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WO2025096658A1 - Compositions et inhibiteurs de polrmt - Google Patents

Compositions et inhibiteurs de polrmt Download PDF

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Publication number
WO2025096658A1
WO2025096658A1 PCT/US2024/053722 US2024053722W WO2025096658A1 WO 2025096658 A1 WO2025096658 A1 WO 2025096658A1 US 2024053722 W US2024053722 W US 2024053722W WO 2025096658 A1 WO2025096658 A1 WO 2025096658A1
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Prior art keywords
compound
alkyl
substituted
cyclopropyl
methyl
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Inventor
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
  • CCD C- terminal polymerase domain
  • NTD N-terminal domain
  • NTE N- terminal extension
  • RNA polymerase encoded by bacteriophage T7.
  • the CTD is also known as the catalytic domain due to its function of catalyzing nucleotide incorporation into a growing RNA molecule during transcription. This domain is highly conserved across species, whereas by contrast the NTE demonstrates significant sequence variability, suggesting organism-specific roles for this domain of POLRMT.
  • POLRMT is of fundamental importance for both expression and replication of the human mitochondrial genome. 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.
  • 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),
  • X1-X5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, - 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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy.
  • X 6 -X 8 are each independently a C, N, S, or O.
  • R 3 is a halogen, a hydrogen, a CrCe alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl.
  • R 4 is a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen.
  • R 3 and R 4 are optionally interconnected they form a C3-C6 cycloalkyl, a substituted C3-C6 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 Ci-Ce alkyl, a substituted Ci-Ce alkyl, an aryl, substituted aryl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Cs-Ce heterocyclyl, substituted Cs-Ce 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)NH2, -CS(O) 2 Y 3 , a -CY 1 S(O) 2 Y 3 .
  • Y 3 is independently hydrogen or Ci-C 4 alkyl optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, Ci-C 4 haloalkoxyl, and Ci-C 4 alkoxyl.
  • Some aspects of the present disclosure include compounds described above, wherein the compound has a POLRMT IC50 of 200 nM or less.
  • Some aspects of the present disclosure include a pharmaceutical composition comprising a compound according to any of the previous claims.
  • 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.
  • 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 are provided herein.
  • alkyl refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in a specified range.
  • CrCe 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 C3 alkyl group allows for the substituent to be located on any of the three carbon atoms.
  • alkoxy refers to an -O-alkyl group.
  • C1-C4 alkoxyl means -O-C1-C4 alkyl.
  • alkoxyl include methoxyl, ethoxyl, propoxyl (e.g., n-propoxyl and isopropoxyl), and the like.
  • haloalkoxy 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 include trifluoromethoxyl, 2,2,2-trifluoroethoxyl, and the like.
  • alkanoyl or “acyl” as used herein refers to an -C(O)-alkyl group.
  • the term “Ci-Ce alkanoyl” means -C(O)-Ci-C6 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.
  • C3-C6 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 (“Ce- C14 aryl”) or preferably, 6 to 12 carbon atoms (“C6-C12 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.
  • 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.
  • C6-C12 cycloaryl means a Ce- C12 aryl fused to a 5- or 6-membered aliphatic or heterocyclic ring.
  • Ce 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, 0 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 thiadiazoly
  • 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.
  • 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.
  • carboxyl refers to a combination of two functional groups attached to a single carbon atom, namely, hydroxyl (OH) and carbonyl (O).
  • 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).
  • 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 compounds of the invention contain at least one basic group (i.e.
  • 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.
  • acidic groups e.g., a carboxylic acid
  • the invention includes the pharmaceutically acceptable salts of the compounds formed with but not limited to alkali metal salts, alkaline earth metal salts or ammonium salts.
  • 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.
  • prodrug 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. Design and use of prodrugs may be found in “Prodrugs 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.
  • X1-X5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy;
  • X 6 -X 8 are each independently a C, N, S, or 0;
  • R 3 is a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl;
  • R4 is a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen; if R3 and R4 are optionally interconnected they form a C 3 -Ce cycloalkyl, a substituted C3-C6 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 Ci-Ce alkyl, a substituted Ci-Ce alkyl, an aryl, substituted aryl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a C3-C6 heterocyclyl, substituted Cs-Cs heterocyclyl, or absent; wherein A1 and A2 may optionally be substituted with one or more members selected from the group consisting of halogen, ester, ether, carboxylic acid, -C(0)NH2, -CS(O)2Y 3 , a -CY 1 S(O) 2 Y 3 ;
  • Y 3 is independently a hydrogen or a C1-C4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4 haloalkoxyl, and a C1-C4 alkoxyl; with the proviso that formula (I) excludes the following compounds:
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, -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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy.
  • Xe-Xs may each independently be a C, N, S, or O.
  • R3 may be a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl.
  • R4 may be a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen.
  • R 3 and R 4 may optionally be interconnected to form a C3-C6 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 A 2 may each independently be a hydrogen, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, an aryl, substituted aryl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Cs-Cs heterocyclyl, substituted Cs-Cs heterocyclyl, or absent.
  • A1 and A 2 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 C1-C4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4 haloalkoxyl, and a C1-C4 alkoxyl.
  • A1 and A 2 may each independently be -C(O)NY 3 Y 4 , -CY 1 (O)NY 3 Y 4 , or - NY 3 Y 4 .
  • Y 3 is independently a hydrogen or a C1-C4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4 haloalkoxyl, and a C1-C4 alkoxyl.
  • Y 4 is independently Y 3 , cyano, C3-C6 cycloheteroalkyl, Ci-Ce amide, Ci-Ce amine, Ci-Ce carboxyl, aryl, Ci-Ce alkyl optionally substituted with one or more halogen groups, 5- or 6-membered heterocyclyl, or C3-C6 cycloalkyl, Ci-Ce alkoxy, Ci-Ce hydroxy, or -C(O)Ci-C4 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), SO2, 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, C1-C4 alkyl, C1-C4 alkoxyl, Ci-C4 haloalkoxyl, carboxyl, oxo, and C1-C4 alkylcarboxylate.
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, -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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy.
  • R3 may be a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl.
  • R4 may be a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen.
  • R 3 and R 4 may optionally be interconnected to form a C3-C6 cycloalkyl, a substituted C3-C6 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.
  • R10-R15 may each independently be a hydrogen, an alkoxy, a halogen, a Ci-Ce alkyl, or a carboxylic acid.
  • Xi may be a Ci-Ce alkyl or a halogen.
  • X2 may be a hydrogen or a halogen.
  • X3 may be a hydrogen, a halogen, or a Ci-Ce alkyl.
  • X4 may be hydrogen
  • X5 may be a hydrogen or a Ci-Ce alkyl.
  • At least two of X2- X5 are hydrogen.
  • At least three of X2- X5 are hydrogen.
  • X2- X5 may be hydrogen.
  • Xi may be methyl or Cl.
  • X2 may be Cl or hydrogen and X3 may be methyl, F, Cl, or hydrogen.
  • R3 may be a hydrogen, a methyl or -CHF2.
  • R4 may be hydrogen
  • R10-R15 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 Xi 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 X3 may be hydrogen or halogen and R 3 may be methyl, -CHF 2 , or -CF 3 .
  • X1-X3 may each be independently hydrogen, halogen, or methyl, and R 3 may be methyl, -CHF 2 , or -CF 3 .
  • X1-X3 may each be independently hydrogen, halogen, or methyl, and R3-R4 are independently hydrogen, methyl, -CHF2, or -CFs.
  • At least one of R10-R15 is carboxylic acid.
  • At least one of R10-R11 is carboxylic acid
  • At least one of R12-R13 is carboxylic acid
  • R14-R15 is carboxylic acid.
  • R12-R13 may each independently be hydrogen, fluorine, methyl, methoxy, or carboxylic acid.
  • R10-R11 and R14-R15 may be hydrogen and the compound may be represented by Formula (lla-2):
  • X1-X5 may each independently be hydrogen, halogen, or Ci-Ce alkyl.
  • R3 may be halogen, hydrogen, Ci-Ce alkyl, substituted Ci-Ce alkyl, or C3-C6 cycloalkyl.
  • R4 may be hydrogen, Ci-Ce alkyl, or substituted Ci-Ce alkyl.
  • R12 and R13 are each independently a Ci-Ce alkyl, a hydrogen, a halogen, a carboxylic acid, an alkoxy, or an amide.
  • Xi may be methyl.
  • X3 may be a halogen or a hydrogen.
  • X 2 , X 4 , and X 5 may be hydrogen.
  • R 3 may be hydrogen, Ci-Ce alkyl, or substituted Ci-Ce alkyl.
  • R 4 may be hydrogen
  • R12 and R13 may each independently be hydrogen, carboxylic acid, alkoxy, or amide.
  • Xi may be methyl
  • X 2 , X4, and X 5 are hydrogen
  • X3 may be a halogen or a hydrogen
  • R3 may be hydrogen, Ci-Ce alkyl, or substituted C1-C5 alkyl
  • R4 may be hydrogen
  • R12 and R13 may each independently be hydrogen, carboxylic acid, alkoxy, or amide.
  • R3 may be difluoromethyl.
  • Rw may be carboxylic acid and Rn may be hydrogen.
  • Rw may be amide and Rn may be hydrogen.
  • Xi may be a halogen
  • X2 may be hydrogen or halogen.
  • X3 may be methyl, halogen, or hydrogen.
  • X4 and X5 may be hydrogen
  • Xi may be a halogen
  • X2 is hydrogen or halogen
  • X3 is methyl, halogen, or hydrogen
  • X4 and X5 are hydrogen.
  • R3 may be difluoromethyl and R4 may be hydrogen
  • R12 and R13 are each independently hydrogen or carboxylic acid.
  • R10 may be carboxylic acid and Rn may be methoxy.
  • Rw may be carboxylic acid and Rn may be methyl.
  • the present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formulae (llb-1) & (llb-2):
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, -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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy.
  • R3 may be a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl.
  • R4 may be a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen.
  • R 3 and R 4 may optionally be interconnected to form a C3-C6 cycloalkyl, a substituted C3-C6 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.
  • R20-R29 may each independently be a hydrogen, a Ci-Ce alkyl, a carboxylic acid, an amide, a substituted amide, an alkoxy, or a halogen.
  • Xi may be a Ci-Ce alkyl.
  • Xi may be a methyl
  • X 2 andX4 may be hydrogen.
  • X3 may be a hydrogen or halogen.
  • X5 may be a hydrogen or a Ci-Ce alkyl.
  • At least two of X 2 - X 5 may be hydrogen.
  • At least three of X2- X5 may be hydrogen.
  • X2-X5 may be hydrogen.
  • R 3 may be a hydrogen, a methyl, or -CHF 2 .
  • R 4 may be hydrogen
  • R20-R29 are each independently a hydrogen, a Ci-Ce alkyl, an alkoxy, a halogen, a carboxylic acid, amide, or a substituted amide.
  • the substituted amide may be substituted with one or more Ci-Ce 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.
  • Xi may be halogen or methyl and R 3 may be hydrogen, methyl, CHF 2 , or CF 3 .
  • X 2 may be hydrogen or halogen and R 3 may be hydrogen, methyl, CHF 2 , or CF 3 .
  • X3 may be hydrogen or halogen and R 3 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 .
  • X1- 3 may each independently be hydrogen, halogen, or methyl
  • X4- X 5 may each independently be hydrogen or halogen
  • R 3 -R 4 may independently be hydrogen, methyl, CHF2, or CF 3 .
  • X1- 3 may each independently be hydrogen, fluorine, chlorine, bromine, or methyl
  • X 4 -Xs are each independently hydrogen or halogen
  • R 3 -R 4 are independently hydrogen, methyl, CHF2, or CF 3 .
  • At least one of R20-R29 may be carboxylic acid.
  • at least one of R20-R23 may be carboxylic acid.
  • At least one of R24-R25 may be carboxylic acid.
  • At least one of R26-R29 may be carboxylic acid.
  • R24-R25 may each independently be hydrogen, fluorine, methyl, methoxy, or carboxylic acid.
  • R24-R25 may each independently be hydrogen or carboxylic acid.
  • R3 and R4 may be interconnected to form a 5-membered cyclic ring.
  • R3 and R4 may be interconnected to form a phenyl ring.
  • the present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (lie):
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, -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 Ci-Cs alkyl optionally substituted with one or more halogen or hydroxy.
  • R3 may be a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl.
  • R4 may be a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen.
  • R 3 and R 4 may optionally be interconnected to form a C 3 -Ce cycloalkyl, a substituted C3-C6 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.
  • A3 is a hydrogen, a Ci-Ce alkyl, a C2-C6 branched alkyl, a Ci-Ce alkyl substituted with heterocyclyl, a Ci-Ce alkyl substituted with a substituted heterocyclyl, or a Ci-Ce alkyl substituted Ci-Ce 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) 2 Y 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 C1-C4 haloalkoxyl, and a C1-C4 alkoxyl.
  • Xi is a hydrogen, a halogen, a cyano, a Ci-Ce alkyl, a substituted Ci- Ce alkyl, a C 3 -Ce cycloalkyl, a substituted C 3 -Ce cycloalkyl, a Ci-Ce alkoxy, a Ci-Ce 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.
  • Xi is a Ci-Ce alkyl.
  • the Ci-Ce alkyl may be methyl or ethyl.
  • Xi is halogen.
  • the halogen may be fluorine, chlorine, or bromine.
  • Xi may be -CH 2 OCH 3 , -CH 2 OH, or -CF 3 .
  • Xi may be -C(O)NH 2 , -C(O)NHCH 3 , or -C(O)NCH 3 CH 3 .
  • X 2 and X 3 may be a hydrogen, a halogen, or a Ci-Ce alkyl.
  • X4 may be a hydrogen, a halogen, a hydroxy, a methoxy, a Ci-Ce alkyl, or a substituted Ci-Ce alkyl.
  • the substituted Ci-Ce alkyl may be -CH 2 OH.
  • X5 may be a hydrogen, halogen, hydroxy, methoxy, a Ci-Ce alkyl, or a substituted Ci-Ce alkyl.
  • a 3 may be a Ci-Ce alkyl or substituted Ci-Ce 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 Ci-Ce 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 .
  • Xi may be Ci-Ce alkyl or halogen.
  • X 2 may be hydrogen or halogen.
  • Xs may be hydrogen, Ci-Ce alkyl, or halogen.
  • X4 may be hydrogen
  • Xi may be Ci-Ce alkyl or hydrogen.
  • R 3 may be Ci-Ce alkyl substituted with one or more halogen.
  • R 3 may be -CHF 2 or -CF 3 .
  • R4 may be hydrogen
  • X1-X5 may each independently be hydrogen, a halogen, or a Ci-Ce alkyl.
  • X3-X4 may each independently be hydrogen, methyl, cyclopropyl, - CHF 2 , or -CF 3 .
  • a 3 may be substituted with at least one halogen, ester, ether, or carboxylic acid.
  • a 3 may be substituted with at least one -C(O)NH 2 , -CS(O) 2 Y 3 , or - CY 1 S(O) 2 Y 3 .
  • 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 (llc-1):
  • Xi may be a Ci-Ce alkyl.
  • X 2 -Xs may be hydrogen.
  • R 3 may be -CHF 2 .
  • R 4 may be hydrogen
  • a 3 may be a Ci-Ce alkyl.
  • B 3 and B 4 may each independently be hydrogen or a Ci-Ce alkyl.
  • Xi is a Ci-Ce alkyl
  • X2-X5 are hydrogen
  • R 3 is - CHF2
  • R 4 is hydrogen
  • a 3 is a Ci-Ce alkyl
  • B 3 and B 4 are each independently hydrogen or a C1-C5 alkyl.
  • B may be amide or substituted amide with Formula (I lc-2a) or Formula (llc-2b):
  • Xi may be Ci-Ce alkyl or halogen.
  • X2-X4 may be hydrogen or halogen.
  • X5 may be hydrogen, halogen, or Ci-Ce alkyl.
  • R3 may be -CHF2, -CFsor a C3- C 6 cycloalkyl.
  • R4 may be hydrogen.
  • A3 may be a Ci-Ce alkyl or branched Ci-Ce alkyl.
  • B3 and B4 may be each independently hydrogen, a Ci-Ce alkyl, a substituted a Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted a C3-C6 cycloalkyl, a C3-C6 heterocyclyl, a substituted a C3-C6 heterocyclyl, phenyl, substituted phenyl.
  • B 3 and B 4 are optionally interconnected they form a 4-membered, 5- membered, 6- membered cycloalkyl ring, substituted cycloalkyl ring, heterocyclyl ring, or substituted heterocyclyl ring.
  • B 5 and B 6 may each independently be hydrogen or Ci-Ce alkyl.
  • the Ci-Ce alkyl may be methyl of ethyl.
  • the branched Ci-Ce alkyl may be -CH 2 (CH 3 )-.
  • the substituted Ci-Ce alkyl may be - CH2CH2OCH3, -CH 2 C(CH 3 )2OH, -CH2CH2OH, -CH2COOH, -CH(CH 3 )COOH, - C(CH 3 ) 2 COOH, methyl-pyridyl, methyl-methyl substituted-pyridyl, methyl cyclopropyl, methyl cyclobutyl, -CH 2 CONH 2 , CH 2 CONHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -CH(CH 3 )CONH 2 , or -CH 2 CF 3 .
  • a 3 may be ethyl and B may be methanesulfonamide
  • a 3 may be ethyl and B may be methoxy.
  • a 3 may be ethyl and B may be substituted sulfoxide.
  • R 3 may be -CHF2, halogen, cyclopropyl, or methyl.
  • R4 may be hydrogen or methyl.
  • R 3 and R 4 may be connected to form a 5-membered cycloalkyl ring.
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, -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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy.
  • R 3 may be a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl.
  • R 4 may be a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen.
  • R 3 and R 4 may optionally be interconnected to form a Cs-Ce cycloalkyl, a substituted C3-C6 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 3 o-R3 4 may each independently be a hydrogen, a carboxylic acid, an ester, a halogen, an amide, a substituted amide, a cyano, an ether, or a Ci-Ce alkyl.
  • Xi may be a Ci-Ce alkyl or a halogen.
  • the Ci-Ce alkyl may be methyl.
  • the halogen may be chlorine.
  • X2 and X 4 may each independently be a hydrogen or a halogen.
  • X3 may be a hydrogen, a Ci-Ce alkyl or a halogen.
  • the Ci-Ce alkyl may be methyl.
  • the halogen may be chlorine or fluorine
  • Xs may be a CrCs alkyl or a hydrogen.
  • At least two of X 2 . X 5 may be hydrogen.
  • At least three of X 2 . X 5 may be hydrogen.
  • X 2 . Xs may be hydrogen.
  • R3 may be Ci-Cs alkyl or Ci-Ce alkyl substituted with one or more halogen.
  • the Ci-Cs alkyl substituted with one or more halogen may be -CHF 2 .
  • the Ci-Cs alkyl may be methyl.
  • R4 may be hydrogen
  • R30-R34 may be hydrogen
  • Rso may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.
  • R31 may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.
  • Rs 2 may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.
  • Rss may be methyl, methoxy, carboxylic acid, -C(O)OCH3, cyano, amide, or substituted amide.
  • R 3 4 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.
  • X1-X5 may each independently be hydrogen, halogen, Cl, F, or methyl, and R3-R4 are independently H, methyl, CHF 2 , or CF 3 .
  • At least one of R30-R34 may be carboxylic acid.
  • At least one of R30-R34 may be amide.
  • At least one of R30-R34 may be ester.
  • At least one of R30-R34 may be ether.
  • At least one of R30-R34 may be cyano.
  • At least one of R30-R34 may be methyl.
  • At least two of R30-R34 may be carboxylic acid, amide, ester, ether, cyano, or methyl.
  • X1-X5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, -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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy;
  • X 2 , X4, and X 5 may be hydrogen.
  • X3 may be a hydrogen or halogen.
  • At least two of X2-X5 may be hydrogen.
  • At least three of X2-X5 may be hydrogen.
  • X2-X5 may be hydrogen
  • R3 may be straight or branched Ci-Ce alkyl optionally substituted with one or more halogen.
  • the straight or branched Ci-Ce alkyl may be substituted with one or more fluorine.
  • Rs may be -CHF2 or -CF3.
  • 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, -CHF2, or -CFs.
  • X1-X5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy;
  • Y is carbon or nitrogen
  • R30-R34 are each independently a hydrogen, a carboxylic acid, a halogen, an amide, a substituted amide, a cyano, a Ci-Ce alkyl, or absent;
  • R3 is a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl;
  • R4 is a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen; if R3 and R4 are optionally interconnected they form a C3-C6 cycloalkyl, a substituted C3-C6 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; and
  • Xi and X 2 may be halogen.
  • the halogen may be fluorine or chlorine.
  • X 2 , X3, and X 5 may be hydrogen.
  • At least two of X 2 -X 5 may be hydrogen.
  • At least three of X 2 -X 5 may be hydrogen.
  • At least one Y may be nitrogen.
  • R30-R34 may each independently be a hydrogen or absent.
  • R 3 may be -CH(CH 3 ) 2 .
  • the present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, according to Formula (III) or Formula (IV):
  • X1-X5 may each independently be a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, -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 C1-C5 alkyl optionally substituted with one or more halogen or hydroxy.
  • R3 may be a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl.
  • R4 may be a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen.
  • R3 and R4 may optionally be interconnected to form a C3-C6 cycloalkyl, a substituted C3-C6 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 may each independently be a hydrogen, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, an aryl, substituted aryl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ca-Ce heterocyclyl, substituted Ca-Ce heterocyclyl, or absent.
  • Ai 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 C1-C4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4 haloalkoxyl, and a C1-C4 alkoxyl.
  • the present disclosure is directed to a compound with any one or Formulae (Illa), (lllb), (IVa), and (IVb):
  • Xi may be Ci-Ce alkyl.
  • X 2 , X3, and X 5 may be hydrogen.
  • X4 may be hydrogen or fluorine.
  • A1 and A 2 may each be independently a hydrogen, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, an aryl, substituted aryl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a C3-C6 heterocyclyl, or substituted C3-C6 heterocyclyl.
  • A1 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 .
  • R 3 may be Ci-Ce alkyl substituted with one or more halogen.
  • R 4 may be a hydrogen
  • Xi may be methyl
  • X4 may behydrogen or fluorine.
  • At least two of X 2 -X 5 may be hydrogen.
  • at least three of X 2 -X 5 are hydrogen.
  • Ai and A 2 may be substituted C Ce alkyl.
  • Ai and A 2 may be substituted ethyl.
  • the ethyl may be substituted with carboxylic acid or amide.
  • Ai and A 2 may be -CH 2 CH3CONH 2 .
  • Ai and A 2 may be substituted C3-C6 cycloalkyl.
  • the substituted C3-C6 cycloalkyl may be a cyclobutyl or cyclohexyl substituted with one or more carboxylic acid.
  • Ai and A 2 may be substituted phenyl.
  • the phenyl may be substituted with one or more carboxylic acid.
  • R3 may be -CHF 2 or -CF3.
  • X1-X5 are each independently a hydrogen, a halogen, a hydroxy, a cyano, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a Ci-Ce alkoxy, optionally substituted with an aryl, a C3-C10 cycloalkyl, -C(O)NH2, -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 Ci-Ce alkyl optionally substituted with one or more halogen or hydroxy;
  • A1 and A2 are each independently a hydrogen, a Ci-Ce alkyl, a substituted Ci-Ce alkyl, an aryl, substituted aryl, a C3-C6 cycloalkyl, a substituted C3-C6 cycloalkyl, a C3-C6 heterocyclyl, substituted Cs-Ce heterocyclyl, or absent; wherein 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)NH2, -CS(O)2Y 3 , a -CY 1 S(O) 2 Y 3 ;
  • Y 3 is independently a hydrogen or a C1-C4 alkyl optionally substituted with one or more groups selected from the group consisting of a halogen, a hydroxyl, a C1-C4 haloalkoxyl, and a C1-C4 alkoxyl;
  • R 3 is a halogen, a hydrogen, a Ci-Ce alkyl, a Ci-Ce alkyl substituted with one or more halogen, or a C3-C6 cycloalkyl;
  • R 4 is a hydrogen, a Ci-Ce alkyl, or a Ci-Ce alkyl substituted with one or more halogen; if R 3 and R 4 are optionally interconnected they form a C3-C6 cycloalkyl, a substituted C3-C6 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-A2 are independently hydrogen or methyl.
  • A1 may be absent and the compound is with Formula (Va-1) or Formula (Vb-1):
  • X2, X3, and X5 are hydrogen
  • X4 is hydrogen or halogen
  • A2 is Ci-Ce alkyl
  • R3 is hydrogen or Ci-Ce alkyl substituted with one or more halogen
  • R4 is hydrogen
  • At least three of X2-X5 may be hydrogen.
  • X2-X5 may be hydrogen
  • the Ci-Ce alkyl may be methyl.
  • the Ci-Ce alkyl substituted with one or more halogen may be - CHF 2 or-CF 3 .
  • the compound is Compound 1 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 2, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 3, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 4, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 5, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 7, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 8, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 9, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 10, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 11 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 12, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 13, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 14, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 15, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 16, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 17, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 18, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 19, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 20, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 21 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 22, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 25, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 26, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 29, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 30, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 31 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 32, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 33, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 34, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 332, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 333, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 358, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 359, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 35, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 36, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 37, or a pharmaceutically acceptable salt thereof: [0333] In certain embodiments, the compound is Compound 38, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 39, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 40, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 41 , or a pharmaceutically acceptable salt thereof: [0337] In certain embodiments, the compound is Compound 42, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 43, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 44, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 45, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 46, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 47, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 48, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 49, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 50, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 51 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 52, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 316, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 317, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 335, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 347, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 355, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 356, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 366, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 367, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 55, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 56, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 57, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 58, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 59, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 60, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 61, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 62, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 63, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 64, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 65, or a pharmaceutically acceptable salt thereof:
  • the compound is, Compound 66, or a pharmaceutically acceptable salt thereof:
  • the compound is, Compound 67, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 68, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 69, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 75, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 319, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 320, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 324, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 325, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 326, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 327, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 328, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 329, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 330, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 331 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 334, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 337, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 338, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 350, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 351 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 352, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 353, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 354, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 357, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 360, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 361 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 362, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 363, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 364, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 370, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 76, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 77, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 78, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 79, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 80, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 81, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 82, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 83, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 84, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 85, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 86, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 87, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 88, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 91, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 92, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 93, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 94, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 95, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 96, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 97, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 98, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 99, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 100, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 101, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 102, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 103, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 104, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 105, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 106, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 107, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 108, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 109, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 110, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 111, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 112, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 113, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 116, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 117, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 118, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 119, or a pharmaceutically
  • the compound is Compound 120, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 121, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 122, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 123, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 124, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 125, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 126, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 127, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 128, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 129, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 130, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 131, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 132, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 133, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 134, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 135, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 136, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 137, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 138, or a pharmaceutically
  • the compound is Compound 139, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 140, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 141, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 142, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 143, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 144, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 145, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 146, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 147, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 148, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 149, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 150, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 156, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 157, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 158, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 159, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 160, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 161, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 162, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 163, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 164, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 165, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 166, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 167, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 168, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 169, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 170, or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 171, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 172, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 173, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 174, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 175, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 176, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 177, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 178, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 179, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 180, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 181 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 182, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 183, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 184, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 185, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 186, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 187, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 188, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 189, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 190, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 192, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 193, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 194, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 195, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 197, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 198, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 199, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 200, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 201 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 202, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 203, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 204, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 205, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 206, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 207, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 210, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 211 , or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 214, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 215, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 216, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 217, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 218, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 219, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 222, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 223, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 224, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 225, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 226, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 227, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 228, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 229, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 230, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 231 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 232, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 233, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 234, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 235, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 236, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 237, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 238, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 239, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 240, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 241 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 242, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 243, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 244, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 245, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 246, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 247, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 248, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 249, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 252, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 253, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 254, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 255, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 256, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 257, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 258, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 259, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 260, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 261 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 262, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 263, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 266, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 267, or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 270, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 271 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 272, or a pharmaceutically acceptable salt thereof: [0605] In one embodiment, the compound is Compound 273, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 274, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 275, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 276, or a pharmaceutically acceptable salt thereof: [0609] In one embodiment, the compound is Compound 277, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 278, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 279, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 280, or a pharmaceutically acceptable salt thereof: [0613] In one embodiment, the compound is Compound 281 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 282, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 283, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 284, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 285, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 286, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 287, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 288, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 289, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 290, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 291 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 292, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 293, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 294, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 295, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 296, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 297, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 298, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 299, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 300, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 301 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 302, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 303, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 304, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 305, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 306, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 307, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 308, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 309, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 310, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 311 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 312, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 313, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 314, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 315, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 318, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 321 , or a pharmaceutically acceptable salt thereof:
  • 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:
  • the compound is Compound 339, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 340, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 341 , or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 342, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 343, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 344, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 345, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 372, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 373, or a pharmaceutically acceptable salt thereof:
  • the compound is Compound 374, or a pharmaceutically acceptable salt thereof:
  • 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.
  • the compound obtained in each step may also be used for the next reaction as a reaction mixture thereof or after obtaining a crude product thereof.
  • the compound obtained in each step may be isolated and/or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like according to a conventional method.
  • reaction time varies depending on the reagents and solvents to be used, unless otherwise specified, it is generally 1 min. to 48 h., preferably 10 min. to 8 h.
  • 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 When a reagent is used as a catalyst, the reagent is used in 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When 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
  • 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 Schutzenmeister) 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.
  • protection or deprotection of a functional group is performed by a known method, for example, the methods described in “Protective Groups in Organic Synthesis, 4 th Ed.” (Theodora W. Greene, Peter G. M. Wuts) Wiley-lnterscience, 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski) Thieme, 2004 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
  • 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.
  • 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. (2020).
  • Formulations for parenteral administration include sterile aqueous or non- aqueous solutions, suspensions, or emulsions.
  • a variety of 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.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylenepolyoxypropylene copolymers may be used to control the release of the active ingredients.
  • the compositions may be administered by oral ingestion.
  • 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.
  • 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.
  • a pharmaceutical composition of this invention further comprises a second therapeutic agent.
  • 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 agent(s) are well known to those skilled in the art. However, it is well within the attending physician to determine the amount of other chemotherapeutic agent(s) to be delivered.
  • 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), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Avelumab, Bexxar (Tositumomab), BiCNU
  • Table 1 correlates Example number with Compound number.
  • 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):
  • Example 3 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-methyl-1 H- pyrazol-3-yl)-1,2,4-oxadiazole (Example 3):
  • Example 4 Synthesis of 5-(5-cyclopropyl-1-methyl-1 H-pyrazol-3-yl)-3-(1-(5-fluoro-2- methylphenyl)cyclopropyl)-1,2,4-oxadiazole (Example 4):
  • Example 5 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(5-isopropyl-1- methyl-1 H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 5)
  • Example 6 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-phenyl-1H- pyrazol-3-yl)-1,2,4-oxadiazole (Example 6)
  • 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)
  • Example 8 Synthesis of 3-(1-(5-fluoro-2-methylphenyl)cyclopropyl)-5-(1-(2- fluorophenyl)-5-methyl-1 H-pyrazol-3-yl)-1 ,2,4-oxadiazole (Example 8)
  • Example 9 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(3- fluorophenyl)cyclopropyl)-1,2,4-oxadiazole (Example 9)
  • Example 10 Synthesis of 3-(1-(3-fluorophenyl)cyclopropyl)-5-(1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazole (Example 10)
  • Example 13 Synthesis of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1 ,2,4-oxadiazole (Example 13)
  • Example 14 Synthesis of 5-(5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1 ,2,4-oxadiazole (Example 14)
  • Example 16 Synthesis of 5-(1 ,4-dimethyl-1 H-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1 ,2,4- oxadiazole (Example 16) [0717] 5-(1 ,4-dimethyl-1 /-/-pyrazol-3-yl)-3-(1-(o-tolyl)cyclopropyl)-1 ,2,4-oxadiazole was synthesized following Scheme 3 using 1 ,4-dimethyl-1H-pyrazole-3-carboxylic acid.
  • 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)-1/-/-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)-1 H-pyrazol-1-yl)propenamide (Example 18)
  • 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.
  • Example 19 Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-1 H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1 ,2,4-oxadiazole (Example 19)
  • Example 20 Synthesis of 5-(5-cyclopropyl-1-(2-(methylsulfonyl)ethyl)-1 H-pyrazol-3-yl)-3- (1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 20)
  • Example 21 Synthesis of 5-(5-methyl-1-(2-(methylsulfonyl)ethyl)-1 H-pyrazol-3-yl)-3-(1-(o- tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 21)
  • Step 1 To a suspension of methyl 5-methyl- 7H-pyrazole-3-carboxylate ( 295 mg, 2.1 mmol) and (Z)-A/'-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. After 16 h, the reaction mixture was filtered through a celite pad, and the filtrate concentrated under reduced pressure.
  • 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)
  • 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)
  • 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)
  • Example 26 Synthesis of 5-(1-(2-(methylsulfonyl)ethyl)-5-(trifluoromethyl)-1 H-pyrazol-3- yl)-3-(1-(o-tolyl)cyclopropyl)-1,2,4-oxadiazole (Example 26)
  • 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)
  • reaction mixture was stirred at ambient temperature for 1 h and fert-butyl 2-bromoacetate (985 mg, 5.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was quenched with crushed ice, extracted with ethyl acetate. The organic extract was washed with ice cold water and brine. Combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography to afford ethyl 1-(2-(tert-butoxy)-2-oxoethyl)-5- (difluoromethyl)-1/7-pyrazole-3-carboxylate (43, 500 mg).
  • 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)
  • 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)-1 H-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)
  • N, /V-diisopropylethylamine (0.04 mL, 0.2 mmol) and propane phosphonic acid anhydride (0.06 mL, 0.20 mmol, 50% in ethyl acetate) were added.
  • 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.

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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/US2024/053722 2023-10-30 2024-10-30 Compositions et inhibiteurs de polrmt Pending WO2025096658A1 (fr)

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Citations (3)

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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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KR101318689B1 (ko) * 2008-09-25 2013-10-16 주식회사 녹십자 칸나비노이드 ｃｂ1 수용체 길항제로서 황 함유 피라졸-헤테로사이클 유도체
WO2023034344A1 (fr) * 2021-08-30 2023-03-09 Pretzel Therapeutics, Inc. Isoquinolinones et quinolinones utiles comme modulateurs de polrmt
US20250326732A1 (en) * 2021-08-30 2025-10-23 Pretzel Therapeutics, Inc. Chromen-2-one modulators of 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 COMPOUND 24 January 2019 (2019-01-24), "5-[5-(Difluoromethyl)-1-methylpyrazol-3-yl]-3-[1-(5-fluoro-2-methylphenyl)cyclopropyl]-1,2,4-oxadiazole | C17H15F3N4O | CID 136570225 - PubChem", XP093312726, Database accession no. 136570225 *
MATTHIAS GEHRINGER; FELIX PAPE; MARÍA MÉNDEZ; PHILIPP BARBIE; ANDREA UNZUE LOPEZ; JULIEN LEFRANC; FRANCA‐MARIA KLINGLER; GERHARD H: "Back in Person: Frontiers in Medicinal Chemistry 2023", CHEMMEDCHEM COMMUNICATIONS, WILEY-VCH, DE, vol. 18, no. 19, 24 July 2023 (2023-07-24), DE , pages n/a - n/a, XP072519962, ISSN: 1860-7179, DOI: 10.1002/cmdc.202300344 *

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