may be carboxylic acid.
  • R 20 -R 23 may be carboxylic acid.
  • at least one of R 24 -R 25 may be carboxylic acid.
  • at least one of R 26 -R 29 may be carboxylic acid.
  • R 24 -R 25 may each independently be hydrogen, fluorine, methyl, methoxy, or carboxylic acid.
  • R 24 -R 25 may each independently be hydrogen or carboxylic acid.
  • wherein R 3 and R 4 may be interconnected to form a 5-membered cyclic ring.
  • R 3 and R 4 may be interconnected to form a phenyl ring.
  • D. Compounds with Formulas (IIc), (IIc-1), (IIc-2a), and (IIc-2b) [0145] The present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (IIc): [0146]
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)
  • Y 1 and Y 2 may each be independently a C 1 -C 6 alkyl optionally substituted with one or more halogen or hydroxy.
  • R 3 may be a halogen, a hydrogen, a C 1 -C 6 alkyl, a C 1 -C 6 alkyl substituted with one or more halogen, or a C 3 -C 6 cycloalkyl.
  • R4 may be a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkyl substituted with one or more halogen.
  • R 3 and R 4 may optionally be interconnected to form a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.
  • a 3 is a hydrogen, a C 1 -C 6 alkyl, a C 2 -C 6 branched alkyl, a C 1 -C 6 alkyl substituted with heterocyclyl, a C 1 -C 6 alkyl substituted with a substituted heterocyclyl, or a C 1 -C 6 alkyl substituted C 1 -C 6 alkoxy.
  • B is -C(O)OH, -C(O)NH 2 , C(O)NHY 3 , C(O)NY 3 Y 4 , -CS(O) 2 Y 3 , - Y 3 CS(O)2Y 3 , or absent.
  • Y 3 and Y 4 may each independently be a C1-C4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C 1 -C 4 haloalkoxyl, and a C 1 -C 4 alkoxyl.
  • X1 is a hydrogen, a halogen, a cyano, a C 1 -C 6 alkyl, a substituted C 1 - C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, a C 1 -C 6 cycloalkoxy, - COOH, -C(O)NH 2 , -C(O)NHY 1 , or -C(O)NY 1 Y 2 and Y 1 and Y 2 are methyl.
  • X1 is a C 1 -C 6 alkyl.
  • the C 1 -C 6 alkyl may be methyl or ethyl.
  • X1 is halogen.
  • the halogen may be fluorine, chlorine, or bromine.
  • the C 3 -C 6 cycloalkyl may be cyclopropyl
  • X1 may be -CH 2 OCH 3 , -CH 2 OH, or -CF 3 .
  • X1 may be -C(O)NH 2 , -C(O)NHCH 3 , or -C(O)NCH 3 CH 3 .
  • X2 and X3 may be a hydrogen, a halogen, or a C 1 -C 6 alkyl.
  • X4 may be a hydrogen, a halogen, a hydroxy, a methoxy, a C 1 -C 6 alkyl, or a substituted C 1 -C 6 alkyl.
  • the substituted C 1 -C 6 alkyl may be -CH 2 OH.
  • X5 may be a hydrogen, halogen, hydroxy, methoxy, a C 1 -C 6 alkyl, or a substituted C 1 -C 6 alkyl.
  • a 3 may be a C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl and B is carboxylic acid.
  • a 3 may be methyl, ethyl, 1-methyl-methyl, dimethyl-methyl, methyl ethyl, dimethyl ethyl, or methyl-cyclopropyl.
  • the methyl may be connected to a thiazole via a carbon-carbon bond.
  • the methyl may also be connected to a phenyl or a cyclopropyl.
  • the substituted C 1 -C 6 alkyl may be substituted methyl, substituted ethyl, or substituted propyl.
  • the substituted methyl may be -C(H)(CH 3 ).
  • the substituted ethyl may be -CH 2 CH(OCH 3 ), -CH 2 CH(OH), - CH 2 C(CH 3 )H, or CH 2 C(CH 3 ) 2 .
  • X 1 may be C 1 -C 6 alkyl or halogen.
  • X 2 may be hydrogen or halogen.
  • X 3 may be hydrogen, C 1 -C 6 alkyl, or halogen.
  • X 4 may be hydrogen.
  • X 1 may be C 1 -C 6 alkyl or hydrogen.
  • R 3 may be C 1 -C 6 alkyl substituted with one or more halogen.
  • R3 may be -CHF 2 or -CF 3 .
  • R4 may be hydrogen.
  • X1-X5 may each independently be hydrogen, a halogen, or a C 1 -C 6 alkyl.
  • X3-X4 may each independently be hydrogen, methyl, cyclopropyl, - CHF 2 , or -CF 3 .
  • A3 may be substituted with at least one halogen, ester, ether, or carboxylic acid. [0173] In some examples, A3 may be substituted with at least one -C(O)NH 2 , -CS(O) 2 Y 3 , or - CY 1 S(O) 2 Y 3 . [0174] In some examples, B may be carboxylic acid, amide, methanesulfonamide, methoxy, substituted amide, amine, substituted amine, or substituted sulfoxide.
  • B may be amine or substituted amine with Formula (IIc-1): [0176] In some embodiments of Formula (IIc-1), X1 may be a C 1 -C 6 alkyl. [0177] In some embodiments of Formula (IIc-1), X2-X5 may be hydrogen. [0178] In some embodiments of Formula (IIc-1), R 3 may be -CHF 2 . [0179] In some embodiments of Formula (IIc-1), R 4 may be hydrogen. [0180] In some embodiments of Formula (IIc-1), A 3 may be a C 1 -C 6 alkyl.
  • B 3 and B 4 may each independently be hydrogen or a C 1 -C 6 alkyl.
  • X 1 is a C 1 -C 6 alkyl
  • X 2 -X 5 are hydrogen
  • R 3 is - CHF 2
  • R 4 is hydrogen
  • A3 is a C 1 -C 6 alkyl
  • B 3 and B 4 are each independently hydrogen or a C 1 -C 6 alkyl.
  • B may be amide or substituted amide with Formula (IIc-2a) or Formula (IIc-2b): Formula (IIc-2a); or
  • X 1 may be C 1 -C 6 alkyl or halogen.
  • X 2 -X 4 may be hydrogen or halogen.
  • X 5 may be hydrogen, halogen, or C 1 -C 6 alkyl.
  • R 3 may be -CHF 2 , -CF 3 or a C 3 - C 6 cycloalkyl.
  • R4 may be hydrogen.
  • A3 may be a C 1 -C 6 alkyl or branched C 1 -C 6 alkyl.
  • B3 and B4 may be each independently hydrogen, a C 1 -C 6 alkyl, a substituted a C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted a C 3 -C 6 cycloalkyl, a C 3 -C 6 heterocyclyl, a substituted a C 3 -C 6 heterocyclyl, phenyl, substituted phenyl.
  • A3 may be ethyl and B may be methanesulfonamide [0197] In some embodiments of Formulae (IIc-2a) and (IIc-2b), A3 may be ethyl and B may be methoxy. [0198] In some embodiments of Formulae (IIc-2a) and (IIc-2b), A3 may be ethyl and B may be substituted sulfoxide. [0199] In some embodiments of Formulae (IIc-2a) and (IIc-2b), R3 may be -CHF 2 , halogen, cyclopropyl, or methyl.
  • X 1 -X 5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1 OY 2 .
  • Y 1 and Y 2 may each be independently a C 1 -C 6 alkyl optionally substituted with one or more halogen or hydroxy.
  • R3 may be a halogen, a hydrogen, a C 1 -C 6 alkyl, a C 1 -C 6 alkyl substituted with one or more halogen, or a C 3 -C 6 cycloalkyl.
  • R4 may be a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkyl substituted with one or more halogen.
  • the C 1 -C 6 alkyl may be methyl.
  • R4 may be hydrogen.
  • R30-R34 may be hydrogen.
  • R30 may be methyl, methoxy, carboxylic acid, -C(O)OCH 3 , cyano, amide, or substituted amide.
  • R31 may be methyl, methoxy, carboxylic acid, -C(O)OCH 3 , cyano, amide, or substituted amide.
  • R32 may be methyl, methoxy, carboxylic acid, -C(O)OCH 3 , cyano, amide, or substituted amide.
  • R33 may be methyl, methoxy, carboxylic acid, -C(O)OCH 3 , cyano, amide, or substituted amide.
  • R34 may be methyl, methoxy, carboxylic acid, -C(O)OCH 3 , cyano, amide, or substituted amide.
  • at least two of R30-R34 may be hydrogen, -OCH 3 , -COOH, -C(O)NH 2 , -C(O)NHCH 3 , cyano, methyl, - C(O)OCH 3 , or fluorine.
  • At least one of R 30 -R 34 may be methyl.
  • at least two of R 30 -R 34 may be carboxylic acid, amide, ester, ether, cyano, or methyl. F.
  • X 1 -X 5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1 OY 2 ; Y 1 and Y 2 are each independently a C 1 -C 6
  • X 1 may be a C 1 -C 6 alkyl or a halogen. In some examples, X 1 may be methyl. In some examples, X 1 may be chlorine. [0234] In some embodiments, X 2 , X 4 , and X 5 may be hydrogen. [0235] In some embodiments, X 3 may be a hydrogen or halogen. [0236] In some embodiments, at least two of X 2 -X 5 may be hydrogen. [0237] In some embodiments, at least three of X 2 -X 5 may be hydrogen. [0238] In some embodiments, X2-X5 may be hydrogen.
  • R3 may be straight or branched C 1 -C 6 alkyl optionally substituted with one or more halogen.
  • the straight or branched C 1 -C 6 alkyl may be substituted with one or more fluorine.
  • R3 may be -CHF 2 or -CF 3 .
  • R4 may be hydrogen.
  • X1-X3 may each independently be hydrogen, fluorine, chlorine, bromine, or methyl
  • X4-X5 may each independently be hydrogen or halogen
  • R3-R4 may each independently be hydrogen, methyl, -CHF 2 , or -CF 3 .
  • X 1 -X 5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1 OY 2 ; Y 1 and Y 2 are each independently a C 1 -C 6 alkyl
  • X1 and X2 may be halogen.
  • the halogen may be fluorine or chlorine.
  • X2, X3, and X5 may be hydrogen.
  • at least two of X2-X5 may be hydrogen.
  • at least three of X2-X5 may be hydrogen.
  • at least one Y may be nitrogen.
  • R30-R34 may each independently be a hydrogen or absent.
  • R3 may be -CH(CH 3 ) 2 . H.
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1 OY 2 .
  • Y 1 and Y 2 may each be independently a C 1 -C 6 alkyl optionally substituted with one or more halogen or hydroxy.
  • R 3 may be a halogen, a hydrogen, a C 1 -C 6 alkyl, a C 1 -C 6 alkyl substituted with one or more halogen, or a C 3 -C 6 cycloalkyl.
  • R 4 may be a hydrogen, a C 1 -C 6 alkyl, or a C 1 -C 6 alkyl substituted with one or more halogen.
  • R 3 and R 4 may optionally be interconnected to form a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, 5-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, 6-membered heterocyclic ring, a substituted 6-membered heterocyclic ring, a phenyl ring, or a substituted phenyl ring.
  • a 1 and A 2 may each independently be a hydrogen, a C 1- C 6 alkyl, a substituted C 1 -C 6 alkyl, an aryl, substituted aryl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 3 -C 6 heterocyclyl, substituted C 3 -C 6 heterocyclyl, or absent.
  • a 1 and A 2 may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH 2 , -CS(O) 2 Y 3 , a -CY 1 S(O) 2 Y 3 .
  • Y 3 may independently be a hydrogen or a C 1 -C 4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C 1 -C 4 haloalkoxyl, and a C 1 -C 4 alkoxyl.
  • the present disclosure is directed to a compound with any one or Formulae (IIIa), (IIIb), (IVa), and (IVb):
  • X 1 may be C 1 -C 6 alkyl.
  • X 2 , X 3 , and X 5 may be hydrogen.
  • X 4 may be hydrogen or fluorine.
  • a 1 and A 2 may each be independently a hydrogen, a C 1- C 6 alkyl, a substituted C 1 -C 6 alkyl, an aryl, substituted aryl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 3 -C 6 heterocyclyl, or substituted C 3 -C 6 heterocyclyl.
  • a 1 and A 2 may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(O)NH 2 , -CS(O) 2 Y 3 , a -CY 1 S(O) 2 Y 3 .
  • R3 may be C 1 -C 6 alkyl substituted with one or more halogen.
  • R4 may be a hydrogen.
  • X1 may be methyl.
  • X4 may behydrogen or fluorine.
  • at least two of X2-X5 may be hydrogen.
  • At least three of X 2 -X 5 are hydrogen.
  • a 1 and A 2 may be substituted C 1 -C 6 alkyl.
  • a 1 and A 2 may be substituted ethyl. The ethyl may be substituted with carboxylic acid or amide.
  • a 1 and A 2 may be -CH(CH 3 )COOH.
  • a 1 and A 2 may be -CH 2 CH 3 COOH.
  • a 1 and A 2 may be -CH 2 CH 3 CONH 2 .
  • A1 and A2 may be substituted C 3 -C 6 cycloalkyl.
  • the substituted C 3 -C 6 cycloalkyl may be a cyclobutyl or cyclohexyl substituted with one or more carboxylic acid.
  • A1 and A2 may be substituted phenyl. The phenyl may be substituted with one or more carboxylic acid.
  • R3 may be -CHF 2 or -CF 3 .
  • X1-X5 may each independently be hydrogen, halogen, or methyl. I.
  • X 1 -X 5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a C 1 -C 6 alkyl, a substituted C 1 -C 6 alkyl, a C 3 -C 6 cycloalkyl, a substituted C 3 -C 6 cycloalkyl, a C 1 -C 6 alkoxy, optionally substituted with an aryl, a C 3 -C 10 cycloalkyl, -C(O)NH 2 , -C(O)NHY 1 , - C(O)NY 1 Y 2 , -COOH, -C(O)OY 1 , -Y 1 COOH, or -Y 1
  • a 1 -A 2 are independently hydrogen or methyl.
  • X 1 -X 5 may be independently hydrogen, halogen, or methyl.
  • R3-R4 may be independently hydrogen, -CHF 2 or -CF 3 .
  • A1 may be absent and the compound is with Formula (Va-1) or Formula (Vb-1):
  • X 1 is C 1 -C 6 alkyl
  • X 2 , X 3 , and X 5 are hydrogen
  • X 4 is hydrogen or halogen
  • A2 is C 1 -C 6 alkyl
  • R3 is hydrogen or C 1 -C 6 alkyl substituted with one or more halogen
  • R4 is hydrogen.
  • at least two of X2-X5 may be hydrogen.
  • at least three of X2-X5 may be hydrogen.
  • X2-X5 may be hydrogen.
  • the C 1 -C 6 alkyl may be methyl.
  • the C 1 -C 6 alkyl substituted with one or more halogen may be - CHF 2 or -CF 3 .
  • J. Compounds [0287] The disclosure is intended to encompass the compounds listed below and the non- stereochemistry and the alternative stereochemistry of the compounds listed below.
  • the compound is Compound 1, or a pharmaceutically acceptable salt thereof: [0289] In certain embodiments, the compound is Compound 2, or a pharmaceutically acceptable salt thereof: [0290] In certain embodiments, the compound is Compound 3, or a pharmaceutically acceptable salt thereof: [0291] In certain embodiments, the compound is Compound 4, or a pharmaceutically acceptable salt thereof: [0292] In certain embodiments, the compound is Compound 5, or a pharmaceutically acceptable salt thereof: [0293] In certain embodiments, the compound is Compound 6, or a pharmaceutically acceptable salt thereof: [0294] In certain embodiments, the compound is Compound 7, or a pharmaceutically acceptable salt thereof: [0295] In certain embodiments, the compound is Compound 8, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 9, or a pharmaceutically acceptable salt thereof: [0297] In certain embodiments, the compound is Compound 10, or a pharmaceutically acceptable salt thereof: [0298] In certain embodiments, the compound is Compound 11, or a pharmaceutically acceptable salt thereof: [0299] In certain embodiments, the compound is Compound 12, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 13, or a pharmaceutically acceptable salt thereof: [0301] In certain embodiments, the compound is Compound 14, or a pharmaceutically acceptable salt thereof: [0302] In certain embodiments, the compound is Compound 15, or a pharmaceutically acceptable salt thereof: [0303] In certain embodiments, the compound is Compound 16, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 17, or a pharmaceutically acceptable salt thereof: [0305] In certain embodiments, the compound is Compound 18, or a pharmaceutically acceptable salt thereof: [0306] In certain embodiments, the compound is Compound 19, or a pharmaceutically acceptable salt thereof: [0307] In certain embodiments, the compound is Compound 20, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 21, or a pharmaceutically acceptable salt thereof: [0309] In certain embodiments, the compound is Compound 22, or a pharmaceutically acceptable salt thereof: [0310] In certain embodiments, the compound is Compound 23 or a pharmaceutically acceptable salt thereof: [0311] In certain embodiments, the compound is Compound 24, or a pharmaceutically acceptable salt thereof: [0312] In certain embodiments, the compound is Compound 25, or a pharmaceutically acceptable salt thereof: [0313] In certain embodiments, the compound is Compound 26, or a pharmaceutically acceptable salt thereof: [0314] In certain embodiments, the compound is Compound 27, or a pharmaceutically acceptable salt thereof: [0315] In certain embodiments, the compound is Compound 28, or a pharmaceutically acceptable salt thereof: [0316] In certain embodiments, the compound is Compound 29, or a pharmaceutically acceptable salt thereof: [0317] In certain embodiments, the compound is Compound 30, or a pharmaceutically acceptable salt thereof: [0318] In certain embodiments, the compound is Compound 31,
  • the compound is Compound 32, or a pharmaceutically acceptable salt thereof: [0320] In certain embodiments, the compound is Compound 33, or a pharmaceutically acceptable salt thereof: [0321] In certain embodiments, the compound is Compound 34, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 332, or a pharmaceutically acceptable salt thereof: [0323] In one embodiment, the compound is Compound 333, or a pharmaceutically acceptable salt thereof: [0324] In one embodiment, the compound is Compound 348, or a pharmaceutically acceptable salt thereof: [0325] In one embodiment, the compound is Compound 349, or a pharmaceutically acceptable salt thereof: [0326] In one embodiment, the compound is Compound 358, or a pharmaceutically acceptable salt thereof: [0327] In one embodiment, the compound is Compound 359, or a pharmaceutically acceptable salt thereof: [0328] In one embodiment, the compound is Compound 368, or a pharmaceutically acceptable salt thereof: [0329] In one embodiment, the compound is Compound 369, or a pharmaceutically acceptable salt thereof: [0330] In certain embodiments, the compound is Compound 35, or a pharmaceutically acceptable salt thereof: [0331] In certain embodiments, the compound is Compound 36, or a pharmaceutically acceptable salt thereof: .
  • the compound is Compound 46, or a pharmaceutically acceptable salt thereof: [0342] In certain embodiments, the compound is Compound 47, or a pharmaceutically acceptable salt thereof: . [0343] In certain embodiments, the compound is Compound 48, or a pharmaceutically acceptable salt thereof: [0344] In certain embodiments, the compound is Compound 49, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 50, or a pharmaceutically acceptable salt thereof: [0346] In certain embodiments, the compound is Compound 51, or a pharmaceutically acceptable salt thereof: [0347] In certain embodiments, the compound is Compound 52, or a pharmaceutically acceptable salt thereof: [0348] In one embodiment, the compound is Compound 316, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 317, or a pharmaceutically acceptable salt thereof: [0350] In one embodiment, the compound is Compound 335, or a pharmaceutically acceptable salt thereof: [0351] In one embodiment, the compound is Compound 336, or a pharmaceutically acceptable salt thereof: [0352] In one embodiment, the compound is Compound 346, or a pharmaceutically acceptable salt thereof: [0353] In one embodiment, the compound is Compound 347, or a pharmaceutically acceptable salt thereof: [0354] In one embodiment, the compound is Compound 355, or a pharmaceutically acceptable salt thereof: [0355] In one embodiment, the compound is Compound 356, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 366, or a pharmaceutically acceptable salt thereof: [0357] In one embodiment, the compound is Compound 367, or a pharmaceutically acceptable salt thereof: [0358] In certain embodiments, the compound is Compound 53, or a pharmaceutically acceptable salt thereof: [0359] In certain embodiments, the compound is Compound 54, or a pharmaceutically acceptable salt thereof: [0360] In certain embodiments, the compound is Compound 55, or a pharmaceutically acceptable salt thereof: [0361] In certain embodiments, the compound is Compound 56, or a pharmaceutically acceptable salt thereof: [0362] In certain embodiments, the compound is Compound 57, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 58, or a pharmaceutically acceptable salt thereof: [0364] In certain embodiments, the compound is Compound 59, or a pharmaceutically acceptable salt thereof: [0365] In certain embodiments, the compound is Compound 60, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 61, or a pharmaceutically acceptable salt thereof: [0367] In certain embodiments, the compound is Compound 62, or a pharmaceutically acceptable salt thereof: [0368] In certain embodiments, the compound is Compound 63, or a pharmaceutically acceptable salt thereof: [0369] In certain embodiments, the compound is Compound 64, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 65, or a pharmaceutically acceptable salt thereof: [0371] In certain embodiments, the compound is, Compound 66, or a pharmaceutically acceptable salt thereof: [0372] In certain embodiments, the compound is, Compound 67, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 68, or a pharmaceutically acceptable salt thereof: [0374] In certain embodiments, the compound is Compound 69, or a pharmaceutically acceptable salt thereof: [0375] In certain embodiments, the compound is Compound 70, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 71, or a pharmaceutically acceptable salt thereof: .
  • the compound is Compound 72, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 73, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 74, or a pharmaceutically acceptable salt thereof: [0380] In certain embodiments, the compound is Compound 75, or a pharmaceutically acceptable salt thereof: [0381] In one embodiment, the compound is Compound 319, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 320, or a pharmaceutically acceptable salt thereof: [0383] In one embodiment, the compound is Compound 324, or a pharmaceutically acceptable salt thereof: [0384] In one embodiment, the compound is Compound 325, or a pharmaceutically acceptable salt thereof: [0385] In one embodiment, the compound is Compound 326, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 327, or a pharmaceutically acceptable salt thereof: [0387] In one embodiment, the compound is Compound 328, or a pharmaceutically acceptable salt thereof: [0388] In one embodiment, the compound is Compound 329, or a pharmaceutically acceptable salt thereof: [0389] In one embodiment, the compound is Compound 330, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 331, or a pharmaceutically acceptable salt thereof: [0391] In one embodiment, the compound is Compound 334, or a pharmaceutically acceptable salt thereof: [0392] In one embodiment, the compound is Compound 337, or a pharmaceutically acceptable salt thereof: [0393] In one embodiment, the compound is Compound 338, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 350, or a pharmaceutically acceptable salt thereof: [0395] In one embodiment, the compound is Compound 351, or a pharmaceutically acceptable salt thereof: [0396] In one embodiment, the compound is Compound 352, or a pharmaceutically acceptable salt thereof: [0397] In one embodiment, the compound is Compound 353, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 354, or a pharmaceutically acceptable salt thereof: [0399] In one embodiment, the compound is Compound 357, or a pharmaceutically acceptable salt thereof: [0400] In one embodiment, the compound is Compound 360, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 361, or a pharmaceutically acceptable salt thereof: [0402] In one embodiment, the compound is Compound 362, or a pharmaceutically acceptable salt thereof: [0403] In one embodiment, the compound is Compound 363, or a pharmaceutically acceptable salt thereof: [0404] In one embodiment, the compound is Compound 364, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 365, or a pharmaceutically acceptable salt thereof: [0406] In one embodiment, the compound is Compound 370, or a pharmaceutically acceptable salt thereof: [0407] In one embodiment, the compound is Compound 371, or a pharmaceutically acceptable salt thereof: [0408] In certain embodiments, the compound is Compound 76, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 77, or a pharmaceutically acceptable salt thereof: [0410] In certain embodiments, the compound is Compound 78, or a pharmaceutically acceptable salt thereof: [0411] In certain embodiments, the compound is Compound 79, or a pharmaceutically acceptable salt thereof: [0412] In certain embodiments, the compound is Compound 80, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 81, or a pharmaceutically acceptable salt thereof: [0414] In certain embodiments, the compound is Compound 82, or a pharmaceutically acceptable salt thereof: [0415] In certain embodiments, the compound is Compound 83, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 84, or a pharmaceutically acceptable salt thereof: [0417] In certain embodiments, the compound is Compound 85, or a pharmaceutically acceptable salt thereof: [0418] In certain embodiments, the compound is Compound 86, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 87, or a pharmaceutically acceptable salt thereof: [0420] In certain embodiments, the compound is Compound 88, or a pharmaceutically acceptable salt thereof: [0421] In certain embodiments, the compound is Compound 89, or a pharmaceutically acceptable salt thereof: [0422] In certain embodiments, the compound is Compound 90, or a pharmaceutically acceptable salt thereof: [0423] In certain embodiments, the compound is Compound 91, or a pharmaceutically acceptable salt thereof: [0424] In certain embodiments, the compound is Compound 92, or a pharmaceutically acceptable salt thereof: [0425] In certain embodiments, the compound is Compound 93, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 94, or a pharmaceutically acceptable salt thereof: [0427] In certain embodiments, the compound is Compound 95, or a pharmaceutically acceptable salt thereof: [0428] In certain embodiments, the compound is Compound 96, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 97, or a pharmaceutically acceptable salt thereof: [0430] In certain embodiments, the compound is Compound 98, or a pharmaceutically acceptable salt thereof: [0431] In certain embodiments, the compound is Compound 99, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 100, or a pharmaceutically acceptable salt thereof: [0433] In certain embodiments, the compound is Compound 101, or a pharmaceutically acceptable salt thereof: [0434] In certain embodiments, the compound is Compound 102, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 103, or a pharmaceutically acceptable salt thereof: [0436] In certain embodiments, the compound is Compound 104, or a pharmaceutically acceptable salt thereof: [0437] In certain embodiments, the compound is Compound 105, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 106, or a pharmaceutically acceptable salt thereof: [0439] In certain embodiments, the compound is Compound 107, or a pharmaceutically acceptable salt thereof: [0440] In certain embodiments, the compound is Compound 108, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 109, or a pharmaceutically acceptable salt thereof: [0442] In certain embodiments, the compound is Compound 110, or a pharmaceutically acceptable salt thereof: [0443] In certain embodiments, the compound is Compound 111, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 112, or a pharmaceutically acceptable salt thereof: [0445] In certain embodiments, the compound is Compound 113, or a pharmaceutically acceptable salt thereof: [0446] In certain embodiments, the compound is Compound 114, or a pharmaceutically acceptable salt thereof: [0447] In certain embodiments, the compound is Compound 115, or a pharmaceutically acceptable salt thereof: . [0448] In certain embodiments, the compound is Compound 116, or a pharmaceutically acceptable salt thereof: [0449] In certain embodiments, the compound is Compound 117, or a pharmaceutically acceptable salt thereof: [0450] In certain embodiments, the compound is Compound 118, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 119, or a pharmaceutically acceptable salt thereof: [0452] In certain embodiments, the compound is Compound 120, or a pharmaceutically acceptable salt thereof: [0453] In certain embodiments, the compound is Compound 121, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 122, or a pharmaceutically acceptable salt thereof: [0455] In certain embodiments, the compound is Compound 123, or a pharmaceutically acceptable salt thereof: [0456] In certain embodiments, the compound is Compound 124, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 125, or a pharmaceutically acceptable salt thereof: [0458] In certain embodiments, the compound is Compound 126, or a pharmaceutically acceptable salt thereof: [0459] In certain embodiments, the compound is Compound 127, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 128, or a pharmaceutically acceptable salt thereof: [0461] In certain embodiments, the compound is Compound 129, or a pharmaceutically acceptable salt thereof: [0462] In certain embodiments, the compound is Compound 130, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 131, or a pharmaceutically acceptable salt thereof: [0464] In certain embodiments, the compound is Compound 132, or a pharmaceutically acceptable salt thereof: [0465] In certain embodiments, the compound is Compound 133, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 134, or a pharmaceutically acceptable salt thereof: [0467] In certain embodiments, the compound is Compound 135, or a pharmaceutically acceptable salt thereof: [0468] In certain embodiments, the compound is Compound 136, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 137, or a pharmaceutically acceptable salt thereof: [0470] In certain embodiments, the compound is Compound 138, or a pharmaceutically acceptable salt thereof: [0471] In certain embodiments, the compound is Compound 139, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 140, or a pharmaceutically acceptable salt thereof: [0473] In certain embodiments, the compound is Compound 141, or a pharmaceutically acceptable salt thereof: [0474] In certain embodiments, the compound is Compound 142, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 146, or a pharmaceutically acceptable salt thereof: [0479] In certain embodiments, the compound is Compound 147, or a pharmaceutically acceptable salt thereof: [0480] In certain embodiments, the compound is Compound 148, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 149, or a pharmaceutically acceptable salt thereof: [0482] In certain embodiments, the compound is Compound 150, or a pharmaceutically acceptable salt thereof: [0483] In certain embodiments, the compound is Compound 151, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 152, or a pharmaceutically acceptable salt thereof: .
  • the compound is Compound 153, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 154, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 155, or a pharmaceutically acceptable salt thereof: [0488] In certain embodiments, the compound is Compound 156, or a pharmaceutically acceptable salt thereof: [0489] In certain embodiments, the compound is Compound 157, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 158, or a pharmaceutically acceptable salt thereof: [0491] In certain embodiments, the compound is Compound 159, or a pharmaceutically acceptable salt thereof: [0492] In certain embodiments, the compound is Compound 160, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 161, or a pharmaceutically acceptable salt thereof: [0494] In one embodiment, the compound is Compound 162, or a pharmaceutically acceptable salt thereof: [0495] In one embodiment, the compound is Compound 163, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 164, or a pharmaceutically acceptable salt thereof: [0497] In one embodiment, the compound is Compound 165, or a pharmaceutically acceptable salt thereof: [0498] In one embodiment, the compound is Compound 166, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 167, or a pharmaceutically acceptable salt thereof: [0500] In one embodiment, the compound is Compound 168, or a pharmaceutically acceptable salt thereof: [0501] In one embodiment, the compound is Compound 169, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 170, or a pharmaceutically acceptable salt thereof. [0503] In one embodiment, the compound is Compound 171, or a pharmaceutically acceptable salt thereof: [0504] In one embodiment, the compound is Compound 172, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 173, or a pharmaceutically acceptable salt thereof: [0506] In one embodiment, the compound is Compound 174, or a pharmaceutically acceptable salt thereof: [0507] In one embodiment, the compound is Compound 175, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 176, or a pharmaceutically acceptable salt thereof: [0509] In one embodiment, the compound is Compound 177, or a pharmaceutically acceptable salt thereof: [0510] In one embodiment, the compound is Compound 178, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 179, or a pharmaceutically acceptable salt thereof: [0512] In one embodiment, the compound is Compound 180, or a pharmaceutically acceptable salt thereof: [0513] In one embodiment, the compound is Compound 181, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 182, or a pharmaceutically acceptable salt thereof: [0515] In one embodiment, the compound is Compound 183, or a pharmaceutically acceptable salt thereof: [0516] In one embodiment, the compound is Compound 184, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 185, or a pharmaceutically acceptable salt thereof: [0518] In one embodiment, the compound is Compound 186, or a pharmaceutically acceptable salt thereof: [0519] In one embodiment, the compound is Compound 187, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 188, or a pharmaceutically acceptable salt thereof: [0521] In one embodiment, the compound is Compound 189, or a pharmaceutically acceptable salt thereof: [0522] In one embodiment, the compound is Compound 190, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 191, or a pharmaceutically acceptable salt thereof: [0524] In one embodiment, the compound is Compound 192, or a pharmaceutically acceptable salt thereof: [0525] In one embodiment, the compound is Compound 193, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 194, or a pharmaceutically acceptable salt thereof: [0527] In one embodiment, the compound is Compound 195, or a pharmaceutically acceptable salt thereof: [0528] In one embodiment, the compound is Compound 196, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 197, or a pharmaceutically acceptable salt thereof: [0530] In one embodiment, the compound is Compound 198, or a pharmaceutically acceptable salt thereof: [0531] In one embodiment, the compound is Compound 199, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 200, or a pharmaceutically acceptable salt thereof: [0533] In one embodiment, the compound is Compound 201, or a pharmaceutically acceptable salt thereof: [0534] In one embodiment, the compound is Compound 202, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 203, or a pharmaceutically acceptable salt thereof: [0536] In one embodiment, the compound is Compound 204, or a pharmaceutically acceptable salt thereof: [0537] In one embodiment, the compound is Compound 205, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 206, or a pharmaceutically acceptable salt thereof: [0539] In one embodiment, the compound is Compound 207, or a pharmaceutically acceptable salt thereof: [0540] In one embodiment, the compound is Compound 208, or a pharmaceutically acceptable salt thereof: [0541] In one embodiment, the compound is Compound 209, or a pharmaceutically acceptable salt thereof: [0542] In one embodiment, the compound is Compound 210, or a pharmaceutically acceptable salt thereof: [0543] In one embodiment, the compound is Compound 211, or a pharmaceutically acceptable salt thereof: [0544] In one embodiment, the compound is Compound 212, or a pharmaceutically acceptable salt thereof: [0545] In one embodiment, the compound is Compound 213, or a pharmaceutically acceptable salt thereof: [0546] In one embodiment, the compound is Compound 214, or a pharmaceutically acceptable salt thereof: [0547] In one embodiment, the compound is Compound 215, or a pharmaceutically acceptable salt thereof: [0548] In one embodiment,
  • the compound is Compound 218, or a pharmaceutically acceptable salt thereof: [0551] In one embodiment, the compound is Compound 219, or a pharmaceutically acceptable salt thereof: [0552] In one embodiment, the compound is Compound 220, or a pharmaceutically acceptable salt thereof: [0553] In one embodiment, the compound is Compound 221, or a pharmaceutically acceptable salt thereof: [0554] In one embodiment, the compound is Compound 222, or a pharmaceutically acceptable salt thereof: [0555] In one embodiment, the compound is Compound 223, or a pharmaceutically acceptable salt thereof: [0556] In one embodiment, the compound is Compound 224, or a pharmaceutically acceptable salt thereof: [0557] In one embodiment, the compound is Compound 225, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 226, or a pharmaceutically acceptable salt thereof: [0559] In one embodiment, the compound is Compound 227, or a pharmaceutically acceptable salt thereof: [0560] In one embodiment, the compound is Compound 228, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 229, or a pharmaceutically acceptable salt thereof: [0562] In one embodiment, the compound is Compound 230, or a pharmaceutically acceptable salt thereof: [0563] In one embodiment, the compound is Compound 231, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 232, or a pharmaceutically acceptable salt thereof: [0565] In one embodiment, the compound is Compound 233, or a pharmaceutically acceptable salt thereof: [0566] In one embodiment, the compound is Compound 234, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 235, or a pharmaceutically acceptable salt thereof: [0568] In one embodiment, the compound is Compound 236, or a pharmaceutically acceptable salt thereof: [0569] In one embodiment, the compound is Compound 237, or a pharmaceutically acceptable salt thereof: [0570] In one embodiment, the compound is Compound 238, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 239, or a pharmaceutically acceptable salt thereof: [0572] In one embodiment, the compound is Compound 240, or a pharmaceutically acceptable salt thereof: [0573] In one embodiment, the compound is Compound 241, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 242, or a pharmaceutically acceptable salt thereof: [0575] In one embodiment, the compound is Compound 243, or a pharmaceutically acceptable salt thereof: [0576] In one embodiment, the compound is Compound 244, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 248, or a pharmaceutically acceptable salt thereof: [0581] In one embodiment, the compound is Compound 249, or a pharmaceutically acceptable salt thereof: [0582] In one embodiment, the compound is Compound 250, or a pharmaceutically acceptable salt thereof: [0583] In one embodiment, the compound is Compound 251, or a pharmaceutically acceptable salt thereof: [0584] In one embodiment, the compound is Compound 252, or a pharmaceutically acceptable salt thereof: [0585] In one embodiment, the compound is Compound 253, or a pharmaceutically acceptable salt thereof: [0586] In one embodiment, the compound is Compound 254, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 255, or a pharmaceutically acceptable salt thereof: [0588] In one embodiment, the compound is Compound 256, or a pharmaceutically acceptable salt thereof: [0589] In one embodiment, the compound is Compound 257, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 258, or a pharmaceutically acceptable salt thereof: [0591] In one embodiment, the compound is Compound 259, or a pharmaceutically acceptable salt thereof: [0592] In one embodiment, the compound is Compound 260, or a pharmaceutically acceptable salt thereof: [0593] In one embodiment, the compound is Compound 261, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 262, or a pharmaceutically acceptable salt thereof: [0595] In one embodiment, the compound is Compound 263, or a pharmaceutically acceptable salt thereof: [0596] In one embodiment, the compound is Compound 264, or a pharmaceutically acceptable salt thereof: [0597] In one embodiment, the compound is Compound 265, or a pharmaceutically acceptable salt thereof: [0598] In one embodiment, the compound is Compound 266, or a pharmaceutically acceptable salt thereof: [0599] In one embodiment, the compound is Compound 267, or a pharmaceutically acceptable salt thereof: [0600] In one embodiment, the compound is Compound 268, or a pharmaceutically acceptable salt thereof: [0601] In one embodiment, the compound is Compound 269, or a pharmaceutically acceptable salt thereof: [0602] In one embodiment, the compound is Compound 270, or a pharmaceutically acceptable salt thereof: [0603] In one embodiment, the compound is Compound 271, or a pharmaceutically acceptable salt thereof: [0604] In one embodiment, the compound is
  • the compound is Compound 286, or a pharmaceutically acceptable salt thereof: [0619] In one embodiment, the compound is Compound 287, or a pharmaceutically acceptable salt thereof: [0620] In one embodiment, the compound is Compound 288, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 289, or a pharmaceutically acceptable salt thereof: [0622] In one embodiment, the compound is Compound 290, or a pharmaceutically acceptable salt thereof: [0623] In one embodiment, the compound is Compound 291, or a pharmaceutically acceptable salt thereof: [0624] In one embodiment, the compound is Compound 292, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 293, or a pharmaceutically acceptable salt thereof: [0626] In one embodiment, the compound is Compound 294, or a pharmaceutically acceptable salt thereof: [0627] In one embodiment, the compound is Compound 295, or a pharmaceutically acceptable salt thereof: [0628] In one embodiment, the compound is Compound 296, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 297, or a pharmaceutically acceptable salt thereof: [0630] In one embodiment, the compound is Compound 298, or a pharmaceutically acceptable salt thereof: [0631] In one embodiment, the compound is Compound 299, or a pharmaceutically acceptable salt thereof: [0632] In one embodiment, the compound is Compound 300, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 301, or a pharmaceutically acceptable salt thereof: [0634] In one embodiment, the compound is Compound 302, or a pharmaceutically acceptable salt thereof: [0635] In one embodiment, the compound is Compound 303, or a pharmaceutically acceptable salt thereof: [0636] In one embodiment, the compound is Compound 304, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 305, or a pharmaceutically acceptable salt thereof: [0638] In one embodiment, the compound is Compound 306, or a pharmaceutically acceptable salt thereof: [0639] In one embodiment, the compound is Compound 307, or a pharmaceutically acceptable salt thereof: [0640] In one embodiment, the compound is Compound 308, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 309, or a pharmaceutically acceptable salt thereof: [0642] In one embodiment, the compound is Compound 310, or a pharmaceutically acceptable salt thereof: [0643] In one embodiment, the compound is Compound 311, or a pharmaceutically acceptable salt thereof: [0644] In one embodiment, the compound is Compound 312, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 313, or a pharmaceutically acceptable salt thereof: [0646] In one embodiment, the compound is Compound 314, or a pharmaceutically acceptable salt thereof: [0647] In one embodiment, the compound is Compound 315, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 318, or a pharmaceutically acceptable salt thereof: [0649] In one embodiment, the compound is Compound 321, or a pharmaceutically acceptable salt thereof: [0650] In one embodiment, the compound is Compound 322, or a pharmaceutically acceptable salt thereof: [0651] In one embodiment, the compound is Compound 323, or a pharmaceutically acceptable salt thereof: [0652] In one embodiment, the compound is Compound 339, or a pharmaceutically acceptable salt thereof: [0653] In one embodiment, the compound is Compound 340, or a pharmaceutically acceptable salt thereof: [0654] In one embodiment, the compound is Compound 341, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 342, or a pharmaceutically acceptable salt thereof: [0656] In one embodiment, the compound is Compound 343, or a pharmaceutically acceptable salt thereof: [0657] In one embodiment, the compound is Compound 344, or a pharmaceutically acceptable salt thereof: [0658] In one embodiment, the compound is Compound 345, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 372, or a pharmaceutically acceptable salt thereof: [0660] In one embodiment, the compound is Compound 373, or a pharmaceutically acceptable salt thereof: [0661] In one embodiment, the compound is Compound 374, or a pharmaceutically acceptable salt thereof: [0662] In one embodiment, the compound is Compound 375, or a pharmaceutically acceptable salt thereof:
  • the compounds inhibits POLRMT.
  • the compounds promote POLRMT.
  • the compounds of the present invention may contain asymmetric carbon atoms (sometimes as the result of a deuterium atom) and thereby may exist as either individual stereoisomers or mixtures of the enantiomers or mixtures of diastereomers. Accordingly, a compound of the present invention may exist as either a racemic mixture, a mixture of diastereomers, or as individual stereoisomers that are substantially free of other stereoisomers. Synthetic, separation, or purification methods to be used to obtain an enantiomer of a given compound are known in the art and are applicable for obtaining the compounds identified herein.
  • the compounds of the present invention may contain double bonds that may exist in more than one geometric isomer. Examples of such double bonds are carbon- carbon double bonds which form alkenes. In the case of carbon-carbon double bonds, the geometric isomers may be E or Z isomers.
  • Compounds of the present invention may exist in amorphous form and/or one or more crystalline forms. As such all amorphous and crystalline forms and mixtures thereof of the compounds of the invention are intended to be included within the scope of the present invention.
  • some of the compounds of the present invention may form solvates with water (i.e., a hydrate) or common organic solvents.
  • Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the compounds of this invention are likewise encompassed within the scope of the compounds of the invention and the pharmaceutically acceptable salts thereof, along with un-solvated and anhydrous forms of such compounds.
  • deuterium isotope content at the deuterium substituted position is greater than the natural isotopic deuterium content (0.015%), more preferably greater than 50%, more preferably greater than 60%, more preferably greater than 75%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%. It will be understood that some variation of natural isotopic abundance may occur in any compound depending upon the source of the reagents used in the synthesis. Thus, a preparation of undeuterated compounds may inherently contain small amounts of deuterated isotopologues, such amounts being insignificant as compared to the degree of stable isotopic substitution of the deuterated compounds of the invention.
  • deuterium may affect how a molecule interacts with enzymes, thereby impacting enzyme kinetics. While in certain cases the increased mass of deuterium as compared to hydrogen may stabilize a compound and thereby improve activity, toxicity, or half-life, such impact is not predictable. In other instances deuteration may have little to no impact on these properties, or may affect them in an undesirable manner. Whether and/or how such replacement will impact drug properties may only be determined if the drug is synthesized, evaluated, and compared to its non-deuterated counterpart. Because some drugs have multiple sites of metabolism or more than one active sites for binding to a target, it is unpredictable as to which sites may benefit by deuterium replacement or to what extent isotope enrichment is necessary to produce a beneficial effect.
  • reaction temperature varies depending on the reagents and solvents to be used, unless otherwise specified, it is generally -78 °C to 300 °C, preferably -78 °C to 150 °C.
  • a reagent is used in 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, relative to the substrate.
  • the reagent is used in 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.
  • the reagent is also a reaction solvent, the reagent is used in a solvent amount.
  • the reaction of each step is performed without solvent or by dissolving or suspending in a suitable solvent.
  • the solvent include the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2- methoxyethanol and the like; ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2- dimethoxyethane and the like; aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like; saturated hydrocarbons: cyclohexane, hexane and the like; amides: N,N- dimethylformamide, N-methylpyrrolidone and the like; halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like; nitriles: acetonitrile and the like; sulfoxides: dimethyl sulfoxide and the like; aromatic organic bases: pyridine and the like; acid
  • reaction of each step is performed according to a known method, for example, the methods described in “Reactions and Syntheses: In the Organic Chemistry Laboratory 2nd Edition” (Lutz F. Tietze, Theophil Eicher, Ulf Diederichsen, Andreas Speicher, Nina Schützenmeister) Wiley, 2015; “Organic Syntheses Collective Volumes 1 – 12” (John Wiley & Sons Inc); “Comprehensive Organic Transformations, Third Edition” (Richard C. Larock) Wiley, 2018 and the like.
  • Deuterated POLRMT modulators of the present invention may be prepared using chemical reactions known to a person of ordinary skill in the art using deuterated starting materials or reagents. Deuterium-containing reagents are well known in the art and may be prepared using known procedures or purchased from commercial sources.
  • the deuterated compounds obtained may be characterized by analytical techniques known to persons of ordinary skill in the art. For example, nuclear magnetic resonance (“NMR”) may be used to determine a compound’s structure while mass spectroscopy (“MS”) may be used to determine the amount of deuterium atom in the compound by comparison to its non-deuterated form.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • Compositions [0680] The present invention further includes pharmaceutical compositions of the compounds or a pharmaceutically acceptable salt of said compounds.
  • the pharmaceutical compositions comprise one or more pharmaceutically acceptable excipients, such excipients being compatible with other ingredients in the composition and also being not toxic or otherwise harmful.
  • excipients include carriers, lubricants, binders, disintegrants, solvents, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents, preservatives, antioxidants, colorants, taste-modifying agents, absorbents, and/or wetting agents.
  • excipients include carriers, lubricants, binders, disintegrants, solvents, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents, preservatives, antioxidants, colorants, taste-modifying agents, absorbents, and/or wetting agents.
  • the pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical, buccal, sublingual, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. Such compositions may be prepared by any methods well known in the art of pharmaceutical formulations and pharmacy. See, e.g., Remington: The Science and Practice of Pharmacy, Elsevier Science, 23rd ed. (
  • Formulations for parenteral administration include sterile aqueous or non- aqueous solutions, suspensions, or emulsions.
  • aqueous carriers may be used, e.g., water, buffered water, saline, and the like.
  • suitable vehicles include polypropylene glycol, polyethylene glycol, vegetable oils, hydrogels, gelatin, hydrogenated naphthalenes, and injectable organic esters, such as ethyl oleate.
  • Such formulations may also contain auxiliary substances, such as preserving, wetting, buffering, emulsifying, and/or dispersing agents.
  • compositions intended for oral use may be prepared in solid or liquid forms, according to any method known to a person of ordinary skill in the art for the manufacture of pharmaceutical compositions.
  • Solid dosage forms for oral administration include capsules (both soft and hard gelatin capsules), tablets, powders, and granules. Generally, these pharmaceutical preparations contain active ingredients admixed with pharmaceutically acceptable excipients.
  • excipients include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, sucrose, glucose, mannitol, cellulose, starch, calcium phosphate, sodium phosphate, kaolin and the like; binding agents, buffering agents, and/or lubricating agents (e.g., magnesium stearate) may also be used. Tablets and capsules may additionally be prepared with release-controlling coatings such as enteric coatings. The compositions may optionally contain sweetening, flavoring, coloring, perfuming, and preserving agents in order to provide a more palatable preparation. [0683] In another embodiment, a pharmaceutical composition of this invention further comprises a second therapeutic agent.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, sucrose, glucose, mannitol, cellulose, starch, calcium phosphate, sodium phosphate, kaolin and the like
  • binding agents e.g., magnesium
  • the second therapeutic agent may be selected from any pharmaceutically active compound; preferably the second therapeutic agent is known to correct mitochondrial dysfunction.
  • the compounds of the invention and second therapeutic agent may be administered together (within less than 24 hours of one another, consecutively or simultaneously) but in separate pharmaceutical compositions.
  • the compounds on the invention and second therapeutic agent may be administered separately (e.g., more than 24 hours of one another.) If the second therapeutic agent acts synergistically with the compounds of this invention, the therapeutically effective amount of such compounds and/or the second therapeutic agent may be less that such amount required when either is administered alone.
  • the compounds described herein may be administered in combination with a chemotherapeutic agent.
  • chemotherapeutic agents include, but are not limited to, Abitrexate (Methotrexate Injection), Abraxane (Paclitaxel Injection), Actemra (Tocilizumab), Adcetris (Brentuximab Vedotin Injection), Adriamycin (Doxorubicin), Adrucil Injection (5-FU (fluorouracil)), Afinitor (Everolimus), Afinitor Disperz (Everolimus), Aldara (Imiquimod), Alimta (PEMET EXED), Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arran
  • Acceptable 1 H NMR shifts and masses are within 5% of the reported values (i.e., all reported measurement values herein also include ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, and/or ⁇ 1%). All reported LCMS values herein also include ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, and/or ⁇ 1%. [0687] The abbreviations used herein are known to a person of ordinary skill in the art.
  • a partial list of abbreviations that may be used herein include: acetonitrile (MeCN), ammonium carbonate (NH4)2CO3, ammonium chloride (NH4Cl), aqueous (aq.), 1,1’- bis(diphenylphosphino)ferrocene (dppf), 1,3-bis(diphenylphosphino)propane (dppp), bis(pinacolato)diboron (B2pin2), N- bromosuccinimide (NBS), bromo-tris-pyrrolidino- phosphonium hexafluorophosphate (PyBroP),boron tribromide (BBr 3 ), butyl lithium (BuLi), calculated (Calcd.), cesium carbonate (Cs 2 CO 3 ), dichloromethane (DCM, CH 2 Cl 2 ), N,N-dicyclohexylcarbodiimide (DCC), dichloroethane (DCE), diethyl
  • Table 1 provides a listing of example compounds of the present invention and IC 50 values for inhibition of POLRMT.
  • Example 1 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Compound 301)
  • Compound 301 Synthesis of 1-(5-fluoro-2-methylphenyl)cyclopropane-1-carbonitrile, 2
  • Step 1 To a stirred solution of KOH (2.3 g, 40.2 mmol) in water (10 mL), 2-(5-fluoro-2- methylphenyl)acetonitrile (1, 500 mg, 3.4 mmol) and TBAB (216 mg, 0.67 mmol) were added at 0 °C.
  • Example 2 Synthesis of 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2- methylphenyl)cyclopropyl)-1,2,4-oxadiazole
  • Example 2 [0694] 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-1,2,4- oxadiazole was synthesized Scheme 1 using 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • LCMS (ESI) Calcd for C 17 H 17 FN 4 O: 312.1, found [M+H] + 313.2.
  • Example 3 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-methyl-1H- pyrazol-3-yl)-1,2,4-oxadiazole (Example 3): [0695] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole was synthesized following Scheme 1 using 1-methyl-1H-pyrazole-3-carboxylic acid.
  • LCMS (ESI) Calcd for C 16 H 15 FN 4 O: 298.1, found [M+H] + 299.2.
  • Example 4 Synthesis of 5-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2- methylphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 4): [0696] 5-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)- 1,2,4-oxadiazole was synthesized following Scheme 1 using 5-cyclopropyl-1-methyl-1H- pyrazole-3-carboxylic acid.
  • Example 5 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1- methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 5) [0697] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1-methyl-1H-pyrazol-3-yl)- 1,2,4-oxadiazole was synthesized following Scheme 1 using 5-isopropyl-1-methyl-1H-pyrazole- 3-carboxylic acid.
  • Example 6 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-phenyl-1H- pyrazol-3-yl)-1,2,4-oxadiazole (Example 6) [0698] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole was synthesized following Scheme 1 using 1-phenyl-1H-pyrazole-3-carboxylic acid.
  • LCMS (ESI) Calcd for C 21 H 17 FN 4 O: 360.3, found [M+H] + 361.2.
  • Example 7 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1- (pyridin-2-yl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 7) [0699] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1-(pyridin-2-yl)-1H-pyrazol-3- yl)-1,2,4-oxadiazole was synthesized following Scheme 1 using 5-isopropyl-1-(pyridin-2-yl)-1H- pyrazole-3-carboxylic acid.
  • Example 8 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-(2- fluorophenyl)-5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 8) [0700] 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-(2-fluorophenyl)-5-methyl-1H-pyrazol-3- yl)-1,2,4-oxadiazole was synthesized following Scheme 1 using 1-(2-fluorophenyl)-5-methyl-1H- pyrazole-3-carboxylic acid.
  • Example 9 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(3- fluorophenyl)cyclopropyl)-1,2,4-oxadiazole (Example 9) [0701] Synthesis of 1-(3-fluorophenyl)cyclopropane-1-carbonitrile, 6 [Step 1]: To a stirred solution of KOH (3.7 g, 66.6 mmol) in water(10 mL), 2-(3-fluorophenyl)acetonitrile (5, 750 mg, 5.6 mmol) and TBAB (360 mg, 1.1 mmol) were added at 0 °C.
  • Example 10 Synthesis of 3-(1-(3-fluorophenyl)cyclopropyl)-5-(1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 10) [0705] 3-(1-(3-fluorophenyl)cyclopropyl)-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4- oxadiazole was synthesized following Scheme 2 using 1-methyl-5-(trifluoromethyl)-1H- pyrazole-3-carboxylic acid.
  • Example 12 Synthesis of 5-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole [0707] Synthesis of 1-(o-tolyl)cyclopropane-1-carbonitrile, 10 [Step 1]: To a stirred solution of NaOH (31.79 g, 457 mmol) in water (50 mL), 2-(o-tolyl)acetonitrile (9, 5 g, 38.1 mmol) and TBAB (2.46 g, 7.62 mmol) were added at 0 °C.
  • Example 13 Synthesis of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 13) [0711] 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 3 using 1-methyl-5-(trifluoromethyl)-1H-pyrazole- 3-carboxylic acid.
  • Example 14 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 14) [0713] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 3 using 5-(difluoromethyl)-1-methyl-1H-pyrazole- 3-carboxylic acid.
  • Example 17 Synthesis of 5-(5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 17) [0719] Synthesis of ethyl 5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate, 15 [Step 1]: To a stirred solution of ethyl 5-(difluoromethyl)-1H-pyrazole-3-carboxylate (13, 2.0 g, 10.5 mmol) in DMF (50 mL) at 0°C, sodium hydride (505 mg, 12.6 mmol) was added at 0 o C.
  • aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ⁇ pH-5 and extracted with a mixture of dichloromethane and isopropyl alcohol (9:1). Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 5-(difluoromethyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylic acid (16, 320 mg).
  • Example 18 Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)propenamide (Example 18) [0724] Synthesis of ethyl 1-(3-amino-3-oxo-propyl)-5-(difluoromethyl)pyrazole-3-carboxylate, 18 and ethyl 2-(3-amino-3-oxo-propyl)-5-(difluoromethyl)pyrazole-3-carboxylate, 18a [Step 1]: To a stirred solution of ethyl 5-(difluoromethyl)-1H-pyrazole-3-carboxylate (13, 500 mg, 2.6 mmol) in dimethylformamide (25 mL), potassium carbonate (1.8 g, 13.1 mmol) was added.
  • the reaction mixture was stirred at ambient temperature for 3 h. After completion, the volatiles were evaporated under reduced pressure.
  • the aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ⁇ pH-5 and extracted with a mixture of ethyl acetate and isopropyl alcohol (1:9). Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • the products were purified by combi-flash chromatography to afford the first product as (Z)-3-(5-((((amino(1-(o-tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-3-(difluoromethyl)- 1H-pyrazol-1-yl)propanamide (20a, 120 mg) and the second product as (Z)-3-(3-((((amino(1-(o- tolyl)cyclopropyl)methylene)amino)oxy)carbonyl)-5-(difluoromethyl)-1H-pyrazol-1- yl)propanamide (20, 90 mg).
  • Example 19 Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 19) [0729] Synthesis of 5-(1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole, 25 [Step 1]: To a suspension of methyl 1H-pyrazole-3-carboxylate (265 mg, 2.1 mmol) and (Z)-N'-hydroxy-1- (o-tolyl)cyclopropane-1-carboximidamide (11, 400 mg, 2.1 mmol) in toluene (4 mL) was added potassium carbonate (581 mg, 4.2 mmol), and the reaction mixture was heated to reflux.
  • Example 21 Synthesis of 5-(5-methyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 21) [0733] Synthesis of 5-(5-methyl-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole, 27 [Step 1]: To a suspension of methyl 5-methyl-1H-pyrazole-3-carboxylate ( 295 mg, 2.1 mmol) and (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1-carboximidamide (11, 400 mg, 2.1 mmol) in toluene (4 mL) was added potassium carbonate (581 mg, 4.2 mmol), and the reaction mixture was heated to reflux.
  • potassium carbonate 581 mg, 4.2 m
  • Example 23 Synthesis of 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid (Example 23) [0739] Synthesis of methyl 5-(trifluoromethyl)-1H-pyrazole-3-carboxylate, 31 [Step 1]: To a stirred solution of 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (30, 900 mg, 5.0 mmol) in methanol (20 mL) at 0 °C was added thionyl chloride (0.73 mL, 10.0 mmol) dropwise.
  • Example 24 Synthesis of 3-(3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)propanamide (Example 24) [0746] Synthesis of 1-(o-tolyl)-N'-((5-(trifluoromethyl)-1H-pyrazole-3-carbonyl)oxy)cyclopropane- 1-carboximidamide, 35 [Step 1]: To a stirred solution of N'-hydroxy-1-(o-tolyl)cyclopropane-1- carboximidamide (11, 500 mg, 2.6 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (520 mg, 2.9 mmol) in dichloromethane (8 mL) were added DIPEA (1.4 mL, 7.9 mmol), EDC.HCl (1.0 g, 5.3 mmol)
  • Example 25 Synthesis of 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)propanoic acid (Example 25) [0750] Synthesis of methyl 5-cyclopropyl-1H-pyrazole-3-carboxylate, 38 [Step 1]: To a stirred solution of 5-cyclopropyl-1H-pyrazole-3-carboxylic acid (37, 1.5 g, 9.8 mmol) in methanol (30 mL) at 0 °C was added thionyl chloride (1.4 mL, 19.7 mmol) dropwise.
  • Example 26 Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-5-(trifluoromethyl)-1H-pyrazol-3- yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 26) [0755] Synthesis of 3-(1-(o-tolyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4- oxadiazole, 32 [Step 1]: To a stirred solution of (Z)-N'-hydroxy-1-(o-tolyl)cyclopropane-1- carboximidamide (11, 410 mg, 2.2 mmol) and ethyl 5-(trifluoromethyl)-1H-pyrazole-3- carboxylate (450 mg, 2.2 mmol) in toluene (6 mL) was added potassium carbonate (600 mg, 4.3 mmol
  • Example 27 Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-methylacetamide (Example 27)
  • Example 28 Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Example 28) [0764] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylate, 48 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H- pyrazol-1-yl)acetic acid (44, 350 mg, 1.4 mmol) in dry dimethylformamide (5 mL), N,N- diisopropylethylamine (0.9 mL, 4.9 mmol) and N-methylmethanamine hydrochloride (1.2 g, 14.1
  • Example 29 Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Example 29) [0768] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(oxetan-3-ylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylate, 3 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H- pyrazol-1-yl)acetic acid (44, 300 mg, 1.2 mmol) in dry tetrahydrofuran (10 mL), n-methyl morpholine (245 mg, 2.4 mmol) and isobutyl chloroformate (165 mg, 1.2
  • Example 30 Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one (Example 30) [0772] Synthesis of tert-butyl 4-(2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H-pyrazol-1- yl)acetyl)piperazine-1-carboxylate, 55 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3- (ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (44, 300 mg, 1.2 mmol) in dichloromethane (5 mL), N,N-diisopropylethylamine (0.04 mL, 0.2 mmol) and propane
  • tert-butyl piperazine-1- carboxylate 54, 225 mg, 1.2 mmol was added and the reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with dichloromethane, washed with saturated solution of aqueous sodium bicarbonate followed by brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography to afford tert-butyl 4-(2-(5-(difluoromethyl)-3-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetyl)piperazine-1-carboxylate (55, 450 mg).
  • Example 31 Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)acetamide (Example 31) [0776] Synthesis of ethyl 5-(difluoromethyl)-1-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)- 1H-pyrazole-3-carboxylate, 58 [Step 1]: To a stirred solution of 2-(5-(difluoromethyl)-3- (ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (44, 300 mg, 1.2 mmol) in dichloromethane (5 mL) were added DIPEA (0.6 mL, 3.6 mmol) and propy
  • Example 32 Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)acetamide
  • Example 32 [0780] Synthesis of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-(difluoromethyl)-1H- pyrazole-3-carboxylate, 61
  • Step 1] To a stirred solution of ethyl 5-(difluoromethyl)-1H-pyrazole- 3-carboxylate (13, 200 mg, 1.0 mmol) in tetrahydrofuran (5 mL), potassium tert-butoxide (355 mg, 3.1 mmol) was added.
  • reaction mixture was heated at 80 °C for 30 min and tert-butyl N-(2-bromoethyl)carbamate (235 mg, 1.0 mmol) was added.
  • the resulting reaction mixture was heated at 80 °C for 6 h.
  • the reaction mixture was quenched with crushed ice, extracted with ethyl acetate and washed with ice cold water and brine. Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • aqueous phase was acidified with 1 N aqueous solution of hydrochloric acid to ⁇ pH-5 and extracted with a mixture of dichloromethane and isopropyl alcohol (9:1). Combined organic extracts was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 1-(2-acetamidoethyl)-5- (difluoromethyl)-1H-pyrazole-3-carboxylic acid (64, 140 mg).
  • Example 34 Synthesis of 5-(5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3- yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 34) [0788] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3- carboxylate, 67 [Step 1]: To a stirred suspension of ethyl 5-(difluoromethyl)-1H-pyrazole-3- carboxylate (13, 1.0 g, 5.3 mmol) and potassium carbonate (2.9 g, 21.0 mmol) in DMF (60 mL) at 0 °C, 1-bromo-2-(methylsulfonyl)ethane (1.5 g, 7.9 mmol) was added.
  • reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with ice-cold water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • Example 35 Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoic acid (Example 35) [0794] Synthesis of tert-butyl 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)propanoate, 71 [Step 1]: To a stirred suspension of 5-(5-(difluoromethyl)- 1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 400 mg, 1.3 mmol) and potassium carbonate (1.2 g, 8.9 mmol) in dimethylformamide (10 m
  • Examples 36a & 36b 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine (Example 36a) & 2-(3-(difluoromethyl)-5- (3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1- amine (Example 36b)
  • peak-1 2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N- dimethylethan-1-amine (36a, 14 mg) and peak-2 as 2-(3-(difluoromethyl)-5-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine (36b, 25 mg).
  • Example 37 Synthesis of N-(2-amino-2-oxoethyl)-2-(5-(difluoromethyl)-3-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetamide (Example 37)
  • tert-butyl-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetate 70, 120 mg
  • tert-butyl 2-(3-(difluoromethyl)-5-(3-(1- (o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetate 72a, 200 mg.
  • Example 38 Synthesis of 1-((5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylic acid (Example 38) [0803] Synthesis of ethyl 1-((5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- y l)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylate, 74 [Step 1]: To a stirred solution of 5-[5- (difluoromethyl)-1H-pyrazol-3-yl]-3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazole (70, 200 mg, 0.632 mmol) in ace
  • Example 39 Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid (Example 39)
  • Scheme 26 [0805] Synthesis of 3-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-2,2-dimethylpropanoic acid, Example 39 and 3-(3-(difluoromethyl)-5-(3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid,
  • Example 178 [Step 1]: To a stirred solution of
  • Example 41 Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-methylethan-1-amine (Example 41) [0810] Synthesis of tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate, 75 [Step 1]: To a stirred solution of triphenylphosphine (1.2g , 1.9 mmol) in THF (15 mL) and DIAD (383.6 mg, 1.9 mmol) at 0 °C, 5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-3-(1-
  • Example 43 Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide (Example 43) [0817] Synthesis of ethyl tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)carbamate, 77 [Step 1]: To a stirred solution of 5-(5- (difluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (70, 340 mg, 1.0 mmol) in
  • Example 44 Synthesis of 2-[5-(difluoromethyl)-3-[3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]- 1H-pyrazol-1-yl]acetic acid (Example 44) Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol- 1-yl)acetic acid, Example 44 [Step 1]: To a stirred solution of tert-butyl 2-(5-(difluoromethyl)-3- (3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetate (72, 200 mg, 0.5 mmol) in dichloromethane (10 mL), trifluoroacetic acid (0.36 m
  • Example 45 Synthesis of N-(2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)ethyl)-N-methylacetamide (Example 45) Sc e e 3 [0820] Synthesis of tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate, 79 [Step 1]: To a stirred solution of triphenylphosphine (1.2g , 1.9 mmol) in THF (15 mL) and DIAD (383.6 mg, 1.9 mmol) at 0 °C, 5-(5-(difluoromethyl)-1H-
  • Example 47 Synthesis of (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)acetyl)glycine (Example 47) [0824] Synthesis of tert-butyl (2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-1H-pyrazol-1-yl)acetyl)glycinate, 81 [Step 1]: To a stirred solution of 2-[5-(difluoromethyl)- 3-[3-[1-(o-tolyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]-1H-pyrazol-1-yl]acetic acid (Example 44, 220 mg, 0.6 mmol)
  • tert-butyl g lycinate 157 mg, 1.2 mmol was added and the resulting reaction mixture was allowed to stir at ambient temperature for 16 h.
  • the reaction mixture was diluted with dichloromethane, washed with saturated solution of sodium bicarbonate followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • Example 48 Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-(2-methoxyethyl)acetamide (Example 48) [0826] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-(2-methoxyethyl)acetamide, Example 48 [Step 1]: To a stirred solution of 2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetic acid (Example 44, 70 mg,
  • Example 49 Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide
  • Scheme 36 [0827] Synthesis of 2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide
  • Example 49 [Step 1]: To a stirred solution of 2-(5- (difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)acetic acid (Example 44, 120 mg, 0.3
  • Example 50 Synthesis of (S)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-1H-pyrazol-1-yl)-1-(3-(dimethylamino)pyrrolidin-1-yl)ethan-1-one (Example 50) [0828] Synthesis of (S)-2-(5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 1H-pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide, Example 50 [Step 1]: To a stirred solution of 2- (5-(difluoromethyl)-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1
  • Example 54 Synthesis of 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-1H-pyrazol-1-yl)propenamide (Example 54) [0836] Synthesis of 3-(5-cyclopropyl-3-(3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H- pyrazol-1-yl)propenamide, Example 54 [Step 5]: To a stirred solution of 3-(5-cyclopropyl-3-(3-(1- (o-tolyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)propanoic acid (Example 22, 60 mg, 0.16 mmol) in DMF (3 mL), were added HATU (90 mg, 0.24 mmol), DIPEA (0.
  • Examples 55a & 55b Synthesis of 5-(4-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 55a) and 5-(4-(difluoromethyl)-1-methyl-1H- pyrazol-5-yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 55b)
  • Example 56 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-2-(1-(o- t olyl)cyclopropyl)oxazole (Example 56) [0840] Synthesis of 5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl chloride, 88 [Step 1]: To a stirred solution of 5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carboxylic acid (87, 140 mg, 0.8 mmol) in SOCl 2 (5.0 mL, 70 mmol) was heated at 60 °C added and stirred for 2 h.
  • Example 56 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-2-(1-(o- tolyl)cyclopropyl)oxazole (Example 56) [0843] Synthesis of 1-(o-tolyl)cyclopropane-1-carboxylic acid, 92 [Step 1]: To a stirred solution of 1-(o-tolyl)cyclopropane-1-carbonitrile (10, 1.00 g, 6 mmol) in 4M LiOH.H 2 O aq. solution (8.0 mL, 25 mmol) was refluxed at 100 °C for 24h with continue stirring.
  • reaction mixture was stirred at ambient temperature for 1 h.
  • the reaction mixture was concentrated under reduced pressure, diluted with water and extracted with 1,2 dichloromethane. The organic extracts were then separated and under reduced pressure.
  • the product was purified by reverse phase prep HPLC purification to afford N-(2-(5-(difluoromethyl)- 1-methyl-1H-pyrazol-3-yl)-2-oxoethyl)-1-(o-tolyl)cyclopropane-1-carboxamide (94, 120 mg).
  • Examples 57a & 57b Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 57a) [0849] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-3- carboxylate, 67 [Step 1]: To a stirred suspension of ethyl 5-(difluoromethyl)-1H-pyrazole-3- carboxylate (13, 1 g, 5.3 mmol) and potassium carbonate (2.9 g, 21.03 mmol) in dimethylformamide (60 mL) at 0 °C, 1-bromo-2-(methylsulfonyl)ethane (1.
  • Example 57b was isolated as other regio-isomer.
  • Examples 58-64 were synthesized in a manner similar to Example 57 from the corresponding pyrazole carboxylic acid.
  • Example 58 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Examples 58) [0855] 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole was synthesized following Scheme 45 using 1-bromo-2-(methylsulfonyl)ethane.
  • Examples 59 & 60 Synthesis of (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)propanamide, (Example 59) and (R)-2-(3-(3- (1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1- yl)propenamide (Example 60) [0856] (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)propenamide and (R)-2-(3-
  • Example 61 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-(3- (methylsulfonyl)propyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 61) [0860] 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-(3- (methylsulfonyl)propyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 61)was synthesized following Scheme 45 using 1-bromo-3-(methylsulfonyl)propane.
  • Example 62 Synthesis of 3-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)thietane 1,1-dioxide (Example 62) [0861] 3-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)thietane 1,1-dioxide (Example 62) was synthesized following Scheme 45 using 3-bromothietane 1,1-dioxide.
  • Example 63 Synthesis of 3-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)propenamide (Example 63) [0862] 3-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)propenamide (Example 63) was synthesized following Scheme 45 using 3- bromopropanamide.
  • Example 64 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)acetamide (Example 64) [0863] 2-(5-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-3-(difluoromethyl)- 1H-pyrazol-1-yl)acetamide (Example 64) was synthesized following Scheme 45 using 3-2- bromoacetamide. LCMS (ESI) Calcd.
  • Example 66 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2,2,2 trifluoroethyl)acetamide (Example 66) [0868] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamid (Example 66) was synthesized following Scheme 46 using 2,2,2-trifluoroethan-1-amine.
  • Example 67 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide (Example 67) [0869] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-hydroxyethyl)acetamide (Example 67) was synthesized following Scheme 46 using 2-aminoethan-1-ol.
  • Example 68 Synthesis of N-(2-amino-2-oxoethyl)-2-(3-(3-(1-(2-chloro-4- fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamide
  • Example 68 N-(2-Amino-2-oxoethyl)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamide
  • Example 68 was synthesized following Scheme 46 using 2-aminoacetamide.
  • Example 69 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide (Example 69) [0871] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide (Example 69) was synthesized following Scheme 46 using 2-(methylamino)ethan-1-ol.
  • Example 72 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Example 72) [0874] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Example 72) was synthesized following Scheme 46 using 2,2,2-trifluoro-N-methylethan-1-amine.
  • Example 73 Synthesis of (R)-2-(2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamido)propenamide (Example 73) [0875] (R)-2-(2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)acetamido)propanamide (Example 73) was synthesized following Scheme 46 using (R)-2-aminopropanamide.
  • Example 74 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylacetamide (Example 74) [0876] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylacetamide (Example 74) was synthesized following Scheme 46 using N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine.
  • Example 75 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-methoxyethyl)-N-methylacetamide (Example 75) [0877] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-methoxyethyl)-N-methylacetamide (Example 75) was synthesized following Scheme 46 using 2-methoxy-N-methylethan-1-amine.
  • Example 76 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-hydroxy-2-methylpropyl)acetamide (Example 76) [0878] 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-hydroxy-2-methylpropyl)acetamide (Example 76) was synthesized following Scheme 46 using 1-amino-2-methylpropan-2-ol.
  • Example 77 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-((1-methylpiperidin-4-yl)methyl)acetamide (Example 77) [0879] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-((1-methylpiperidin-4-yl)methyl)acetamide (Example 77) was synthesized following Scheme 46 using (1-methylpiperidin-4-yl)methanamine.
  • Example 78 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(1-cyanocyclopropyl)acetamide (Example 78) [0880] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(1-cyanocyclopropyl)acetamide (Example 78) was synthesized following Scheme 46 using 1-aminocyclopropane-1-carbonitrile.
  • Example 79 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-(methylamino)-2-oxoethyl)acetamide (Example 79) [0881] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-(methylamino)-2-oxoethyl)acetamide (Example 79) was synthesized following Scheme 46 using 2-amino-N-methylacetamide.
  • Example 80 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(cyclopropylmethyl)acetamide (Example 80) [0882] 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(cyclopropylmethyl)acetamide (Example 80) was synthesized following Scheme 46 using cyclopropylmethanamine.
  • Example 81 Synthesis of N-(2-amino-2-oxoethyl)-2-(3-(3-(1-(2-chloro-4- fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N- methylacetamide (Example 81) [0883] N-(2-Amino-2-oxoethyl)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N-methylacetamide (Example 81) was synthesized following Scheme 46 using 2-(methylamino)acetamide.
  • Example 82 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(cyclobutylmethyl)acetamide (Example 82) [0884] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(cyclobutylmethyl)acetamide was synthesized following Scheme 46 using cyclobutylmethanamine.
  • Example 83 Synthesis of (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxypyrrolidin-1-yl)ethan-1-one (Example 83) [0885] (S)-2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxypyrrolidin-1-yl)ethan-1-one (Example 83) was synthesized following Scheme 46 using (S)-3-methoxypyrrolidine.
  • Example 84 Synthesis of (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxypyrrolidin-1-yl)ethan-1-one (Example 84) [0886] (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxypyrrolidin-1-yl)ethan-1-one (Example 84) was synthesized following Scheme 46 using (R)-3-methoxypyrrolidine.
  • Example 85 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3-methoxyazetidin-1-yl)ethan-1-one (Example 85) [0887] 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-1-(3-methoxyazetidin-1-yl)ethan-1-one (Example 85) was synthesized following Scheme 46 using 3-methoxyazetidine.
  • Example 86 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3,3-difluoropyrrolidin-1-yl)ethan-1-one (Example 86) [0888] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-1-(3,3-difluoropyrrolidin-1-yl)ethan-1-one (Example 86) was synthesized following Scheme 46 using 3,3-difluoropyrrolidine.
  • Example 87 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Example 87) [0889] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Example 87) was synthesized following Scheme 46 using pyrrolidine.
  • Example 88 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)ethan-1-one (Example 88) [0890] 2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)ethan-1-one (Example 88) was synthesized following Scheme 46 using 3,3-difluoroazetidine.
  • Example 89 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-hydroxy-2-methylpropyl)-N-methylacetamide (Example 89) [0891] 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)- 1H-pyrazol-1-yl)-N-(2-hydroxy-2-methylpropyl)-N-methylacetamide (Example 89) was synthesized following Scheme 46 using 2-methyl-1-(methylamino)propan-2-ol.
  • Examples 90 & 91 Synthesis of (S)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide (Example 90) & (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide (Example 91) [0892] (S)-2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5
  • Preparative chiral HPLC method SFC preparative purification was performed on Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using C Amylose A (30.0 mm x 250mm ), 5 ⁇ Column operating at 35 oC temperature, maintaining flow rate of 110 ml/min, using 75 % CO2 in super critical state & 25% of methanol as mobile phase, Run this isocratic mixture up to 14.0 minutes and also maintained the isobaric condition of 100 bar at 254 nm wavelength.
  • Example 92 Synthesis of (S)-2-(2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamido)propenamide (Example 92) [0896] (S)-2-(2-(3-(3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-pyrazol-1-yl)acetamido) propanamide (Example 92) was synthesized following Scheme 46 using 2-aminopropanamide.
  • Preparative chiral HPLC method SFC preaparative purification was performed on Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using I Cullulose J (30.0 mm x 250 mm), 5 min column operating at 35 °C temperature, maintaining flow rate of 90 mL/min, using 85% CO2 in super critical state and 15% of MeOH mobile phase. Run this isocratic mixture up to 14 min and also maintained the isobaric condition of 100 bar at 220 nm.
  • Example 93 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(piperidin-4-ylmethyl)acetamide (Example 93)
  • Scheme 47 [0898] Synthesis of tert-butyl 4-((2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamido)methyl)piperidine-1-carboxylate, 101 [Step 1]: tert-Butyl 4-((2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadia
  • Example 94 Synthesis of (2-(3-(3-(1-(2-chloro-4-fluorophenyl) cyclopropyl)-1,2,4-oxadiazol-5- yl)-5-(difluoromethyl)-1H-pyrazol-1-yl) acetyl) glycine (Example 94)
  • Example 96 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)- 5-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one (Example 96) Scheme 50 [0905] Synthesis of tert-butyl 4-(2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)piperazine-1-carboxylate, 106 [Step 1]: tert-Butyl 4-(2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-
  • Examples 97 & 98 Synthesis of (R)-2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)propanoic acid (Example 97) and (S)-2-(3-(3- (1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1- yl)propanoic acid (Example 98) Scheme 51 [0907] Synthesis of tert-butyl 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5- yl)-5-(difluoromethyl)-1H-pyrazol-1-y
  • Example 99 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-methyl-1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 99) [0912] Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-methyl-1H-pyrazol-3-yl)- 1,2,4-oxadiazole, 113 [Step 1]: 3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-5-(5-methyl-1H- p yrazol-3-yl)-1,2,4-oxadiazole 113 was synthesized following Scheme 49 using methyl 5- methyl-1H-pyrazole-3-carboxylate.
  • Example 100 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(1-(2- (methylsulfonyl)ethyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 100) [0914] Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(trifluoromethyl)-1H-pyrazol- 3-yl)-1,2,4-oxadiazole, 115 [Step 1]: 3-(1-(2-Chloro-4-fluorophenyl)cyclopropyl)-5-(5- (trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole 115 was synthesized following Scheme 49 using methyl 5-(trifluoromethyl)-1H-pyrazole-3-carboxylate.
  • Example 101 Synthesis of 2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)-N-(oxetan-3-yl)acetamide (Example 101)
  • Scheme 54 [0916] Synthesis of ethyl 5-(difluoromethyl)-1-(2-(oxetan-3-ylamino)-2-oxoethyl)-1H-pyrazole-3- carboxylate, 116 (Step-1): Ethyl 5-(difluoromethyl)-1-(2-(oxetan-3-ylamino)-2-oxoethyl)-1H- pyrazole-3-carboxylate (116) was synthesized following Scheme 49 using oxetan-3-amine.
  • Example 102 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(1-(2- (methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 102)
  • Examples 103a & 103b Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(4- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 103a) [0920] Synthesis of methyl 4-formyl-1-methyl-1H-pyrazole-3-carboxylate, 120 & 120a [Step 1]: To a solution of methyl 4-formyl-1H-pyrazole-3-carboxylate (119, 700 mg, 4.5 mmol) in DMF (5 mL), K 2 CO 3 (1.2 g, 9.0 mmol) was added and the reaction mixture was stirred for 15 minutes under nitrogen atmosphere.
  • Example 104 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(4,5-dimethyl-1- (2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 104) Scheme 57 [0923] Synthesis of (Z)-1-(2-chloro-4-fluorophenyl)-N'-((4,5-dimethyl-1H-pyrazole-3- carbonyl)oxy)cyclopropane-1-carboximidamide, 123 [Step-1]: To a stirred solution of 4,5- dimethyl-1H-pyrazole-3-carboxylic acid (122, 120 mg, 0.9 mmol) and (Z)-1-(2-chloro-4- fluorophenyl)-N'-hydroxycyclopropane-1-carboximidamide (215 mg, 0.9 mmol) in dichloromethane (2 mL), DI
  • Example 105 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(1-(2- (methylsulfonyl)ethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-1,2,4-oxadiazole (Example 105) [0926] Synthesis of (Z)-1-(2-chloro-4-fluorophenyl)-N'-((1,4,5,6-tetrahydrocyclopenta[c]pyrazole- 3-carbonyl)oxy)cyclopropane-1-carboximidamide, 126 [Step-1]: To a stirred solution of 1,4,5,6- tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid (125, 110 mg, 0.7 mmol) and (Z)-1-(2-chloro- 4-fluorophenyl)-N'-hydroxycyclopropane-1-car
  • Examples 106a & 106b Synthesis of 5-(5-Bromo-4-methyl-1-(2-(methylsulfonyl)ethyl)-1H- pyrazol-3-yl)-3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazole (Example 106a) and 5-(3-bromo-4-methyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-5-yl)-3-(1-(2-chloro-4- fluorophenyl)cyclopropyl)-1,2,4-oxadiazole (Example 106b) [0929] Synthesis of methyl 5-bromo-4-methyl-1H-pyrazole-3-carboxylate, 129 [Step 1]: To a solution of methyl 4-methyl-1H-pyrazole-3-carboxylate (128, 100 mg, 0.7 mmol) in water (1 mL),
  • Methyl 5- bromo-4-methyl-1H-pyrazole-3-carboxylate (129, 80 mg, 0.37 mmol) was added to the reaction mixture and the resulting reaction mixture was heated at 100 °C for 16 h. After completion, volatiles were evaporated, diluted with ethyl acetate and washed with water (twice). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Example 107 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(1,4-dimethyl-1H- pyrazol-3-yl)-1,2,4-oxadiazole (Example 107) [0934] Synthesis of (Z)-1-(2-chloro-4-fluorophenyl)-N'-((1,4-dimethyl-1H-pyrazole-3- carbonyl)oxy)cyclopropane-1-carboximidamide, 132 [Step 1]: To a solution of (Z)-1-(2-chloro-4- fluorophenyl)-N'-hydroxycyclopropane-1-carboximidamide (185 mg, 0.811 mmol) and 1,4- dimethyl-1H-pyrazole-3-carboxylic acid ( 131, 125 mg, 0.89 mmol) in dichloromethane (1 mL), DIPEA ( 0.39 mL, 2.21 mmol ),
  • Example 108 Synthesis of 3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-4-methyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazole-5-carbaldehyde (Example 108) [0936] Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(4-methyl-1-(2- (methylsulfonyl)ethyl)-5-vinyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole, 133 [Step 1]: To a stirred solution of 5-(5-bromo-4-methyl-1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)-3-(1-(2-chloro-4- fluorophenyl)cyclopropyl)-1,2,4-
  • Example 110 Synthesis of 2-(2-(3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4- oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-methylpropanoic acid (Example 110)
  • Examples 111a & 111b Synthesis of 1-((3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)- 1,2,4-oxadiazol-5-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylic acid (Example 111a) and 1-((5-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol- 5-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl)methyl)cyclopropane-1-carboxylic acid (Example 111b) [0941] Synthesis of 1-((3-(3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-5- (difluoromethyl)-1H-
  • reaction mixture was stirred for 15 min and ethyl 1- (bromomethyl) cyclopropanecarboxylate (210 mg, 1 mmol) was added. Resulting reaction mixture was stirred at ambient temperature for 16 h, quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate and washed with water followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • 1 H NMR 400 MHz, DMSO-d 6 ): ⁇ H 7.85-7.6 (m, 2H), 7.50-7.47 (dd, 1H), 7.27-7.22 (m, 1H), 7.20 (s, 1H), 4.47 (s, 2H), 1.71 (m, 2H), 1.47-1.44 (m, 2H), 1.11 (s, 2H), 1.02 (s, 2H).
  • Example 111b LCMS (ESI) Calcd.
  • Example 112 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1- phenylcyclopropyl)-1,2,4-oxadiazole (Example 112) [0942] Synthesis of ethyl 5-(difluoromethyl)-1H-pyrazole-3-carboxylate, 13 [Step-1]: 2,2- difluoroethan-1-amine (138, 5.0 g, 61.7 mmol), tert-Butyl nitrite (8.8 mL, 74.0 mmol) and acetic acid (0.4 mL, 6.2 mmol) was taken in chloroform (5 ml) and heated to 55 °C for 20 min.
  • Example 113 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-fluoro-5- methylphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 113) [0951] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-fluoro-5- methylphenyl)cyclopropyl)-1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'- ((5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)-1-(2-fluoro-5- methylphenyl)cyclopropane-1-carboximidamide.
  • Example 114 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(pyridin-2- yl)cyclopropyl)-1,2,4-oxadiazole (Example 114) [0952] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(pyridin-2-yl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1-methyl-1H- pyrazole-3-carbonyl)oxy)-1-(pyridin-2-yl)cyclopropane-1-carboximidamide.
  • Example 115 Synthesis of 3-(1-(2-bromophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1- methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 115) [0953] 3-(1-(2-bromophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazole was synthesized following Scheme 64 using (Z)-1-(2-bromophenyl)-N'-((5- (difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1-carboximidamide.
  • Example 116 Synthesis of 3-(1-(2-chlorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1- methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 116) [0954] 3-(1-(2-chlorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazole was synthesized following Scheme 64 using (Z)-1-(2-chlorophenyl)-N'-((5- (difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1-carboximidamide.
  • Example 117 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(pyridin-3- yl)cyclopropyl)-1,2,4-oxadiazole (Example 117) [0955] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(pyridin-3-yl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1-methyl-1H- pyrazole-3-carbonyl)oxy)-1-(pyridin-3-yl)cyclopropane-1-carboximidamide.
  • Example 118 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(pyridin-4- yl)cyclopropyl)-1,2,4-oxadiazole (Example 118) [0956] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(pyridin-4-yl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1-methyl-1H- pyrazole-3-carbonyl)oxy)-1-(pyridin-4-yl)cyclopropane-1-carboximidamide.
  • Example 119 Synthesis of 3-(1-(3-chloro-5-fluorophenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 119) [0957] 3-(1-(3-chloro-5-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3- yl)-1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-1-(3-chloro-5- fluorophenyl)-N'-((5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1- carboximidamide.
  • Example 120 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(2-(5-fluoro-2- methylphenyl)propan-2-yl)-1,2,4-oxadiazole (Example 120) [0958] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(2-(5-fluoro-2-methylphenyl)propan-2- yl)-1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1- methyl-1H-pyrazole-3-carbonyl)oxy)-1-(3-fluoro-5-methylphenyl)cyclopropane-1- carboximidamide.
  • Example 121 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(p- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 121) [0959] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(p-tolyl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1-methyl-1H- pyrazole-3-carbonyl)oxy)-1-(p-tolyl)cyclopropane-1-carboximidamide.
  • Example 122 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(m- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 122) [0960] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(m-tolyl)cyclopropyl)-1,2,4- oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1-methyl-1H- pyrazole-3-carbonyl)oxy)-1-(m-tolyl)cyclopropane-1-carboximidamide.
  • Example 123 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(3- methylpyridin-2-yl)cyclopropyl)-1,2,4-oxadiazole (Example 123) [0961] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(3-methylpyridin-2-yl)cyclopropyl)- 1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1- methyl-1H-pyrazole-3-carbonyl)oxy)-1-(3-methylpyridin-2-yl)cyclopropane-1-carboximidamide.
  • Example 124 Synthesis of 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 124) [0962] 3-(1-(2-chloro-4-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3- yl)-1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1- methyl-1H-pyrazole-3-carbonyl)oxy)-1-(2-(trifluoromethyl)phenyl)cyclopropane-1- carboximidamide.
  • Example 125 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2- methylpyridin-3-yl)cyclopropyl)-1,2,4-oxadiazole (Example 125) [0963] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-methylpyridin-3-yl)cyclopropyl)- 1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1- methyl-1H-pyrazole-3-carbonyl)oxy)-1-(2-methylpyridin-3-yl)cyclopropane-1-carboximidamide.
  • Example 126 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2,5- difluorophenyl)cyclopropyl)-1,2,4-oxadiazole (Example 126) [0964] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2,5-difluorophenyl)cyclopropyl)- 1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1- methyl-1H-pyrazole-3-carbonyl)oxy)-1-(2,5-difluorophenyl)cyclopropane-1-carboximidamide.
  • Example 127 Synthesis of 3-(1-(2-chloro-5-fluorophenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 127) [0965] 3-(1-(2-chloro-5-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3- yl)-1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-1-(2-chloro-5- fluorophenyl)-N'-((5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1- carboximidamide.
  • Example 128 Synthesis of 3-(1-(2-chloro-3-fluorophenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 128) [0966] 3-(1-(2-chloro-3-fluorophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3- yl)-1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-1-(2-chloro-3- fluorophenyl)-N'-((5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)cyclopropane-1- carboximidamide.
  • Example 129 Synthesis of (5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2,5- dimethylphenyl) cyclopropyl)-1,2,4-oxadiazole (Example 129) [0967] (5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2,5-dimethylphenyl) cyclopropyl)- 1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1- methyl-1H-pyrazole-3-carbonyl)oxy)-1-(2,5-dimethylphenyl)cyclopropane-1-carboximidamide.
  • Example 130 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-methyl- 5-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazole (Example 130) [0968] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-methyl-5-(trifluoromethyl)phenyl) cyclopropyl) -1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5- (difluoromethyl)-1-methyl-1H-pyrazole-3-carbonyl)oxy)-1-(2-methyl-5- (trifluoromethyl)phenyl)cyclopropane-1-carboximidamide.
  • Example 131 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2- phenoxyphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 131) [0969] 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-phenoxyphenyl)cyclopropyl)- 1,2,4-oxadiazole was synthesized following Scheme 64 using (Z)-N'-((5-(difluoromethyl)-1- methyl-1H-pyrazole-3-carbonyl)oxy)-1-(2-phenoxyphenyl)cyclopropane-1-carboximidamide.
  • Example 132 Synthesis of 2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazol-3-yl)cyclopropyl)benzoic acid (Example 132)
  • Example 133 Synthesis of 2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazol-3-yl)cyclopropyl)benzamide (Example 133)
  • Example 134 Synthesis of 2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazol-3-yl)cyclopropyl)-N-methylbenzamide (Example 134) Scheme 67 [0978] Synthesis of 2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)cyclopropyl)-N-methylbenzamide, Example 134 [Step 1]: To a stirred solution of 2-(1-(5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)cyclopropyl)benzoic acid (Example 132, 100 mg, 0.3 mmol) in DMF (2 mL), N,N-diisopropylethylamine (0.2
  • Example 135 Synthesis of 2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazol-3-yl)cyclopropyl)-N,N-dimethylbenzamide (Example 135) [0979] Synthesis of 2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)cyclopropyl)-N,N-dimethylbenzamide, 135 [Step 1]: To a stirred solution of 2-(1-(5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)cyclopropyl)benzoic acid (132, 100 mg, 0.3 mmol) in DMF (2 mL), N,N-diisopropylethylamine (0.2
  • Example 136 Synthesis of 2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazol-3-yl)cyclopropyl)benzonitrile (Example 136) [0980] Synthesis of 2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)cyclopropyl)benzonitrile, 136 [Step 1]: To a solution of 2-(1-(5-(5-(difluoromethyl)-1-methyl- 1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)cyclopropyl)benzamide (133, 90 mg, 0.3 mmol) and triethylamine (0.25 mL, 1.5 mmol) in dry dichloromethane (5 mL) at 0 °C, triflu
  • Example 137 Synthesis of (2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)methanol (Example 137) [0981] Synthesis of (2-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)methanol, Example 138 [Step 1]: To a stirred solution of 2-(1-(5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)cyclopropyl)benzaldehyde (149, 200 mg, 0.6 mmol) in THF (3 mL), sodium borohydride (45 mg, 1.2 mmol) was added at
  • Example 138 Synthesis of (2-(1-(5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)methanol (Example 138) [0983] Synthesis of (2-(1-(5-(5-(difluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)methanol, Example 138 [Step 1]: To a stirred solution of 2-(1-(5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)cyclopropyl)benzaldehyde (149, 30 mg, 0.1 mmol) in tetrahydrofuran (1 mL), sodium borohydride (6.6 mg, 0.2mmol) was added at 0
  • Example 139 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2- ethylphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 139) [0984] Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2- ethylphenyl)cyclopropyl)-1,2,4-oxadiazole, Example 139 [Step 6]: A stirred solution of 5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-vinylphenyl)cyclopropyl)-1,2,4-oxadiazole (148, 150 mg, 0.4 mmol) in ethanol (4 mL) was purged with Argon gas for 5 min.
  • Example 140 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-(methyl- d 3 )phenyl)cyclopropyl)-1,2,4-oxadiazole (Example 140) Scheme 73 [0985] Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-(methyl- d3)phenyl)cyclopropyl)-1,2,4-oxadiazole, Example 140, (Step-1): To a stirred solution of 3-(1-(2- bromophenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 115, 80 mg, 0.2 mmol) in 1,4-dioxane (2 mL) and water (0.5mL) mixture,
  • Example 141 Synthesis of 3-(1-(2-cyclopropylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1- methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 141)
  • Example 142 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-fluoro-6- methylphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 142)
  • Scheme 75 [0987] Synthesis of 2-(2-fluoro-6-methylphenyl)acetonitrile, 151
  • Step 1 To a stirred solution of 2-(bromomethyl)-1-fluoro-3-methylbenzene (150, 1.0 g, 4.9 mmol) in acetonitrile (10 mL), K 2 CO 3 (1.4 g, 9.9 mmol) was added followed by trimethylsilylformonitrile (0.9 mL, 7.4 mmol) and the resulting reaction mixture was heated at 100 °C for 16h.
  • Example 144 Synthesis of 3-(1-(5-bromo-2-methylphenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 144) [0998] Synthesis of 4-bromo-2-(bromomethyl)-1-methylbenzene, 163 [Step 1]: To a suspension of (5-bromo-2-methylphenyl) methanol (162, 1.5 g, 7.5 mmol) in dichloromethane (10 mL), PBr 3 (0.8 mL, 8.2 mmol) was added drop wise at 0 °C and the reaction mixture was stirred at same temperature for 1h.
  • PBr 3 0.8 mL, 8.2 mmol
  • Example 145 Synthesis of (3-(1-(5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4- oxadiazol-3-yl)cyclopropyl)-4-methylphenyl)methanol (Example 145) [1004] Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(2-methyl-5- vinylphenyl)cyclopropyl)-1,2,4-oxadiazole, 169 [Step 1]: To a stirred solution of potassium vinyl trifluoroborate (2, 80 mg, 0.6 mmol) in 1,4-dioxane (8 mL):Water (2mL) mixture, K 2 CO 3 (255 mg, 1.8 mmol) and 3-(1-(5-bromo-2-methylphenyl)cyclopropyl)-5-(5-(difluoromethyl)-1-methyl-1H-
  • Example 146 Synthesis of 3-(1-(2-(cyclopentyloxy)phenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 146)
  • Scheme 79 [1007] Synthesis of 2-(2-(cyclopentyloxy)phenyl)acetonitrile, 172 [Step 1]: To a stirred solution of 2-(2-hydroxyphenyl)acetonitrile (171, 500 mg, 4 mmol) and bromocyclopentane (840 mg, 5.5 mmol) in DMSO (5 mL), K 2 CO 3 was added (1.0 g, 7.5 mmol).
  • Example 147 Synthesis of 3-(1-(5-chloro-2-methylphenyl)cyclopropyl)-5-(5- (difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 147)
  • Example 150 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(5-fluoro-2- methylphenyl)cyclopropyl)isoxazole (Example 150)
  • Example 151 Synthesis of 3-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-5-(1-(5-fluoro-2- methylphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 151) [1033] Synthesis of 5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carboxamide, 197 [Step 1: To a stirred solution of 5-(difluoromethyl)-1-methyl-1H-pyrazole-3-carboxylic acid (87, 200 mg, 1.2 mmol) in THF (2mL) and DMF (1mL) were added HOBt (230 mg, 1.70 mmol),EDC.HCl (330 mg, 1.70 mmol) and DIPEA (0.62 mL, 4.6 mmol) followed by (NH 4 ) 2 CO 3 (440 mg, 4.6 mmol) and stirred the reaction mixture at ambient temperature for 17 h.
  • Example 152 Synthesis of 2-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-5-(1-(5-fluoro-2- methylphenyl)cyclopropyl)-1,3,4-oxadiazole (Example 152)
  • Scheme 84 [1038] Synthesis of 1-(5-fluoro-2-methylphenyl)cyclopropane-1-carbohydrazide, 202 [Step 1]: To a stirred solution of 1-(5-fluoro-2-methylphenyl)cyclopropane-1-carboxylic acid (201, 500 mg, 2.6 mmol) in DMA (2mL) was added DIPEA (0.9 mL, 5.2 mmol) followed by EDC.HCl (494 mg, 2.6 mmol) and HOBT (348 mg, 2.6 mmol) and stirred at 0 °C for 15 mins.
  • Example 153 Synthesis of 3-(1-(2-chloro-3-fluorophenyl)cyclopropyl)-5-(1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 153)
  • Scheme 85 [1041] Synthesis of 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid, 205 [Step 1] : To a stirred solution of ethyl 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (204, 450 mg, 2.20 mmol) in THF(2 mL), methanol(1 mL) and water (0.5 mL), LiOH.H 2 O ( 278 mg, 6.61 mmol) was added at 0 °C and the reaction mixture was stirred for 12h at ambient temperature.

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Abstract

La présente invention concerne de nouveaux composés d'oxadiazole et des composés qui sont des inhibiteurs de l'ARN polymérase mitochondriale.
PCT/US2024/053724 2023-10-30 2024-10-30 Compositions et inhibiteurs de polrmt Pending WO2025096660A1 (fr)

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WO2023177700A2 (fr) * 2022-03-16 2023-09-21 Anima Biotech Inc. Modulateurs de traduction d'arnm c-myc et leurs utilisations dans le traitement du cancer

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WO2023034346A1 (fr) * 2021-08-30 2023-03-09 Pretzel Therapeutics, Inc. Composés de chromèn-2-one modulateurs de polrmt
WO2023034344A1 (fr) * 2021-08-30 2023-03-09 Pretzel Therapeutics, Inc. Isoquinolinones et quinolinones utiles comme modulateurs de polrmt

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US20080280876A1 (en) * 2006-12-15 2008-11-13 Hobson Adrian D Novel oxadiazole compounds
US8470811B2 (en) * 2010-05-08 2013-06-25 Bayer Intellectual Property Gmbh Substituted heterocyclylbenzylpyrazoles and use thereof
WO2023177700A2 (fr) * 2022-03-16 2023-09-21 Anima Biotech Inc. Modulateurs de traduction d'arnm c-myc et leurs utilisations dans le traitement du cancer

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DATABASE PubChem 13 September 2019 (2019-09-13), ANONYMOUS: "3-[1-(5-Fluoro-2-methylphenyl)cyclopropyl]-5-(5-methoxy-1-methylpyrazol-3-yl)-1,2,4-oxadiazole | C17H17FN4O2 ", XP093311711, Database accession no. CID 139002672 *
DATABASE PubChem 15 June 2016 (2016-06-15), ANONYMOUS: "N-methyl-1-[5-(1-phenylpyrazol-3-yl)-1,2,4-oxadiazol-3-yl]propan-2-amine | C15H17N5O | ", XP093311718, Database accession no. CID 120387505 *
DATABASE PubChem 23 November 2020 (2020-11-23), ANONYMOUS: "5-[1-(2,6-Difluorophenyl)-4-methylpyrazol-3-yl]-3-[(2-methylphenyl)methyl]-1,2,4-oxadiazole | C20H16F2N4O | ", XP093311723, Database accession no. CID 154797673 *

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