WO2023049199A1 - Azole compounds - Google Patents

Azole compounds Download PDF

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Publication number
WO2023049199A1
WO2023049199A1 PCT/US2022/044277 US2022044277W WO2023049199A1 WO 2023049199 A1 WO2023049199 A1 WO 2023049199A1 US 2022044277 W US2022044277 W US 2022044277W WO 2023049199 A1 WO2023049199 A1 WO 2023049199A1
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Prior art keywords
unsubstituted
compound
substituted
phenyl
alkyl
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PCT/US2022/044277
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French (fr)
Inventor
Suvi Tuula Marjukka Orr
Xiaojun Han
Jianguo Cao
Christian Cho-Hua Lee
Igor Mochalkin
Quyen-Quyen Thuy Do
Peter Qinhua HUANG
Kevin Duane Bunker
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Zeno Management, Inc.
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Publication of WO2023049199A1 publication Critical patent/WO2023049199A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Transcriptional enhanced associate domain (TEAD) transcription factors are key components of the Hippo signaling pathway.
  • the human TEAD proteins include four paralogous transcription factors, each with an N-terminal TEA domain, DNA-binding domain, proline-rich region, and C-terminal YAP/TAZ-binding domain. TEAD proteins have been implicated as playing a role in development, cell proliferation, regeneration and tissue homeostasis.
  • SUMMARY [0004] Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein relate to a pharmaceutical composition that can include an effective amount of one or more of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • Some embodiments described herein relate to a method for treating a disorder, a condition and/or a disease described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a disorder, a condition and/or a disease described herein.
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disorder, a condition and/or a disease described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disorder, a condition and/or a disease described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a disorder, a condition and/or a disease described herein.
  • the disorder, the condition and/or the disease can be selected from an autoimmune disorder, an inflammatory condition and a cancer.
  • Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD in a cell that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting a YAP/TAZ- TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • DETAILED DESCRIPTION Definitions [0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise.
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfon
  • Ca to Cb in which “a” and “b” are integers refer to the number of carbon atoms in a group.
  • the indicated group can contain from “a” to “b”, inclusive, carbon atoms.
  • a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a fully saturated aliphatic hydrocarbon group.
  • the alkyl moiety may be branched or straight chain.
  • branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like.
  • straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, n-heptyl and the like.
  • the alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • An alkyl group may be substituted or unsubstituted.
  • alkenyl used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. An alkenyl group may be unsubstituted or substituted.
  • alkynyl used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like.
  • alkynyl group may be unsubstituted or substituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
  • fused refers to two rings which have two atoms and one bond in common.
  • bridged cycloalkyl refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms.
  • Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
  • a cycloalkyl group may be unsubstituted or substituted.
  • Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl;
  • examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.
  • cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion.
  • a cycloalkenyl group may be unsubstituted or substituted.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a C6-C14 aryl group, a C 6 -C 10 aryl group or a C 6 aryl group.
  • Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • heteroatoms for example, 1, 2 or 3 heteroatoms
  • the number of atoms in the ring(s) of a heteroaryl group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms.
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,
  • heteroaryl group may be substituted or unsubstituted.
  • heterocyclyl refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
  • the rings When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
  • the term “fused” refers to two rings which have two atoms and one bond in common.
  • bridged heterocyclyl refers to compounds wherein the heterocyclyl contains a linkage of one or more atoms connecting non-adjacent atoms.
  • spiro refers to two rings which have one atom in common and the two rings are not linked by a bridge.
  • Heterocyclyl group can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
  • any nitrogens in a heterocyclyl may be quaternized.
  • Heterocyclyl groups may be unsubstituted or substituted.
  • heterocyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2- dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3- dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxa
  • spiro heterocyclyl groups examples include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6- azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and 2- azaspiro[3.4]octane.
  • cycloalkyl(alkyl) refer to a cycloalkyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and cycloalkyl group of a cycloalkyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to cyclopropyl(alkyl), cyclobutyl(alkyl), cyclopentyl(alkyl) and cyclohexyl(alkyl).
  • aryl(alkyl) refers to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted.
  • heteroaryl(alkyl) refers to a heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaryl(alkyl) may be substituted or unsubstituted.
  • heterocyclyl(alkyl) refers to a heterocyclic group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a heterocyclyl(alkyl) may be substituted or unsubstituted.
  • lower alkylene groups are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms.
  • Examples include but are not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 - ) and butylene (-CH 2 CH 2 CH 2 CH 2 -).
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a cycloalkyl group (e.g., ).
  • a cycloalkyl group e.g., ).
  • alkoxy refers to the Formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • a non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, iso-butoxy
  • acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted. [0030] A “cyano” group refers to a “-CN” group.
  • halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-amido may be substituted or unsubstituted.
  • S-sulfonamido refers to a “-SO2N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-sulfonamido may be substituted or unsubstituted.
  • An O-carboxy may be substituted or unsubstituted.
  • a C-carboxy may be substituted or unsubstituted.
  • a “nitro” group refers to an “–NO2” group.
  • a “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a sulfenyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl and polyhaloalkyl).
  • a halogen e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl and polyhaloalkyl.
  • groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl.
  • a haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • a halogen e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy.
  • groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • amino as used herein refers to a –NH 2 group.
  • a “mono-substituted amine” group refers to a “-NHRA” group in which RA can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
  • the R A may be substituted or unsubstituted. Examples of mono-substituted amino groups include, but are not limited to, ⁇ NH(methyl), ⁇ NH(phenyl) and the like.
  • a “di-substituted amine” group refers to a “-NR A R B ” group in which R A and RB can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
  • R A and R B can independently be substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl as described herein that includes 1, 2 or 3 hydroxy (–OH) groups attached to the alkyl.
  • the alkyl portion of the hydroxyalkyl can be straight-chained or branched. Additionally, the alkyl portion can be a lower alkyl.
  • hydroxyalkyl examples include, but are not limited to, –CH 2 -OH, –CH 2 CH 2 -OH, – CH(CH 3 )OH, –C(CH 3 ) 2 OH and –C(CH 2 CH 2 )OH.
  • aminoalkyl refer to an alkyl as described herein that includes 1, 2 or 3 amino (–NH 2 ) groups attached to the alkyl.
  • the alkyl portion of the aminoalkyl can be straight-chained or branched. Additionally, the alkyl portion can be a lower alkyl.
  • heteroaryl rings include, but are not limited to, –CH 2 -NH 2 , –CH 2 CH 2 -NH 2 , –CH(CH 3 )NH 2 , – C(CH 3 ) 2 NH 2 and –C(CH 2 CH 2 )NH 2 .
  • substituents e.g., haloalkyl
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
  • a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
  • the term “radical” can be used interchangeably with the term “group.”
  • pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound.
  • compositions can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate).
  • hydrohalic acid e.g., hydrochloric acid or hydrobromic acid
  • sulfuric acid e.g., sulfuric acid
  • nitric acid e.g., 1,3-dihydroxypropyl dihydrogen phosphate
  • Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p- toluenesulfonic, trifluoroacetic, benzoic, salicylic, 2-oxopentanedioic or naphthalenesulfonic acid.
  • an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).
  • hydrogens or isotopes thereof e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).
  • the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half- life or reduced dosage requirements.
  • Each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [0061] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • Ring A can be an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted bicyclic heteroaryl or an unsubstituted or a substituted bicyclic heterocyclyl, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heterocycl
  • R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 can be a substituted substituent as described herein.
  • R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and/or R 11 can be substituted one or more times (such as 1, 2, 3, 4 or more than 4 times) with groups independently selected from those provided for “optionally substituted.”
  • R 2 can be a variety of structures.
  • R 2 can be an unsubstituted or a substituted C 3 -C 10 cycloalkyl. In other embodiments, R 2 can be an unsubstituted or a substituted C 2 -C 10 heterocyclyl. In still other embodiments, R 2 can be a cyclic amide, such as . In yet stil 2 l other embodiments, R can be .
  • the C 3 - C 10 cycloalkyl for R 2 can be monocyclic or multicyclic (for example, bicyclic). Similarly, the unsubstituted or a substituted C2-C10 heterocyclyl for R 2 can be monocyclic or multicyclic (such as bicyclic).
  • the unsubstituted or a substituted C2-C10 heterocyclyl for R 2 can be a 4- to 12-membered heterocyclyl that includes 1, 2, 3, 4 or 5 heteroatoms selected from N (nitrogen), O (oxygen) and S (sulfur).
  • R 2 is an unsubstituted or a substituted bicyclic C3- C10 cycloalkyl or an unsubstituted or a substituted bicyclic C2-C10 heterocyclyl
  • the two rings of C 3 -C 10 cycloalkyl and/or C 2 -C 10 heterocyclyl can be joined in a fused or spiro-fashion.
  • R 2 when R 2 is , a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure of Formula (Ia): (Ia).
  • the ring of R 2 when R 2 is , can vary.
  • Y 1 can be –CH 2 –, and can be an optionally substituted pyrrolidinone.
  • Y 1 can be –CH 2 CH 2 –, and R 2 can be an optionally substituted piperidinone.
  • R 2 can be an optionally substituted oxazolidinone when Y 1 is –O–.
  • Y 1 can be –OCH 2 –, and R 2 can be an optionally substituted morpholinone having the structure .
  • the ring of R 2 can be substituted with one or more fluoros.
  • R 2 is .
  • R 2 is .
  • the ring of R 2 can be also substituted with an unsubstituted alkyl.
  • Y 1 can be –C(CH 3 )2–, and can be .
  • R 2 can be ,
  • R 6 can be hydrogen.
  • R 6 can be a halogen, such as –F or –Cl.
  • R 6 can be –CN.
  • R 6 can also be a saturated or unsaturated straight-chained or branched hydrogen carbon.
  • R 6 can be an unsubstituted or a substituted C 1 -C 6 alkyl.
  • C 1 -C 6 alkyls for R 6 include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched).
  • Suitable C3-6 cycloalkyls for R 6 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[1.1.1]pentyl. [0071] Various other groups can be present for R 6 . In some embodiments, R 6 can be an unsubstituted or a substituted C 1 -C 6 haloalkyl.
  • Exemplary C 1 -C 6 haloalkyls include the following: –CF 3 , –CCl 3 , –CHF 2 , –C(CH 3 )F 2 , –CHCl 2 , –CH 2 F, –CH(CH 3 )F, –CH 2 CF 3 , –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F and –CH 2 CH 2 CH 2 Cl.
  • R 6 can be an unsubstituted or a substituted C 1-6 alkoxy, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxyl, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched).
  • R 6 can be an unsubstituted or a substituted hydroxyalkyl.
  • R 6 can be an unsubstituted or a substituted hydroxy-C 1-6 alkyl.
  • R 6 can be an unsubstituted or a substituted aminoalkyl, sus as an unsubstituted or a substituted amino-C 1-6 alkyl.
  • the alkyl portion of a hydroxyalkyl and an aminoalkyl can be straight-chained or branched. Additionally, one or more hydroxy groups (such as 1, 2 or 3) can be present for a hydroxyalkyl, and one or more amino groups (for example, 1, 2 or 3) can be present for an aminoalkyl.
  • a non-limiting list of hydroxyalkyls and aminoalkyls include the following: –CH 2 -OH, –CH 2 CH 2 -OH, –CH(CH 3 )OH, –C(CH 3 ) 2 OH, –C(CH 2 CH 2 )OH, –CH 2 -NH 2 , –CH 2 CH 2 -NH 2 , –CH(CH 3 )NH 2 , –C(CH 3 )2NH 2 and –C(CH 2 CH 2 )NH 2 .
  • the various R 6 substituents can be unsubstituted or substituted. In some embodiments, when R 6 is substituted, one or more moieties (such as 1, 2, 3 or more than 3) can be present.
  • Some moieties that can be present on a substituted C 3-6 cycloalkyl, a substituted C 1 -C 6 alkyl, a substituted C2-C6 alkenyl, a substituted C2-6 alkynyl, a substituted C 1 -C 6 haloalkyl, a substituted C 1-6 alkoxy, a substituted hydroxyalkyl and a substituted aminoalkyl for R 6 are described herein.
  • the R 6 groups provided herein can be substituted 1, 2, 3, or more than 3 times with moieties selected from deuterium and halogen, except for a substituted C 1 -C 6 alkyl and a substituted C 1 -C 6 haloalkyl, which can be substituted 1, 2, 3, or more than 3 times with deuterium.
  • the carbon to which R 6 is attached can be a chiral center.
  • the carbon to which R 6 is attached can be in the (R)- configuration.
  • the carbon to which R 6 is attached can be in the (S)- configuration.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can have the structure .
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can have the structure .
  • R 7 can be hydrogen.
  • R 7 can be cyano.
  • R 7 can be an unsubstituted C 1 -C 6 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight- chained or branched).
  • R 7 can be an unsubstituted C 1 -C 6 haloalkyl, including those described herein.
  • R 7 can be an unsubstituted hydroxyalkyl.
  • R 7 can be an unsubstituted hydroxy-C 1 -C 6 alkyl.
  • Suitable hydroxyalkyls are described herein, and include –CH 2 -OH, –CH 2 CH 2 -OH, –CH(CH 3 )OH, C(CH 3 )2OH and –C(CH 2 CH 2 )OH.
  • R 7 can be substituted, such as a substituted C 1 -C 6 alkyl, a substituted C 1 -C 6 haloalkyl or a substituted hydroxyalkyl (such as a substituted hydroxy-C 1 -C 6 alkyl, for example, –CH(OH)CF 3 and –CH(OH)CHF2).
  • a substituted C1- C 6 alkyl can be substituted 1, 2, 3, or more than 3 times with deuterium, such as –CH 2 D, –CHD 2 , –CD 3 , –CD 2 CD 3 and –C(CD 3 ) 3 .
  • a variety of substituents can be present when R 7 is substituted, such as those described herein.
  • R 2 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure of Formula (Ib): ( ) [0075]
  • R 8 and R 9 can be each hydrogen.
  • at least one of R 8 and R 9 can be a non-hydrogen group.
  • one of R 8 and R 9 can be hydrogen, and the other of R 8 and R 9 can be –F, –CN, an unsubstituted or a substituted C 1 -C 6 alkyl or an unsubstituted C 1 -C 6 haloalkyl.
  • one of R 8 and R 9 can be –F, –CN, an unsubstituted or a substituted C 1 -C 6 alkyl or an unsubstituted C 1 -C 6 haloalkyl
  • the other of R 8 and R 9 can be –F, –CN, an unsubstituted or a substituted C 1 -C 6 alkyl or an unsubstituted C 1 -C 6 haloalkyl.
  • R 8 and R 9 can be taken together along with the carbon to which R 8 and R 9 are attached to form an unsubstituted or a substituted monocyclic cycloalkyl, wherein the substituted monocyclic cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen (such as F or Cl), hydroxy, an unsubstituted C 1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), an unsubstituted C 1-4 alkoxy (for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec- butoxy and tert-butoxy) and an unsubstituted C 1-4 haloalkyl (such as –CF 3 , –CCl 3
  • the monocyclic cycloalkyl that can be formed by taking together R 8 and R 9 along with the carbon to which R 8 and R 9 are attached can include three to four carbons or three to six carbons. In other embodiments, R 8 and R 9 can be taken together along with the carbon to which R 8 and R 9 are attached to form unsubstituted monocyclic heterocyclyl.
  • the groups coming off to the nitrogen of can be such that –NR 10 R 11 can be amino, a mono-substituted amine or a di-substituted amine.
  • R 10 and R 11 can be each hydrogen. In other embodiments, R 10 can be hydrogen; and R 11 can be an unsubstituted C 1 -C 6 alkyl.
  • R 10 and R 11 can be each an unsubstituted C 1 -C 6 alkyl. Suitable C 1 -C 6 alkyl are provided herein.
  • R 10 can be hydrogen; and R 11 can be a substituted C 1 -C 6 alkyl.
  • R 10 and R 11 can be each a substituted C 1 -C 6 alkyl.
  • various moieties can substitute R 10 and/or R 11 .
  • Moieties that can substitute R 10 and/or R 11 include those described herein. For example, R 10 and/or R 11 can be substituted 1, 2, 3 or more than 3 times with moieties independently selected from deuterium, halogen and hydroxy.
  • a cyclic moiety can be formed by taking R 10 and R 11 together along with the nitrogen to which R 10 and R 11 are attached.
  • R 10 and R 11 can be together along with the nitrogen to which R 10 and R 11 are attached to form an unsubstituted or a substituted 3- to 8-membered heterocyclyl, such as an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl.
  • the 3- to 8- membered heterocyclyl can include additional heteroatoms besides the nitrogen to which R 10 and R 11 are attached.
  • Exemplary heteroatoms that can be included in the cyclic ring from taking R 10 and R 11 together include a second nitrogen, oxygen and sulfur.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof includes a five-membered ring having the structure .
  • the five-membered ring can be an azole, and can be an aromatic. In some embodiments, can have the structure .
  • azoles include, but are not limited, to imidazole, pyrazole, oxazole, 1,3,4-oxadiazole, triazole and 1,3,4-thiadiazole.
  • X 2 can be CR 3c ; X 3 can be N; and X 4 can be NR 3b .
  • X 2 can be CR 3c ; X 3 can be N; and X 4 can be O.
  • X 2 can be N; X 3 can be CR 3c ; and X 4 can be O.
  • X 2 can be N; X 3 can be N; and X 4 can be O.
  • X 2 can be CR 3c ; X 3 can be N; and X 4 can be S.
  • X 2 can be N; X 3 can be N; and X 4 can be S.
  • X 2 can be NR 3b ; X 3 can be N; and X 4 can be CR 3c .
  • R 3b can be hydrogen.
  • R 3b can be an unsubstituted C 1 -C 6 alkyl.
  • R 3b can be a substituted C 1 -C 6 alkyl.
  • Ring A can be joined to the rest of the molecule at two different positions (which may be two adjacent carbons in a 1,2-relationship, or a 1,3-relationship or a 1,4 relationship).
  • Ring A can be an aromatic monocyclic ring or a non-aromatic monocyclic or bicyclic heterocyclyl.
  • Ring A can be an unsubstituted phenyl.
  • Ring A can be an unsubstituted monocyclic heteroaryl.
  • Ring A can be an unsubstituted monocyclic heterocyclyl.
  • Ring A can be an unsubstituted bicyclic heterocyclyl.
  • Ring A can be a substituted phenyl. In other embodiments, Ring A can be a substituted monocyclic heteroaryl. In still other embodiments, Ring A can be a substituted monocyclic heterocyclyl. In yet still other embodiments, Ring A can be a substituted bicyclic heterocyclyl.
  • the heteroaryl and the heterocyclyl can include 1, 2, 3 or 4 heteroatoms. Suitable heteroatoms that can be present in a heteroaryl, a monocyclic heterocyclyl and a bicyclic heterocyclyl include O (oxygen), S (sulfur) and N (nitrogen). As described herein, Ring A can be substituted.
  • Ring A can be (including any nitrogens present of the monocyclic and/or bicyclic heterocyclyl, substituted one or more times (such as 1, 2, 3 or 4 times) with moieties independently selected from –F, –Cl, –CN, an unsubstituted C 1-6 alkyl (such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched)), a-deuterium substituted C 1-6 alkyl (for example, –CD 3 , –CD 2 CD 3 , –CD 2 CD 2 CD 3 , –CD(CD 3 ) 2 , –CD 2 CD(CD 3 ) 2 and –CD 2 C(CD 3 ) 3 ), hydroxy, an unsubstituted
  • Ring A moieties that include one or more heteroatoms include, but are not limited to, pyridine, pyrazole, triazole (such as 1,2,3-triazole), imidazole, 1H-indazole, pyrazolo[1,5- a]pyridine, pyridin-2-one and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, wherein each can be unsubstituted or substituted as described herein.
  • Ring A can be any cyclic groups for Ring A include, but are not limited to the following: , , , , , , , , wherein the asterisk indicates the point of attachment to X 1 , and wherein each of these groups can be unsubstituted or substituted as described herein, including replacement of the hydrogen of a NH group with a moiety described herein (including those provided in the previous paragraph).
  • R 1 A variety of rings can be present for R 1 , wherein R 1 can be unsubstituted or substituted.
  • the rings that can be present R 1 can be non-aromatic or aromatic.
  • R 1 can be an unsubstituted or a substituted cycloalkyl.
  • cycloalkyls that can be present for R 1 include a 3- to 8-membered monocyclic cycloalkyl and a 5- to 10-membered bicyclic cycloalkyl.
  • Suitable cycloalkyl for R 1 can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and bicyclo[1.1.1]pentyl.
  • R 1 can be an unsubstituted or a substituted aryl.
  • R 1 can be an unsubstituted or a substituted phenyl or an unsubstituted or a substituted naphthyl. In some embodiments, R 1 can be an unsubstituted or a substituted monocyclic heteroaryl. In other embodiments, R 1 can be an unsubstituted or a substituted monocyclic heterocyclyl. In still other embodiments, R 1 can be an unsubstituted or a substituted monocyclic heteroaryl. In yet still other embodiments, R 1 can be an unsubstituted or a substituted monocyclic heterocyclyl.
  • the heteroaryl and the heterocyclyl that can present for R 1 can include one or more than one heteroatoms (such as 1, 2, 3 or 4 heteroatoms). Suitable heteroatoms include N (nitrogen), O (oxygen) and S (sulfur). When R 1 is substituted, a variety of moieties can be present.
  • R 1 can be a substituted with one or more substituents (for example, 1, 2, 3, or 4 substituents) selected from –F, –Cl, –CF 3 , –CH 2 CF 3 , an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy and an unsubstituted C 1-6 haloalkoxy (such as –OCF 3 , –OCCl3, –OCHF2, –OC(CH 3 )F2, –OCHCl2, – OCH 2 F, –OCH(CH 3 )F, –OCH 2 CF 3 , –OCH 2 Cl, –OCH 2 CH 2 F, –OCH 2 CH 2 Cl, –OCH 2 CH 2 CH 2 F, – OCH 2 CH 2 CH 2 Cl, –OCF2Cl and –OCFCl2).
  • substituents for example, 1, 2, 3, or 4 substituents
  • R 1 can be unsubstituted.
  • One example of a ring structure of R 1 is 1 2 3 , wherein Z , Z , Z , Z 4 and Z 5 can be independently CR 12 or N; and each R 12 can be hydrogen, –F, –Cl, an unsubstituted C 1 -C 6 alkyl, –CF 3 , –CH 2 CF 3 , an unsubstituted C 1 - 6 alkoxy or an unsubstituted C 1 - 6 haloalkoxy.
  • Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be each CH.
  • Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be each CR 12 , wherein one or more R 12 ’s (for example 1, 2 or 3 R 12 ’s) can be selected from –F, –Cl, an unsubstituted C 1 -C 6 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched)), an unsubstituted C 1-6 alkoxy (for example, –methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy
  • At least one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be N (nitrogen).
  • one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be N (nitrogen); and the remaining four of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be each CR 12 .
  • Z 1 , Z 2 , Z 3 and Z 4 can each be hydrogen and Z 5 can be N, or Z 1 , Z 2 , Z 3 and Z 5 can each be hydrogen and Z 4 can be N.
  • two of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be N (nitrogen); and the remaining three of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each CR 12 .
  • R 1 Another example of a ring structure of R 1 is , wherein Z 6 , Z 7 , Z 8 , Z 9 and Z 10 can be independently CHR 13 or N; and each R 13 can be hydrogen, –F, –Cl, an unsubstituted C 1 -C 6 alkyl, –CF 3 , –CH 2 CF 3 , an unsubstituted C 1-6 alkoxy or an unsubstituted C 1-6 haloalkoxy.
  • Z 6 , Z 7 , Z 8 , Z 9 and Z 10 can be each CH 2 .
  • Z 6 , Z 7 , Z 8 , Z 9 and Z 10 can be each CHR 13 , wherein one or more R 13 ’s (for example 1, 2 or 3 R 13 ’s) can be selected from –F, –Cl, an unsubstituted C 1 -C 6 alkyl (such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched)), an unsubstituted C 1-6 alkoxy (for example, –methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-but
  • R 1 can be directly attached to a carbon of Ring A or through a linker.
  • X 1 can be absent.
  • X 1 can be –NH.
  • X 1 can be –N(an unsubstituted C 1 -C 6 alkyl).
  • X 1 can be –N(a substituted C 1 -C 6 alkyl).
  • X 1 can be –(CH 2 )–NH–*, –(CH 2 )–N(an unsubstituted C 1 -C 6 alkyl)–* or –(CH 2 )–N(a substituted C 1 -C 6 alkyl)–*, wherein the “*” indicates the attachment point to Ring A.
  • X 1 can be –O– or –S–.
  • X 1 can be –CH 2 –.
  • X 1 can be –CH(an unsubstituted C 1 -C 6 alkyl)–. In some embodiments, X 1 can be –C(an unsubstituted C 1 -C 6 alkyl) 2 –. In other embodiments, X 1 can be –CH(an unsubstituted C 1 -C 6 alkyl)–. In still other embodiments, X 1 can be –C(a substituted C 1 -C 6 alkyl)2– . In still other embodiments, X 1 can be –C(R 4 R 5 )–, wherein R 4 and R 5 are taken together to form an unsubstituted C 3-8 cycloalkyl.
  • X 1 can be –C(R 4 R 5 )–, wherein R 4 and R 5 are taken together to form a substituted C 3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen, hydroxy, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 alkoxy and an unsubstituted C 1-4 haloalkyl.
  • the cycloalkyl that can be formed by taking R 4 and R 5 together along with the carbon to which R 4 and R 5 attached can be a monocyclic C3-8 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexyl.
  • R 4 and R 5 are taken together to form a substituted C 3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted 1 or 2 times with a substituent independently selected from –F, –Cl, –OH, –CH 3 , –OCH 3 and –CF 3 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be where: Ring A can be an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted bicyclic heteroaryl or an unsubstituted or a substituted bicyclic heterocyclyl, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C 1 - 6 alkyl
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be where: Ring A can be an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted bicyclic heteroaryl or an unsubstituted or a substituted bicyclic heterocyclyl, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C 1-6 alkyl, an
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be where: Ring A can be an unsubstituted or a substituted monocyclic heteroaryl, when the monocyclic heteroaryl is substituted, the monocyclic heteroaryl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy and an unsubstituted C 1-6 haloalkyl; X 1 can be –(CH 2 )n–NR 3a –; X 2 and X 3 can be each N (nitrogen); X 4 can be O (oxygen); R 1 can be an unsubstituted or a substituted phenyl, wherein when the phenyl is substituted, the phenyl can be substituted with one or more substituents selected from –F, –Cl, –CF 3 ,
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be where: Ring A can be an unsubstituted or a substituted monocyclic heteroaryl, when the monocyclic heteroaryl is substituted, the monocyclic heteroaryl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 alkoxy and an unsubstituted C 1 - 6 haloalkyl; X 1 can be –(CH 2 ) n –NR 3a –; X 2 and X 3 can be each N (nitrogen); X 4 can be O (oxygen); R 1 can be an unsubstituted or a substituted monocyclic cycloalkyl, wherein when the monocyclic cycloalkyl is substituted, the monocyclic cycloalkyl can be substituted with one or more substituents selected from –F, –
  • R 7 can be an unsubstituted C 1 -C 6 alkyl, an unsubstituted C 1 -C 6 haloalkyl or an unsubstituted hydroxyalkyl.
  • R 1 can be a substituted phenyl, for example, a mono- substituted phenyl (such as ortho-mono-substituted phenyl, meta-mono-substituted phenyl or para- mono-substituted phenyl).
  • R 1 can be a substituted monocyclic cycloalkyl, for example, a mono-substituted monocyclic cycloalkyl, such as a mono- substituted cyclohexyl.
  • R 1 can be a substituted monocyclic cycloalkyl, for example, a mono-substituted monocyclic cycloalkyl, such as a mono- substituted cyclohexyl.
  • Examples of compounds of Formula (I), and pharmaceutically acceptable salts thereof include the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof can be .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2021/102204. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be selected from (R)-3-methyl-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, (S)-3- methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin- 2-one, 3-methyl-3-(5-(2-((4-trifluoromethyl)phenyl)amino)pyridin-3-yl]-(1,3,4)oxadiazol-2-yl)- pyrrolidin-2-
  • R 2 cannot be , wherein Y 1 is –CH 2 –; R 6 is an unsubstituted C1- C6 alkyl; and R 7 is hydrogen. In some embodiments, R 2 cannot be , wherein Y 1 is – CH 2 CH 2 –; R 6 is an unsubstituted C 1 -C 6 alkyl; and R 7 is hydrogen. In some embodiments, Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and .
  • Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and In some embodiments, R 1 cannot be a para-substituted phenyl, such as a trifluoromethyl para-substituted phenyl).
  • Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and .
  • R 2 when R 2 is , wherein Y 1 is – CH 2 CH 2 –; R 6 is an unsubstituted C 1 -C 6 alkyl; and R 7 is hydrogen, then Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and .
  • Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and .
  • Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2019/222431.
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be selected from: (R)-3-methyl-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3- (5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, 3- methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2- one, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino )phenyl)-1,3,4-oxadiazol-2-yl )cyclopentanol, 1- (5-(2-((4-(triflu
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2018/231745.
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2016/049586. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in U.S. 2009/0156592. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2012/135581. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2009/094445.
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be where X 1 is –O–.
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be where X 1 is –O–; and Ring A is phenyl.
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be where Ring A is phenyl.
  • Ring A cannot an unsubstituted or a substituted be 1H-pyrazolo[3,4-b]pyridine, such as an unsubstituted or a substituted . In some embodiments, Ring A cannot be an unsubstituted or a substituted be 1H-pyrazolo[3,4-b]pyridine, such as an unsubstituted or a substituted ; and R 1 is an unsubstituted or a substituted tetrahydropyran.
  • Ring A cannot an unsubstituted or a substituted be 1H-pyrazolo[3,4-b]pyridine, such as an unsubstituted or a substituted 1 3a 1 ; when X is NR (such as NH); and R is an unsubstituted or a substituted tetrahydro-2H-pyran.
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be where Ring A is phenyl; and R 1 is aryl, such as phenyl. In some embodiments, cannot be
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be where Ring A is phenyl; and is .
  • a compound of Formula (I), or pharmaceutically acceptable salts thereof cannot be where Ring A is phenyl; R 1 is aryl (for example, phenyl); and is .
  • R 1 cannot be an unsubstituted or a substituted C 3 -C 10 cycloalkyl, for example, R 1 cannot be an unsubstituted or a substituted cyclopropyl, an unsubstituted or a substituted cyclobutyl and/or an unsubstituted or a substituted cyclopentyl.
  • R 1 cannot be an unsubstituted or a substituted oxirane, an unsubstituted or a substituted oxetane, an unsubstituted or a substituted tetrahydrofuran, an unsubstituted or a substituted 1,3-dioxolane, an unsubstituted or a substituted tetrahydropyran and/or an unsubstituted or a substituted 1,3-dioxane.
  • R 1 cannot be an unsubstituted or a substituted pyrrolidine, an unsubstituted or a substituted piperidine and/or an unsubstituted or a substituted piperazine.
  • R 1 cannot be an unsubstituted or a substituted pyrimidine-2,4(1H,3H)-dione. In some embodiments, R 1 cannot be an unsubstituted or a substituted bicyclic heterocyclyl. In some embodiments, R 1 cannot be an unsubstituted or a substituted isoindoline, an unsubstituted or a substituted 1,2,3,4-tetrahydroisoquinoline and/or an unsubstituted or a substituted 2H-benzo[b][1,4]oxazin-3(4H)-one.
  • R 2 cannot be an unsubstituted or a substituted pyrrolidine and/or an unsubstituted or a substituted piperidine. In some embodiments, R 2 cannot be an unsubstituted or a substituted . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where R 2 is . In some embodiments, R 10 and/or R 11 cannot be an unsubstituted or a substituted C 1 -C 6 alkyl.
  • R 10 and/or R 11 cannot be a substituted C 1 -C 6 alkyl, such as an alkynyl substituted C 1 -C 6 alkyl, a cyano substituted C 1 -C 6 alkyl. In some embodiments, R 10 and R 11 cannot be each hydrogen. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be selected from: , pharmaceutically acceptable salts thereof). Synthesis [0092] Compounds of the Formula (I), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein.
  • Scheme 1 [0093]
  • R 1 , X 1 , Ring A and R 6 can be as described herein.
  • the carboxylic ester and reacting group (RG) can be in various relationships (such as 1,2, 1,3- 1,4-relationship, etc.).
  • amine or halide of general Formula (1a) can be reacted with aryl halide, heteroaryl halide or boronate of general Formula (1b) to obtain a compound of general Formula (1c).
  • hydrazide of general Formula (2a) can be reacted with an acid of general Formula (2b) (wherein PG indicates a suitable protecting group) to obtain a compound of general Formula (2c).
  • Cyclization of a compound of general Formula (2c) can provide a compound of general Formula (2d) that can undergoes deprotonation and a substitution to form a compound of general Formula (2e).
  • Deprotection of a compound of general Formula (2e) can provide a compound of general Formula (2f) that can be separated under chiral SFC or HPLC to obtain compounds of general Formulae (IIA) and (IIB).
  • R 1 , Ring A and R 6 can be as described herein.
  • the carboxylic ester and bromide can be in various relationships (such as 1,2, 1,3- 1,4-relationship, etc.).
  • amide coupling of an acid of general Formula (3a) and hydrazide of general Formula (3b) can provide a compound of general Formula (3c).
  • Cyclization of a compound of general Formula (3c) can provide a compound of general Formula (3d) that can undergo a coupling reaction with a reagent (such as aryl amine, heteroaryl amine, aliphatic amine, aryl boronic acid or heteroaryl boronic acid) to provide a compound of general Formula (3e).
  • a reagent such as aryl amine, heteroaryl amine, aliphatic amine, aryl boronic acid or heteroaryl boronic acid
  • compositions [0096] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • composition refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
  • an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • stabilizers such as anti-oxidants and metal-chelating agents are excipients.
  • the pharmaceutical composition comprises an anti-oxidant and/or a metal-chelating agent.
  • a “diluent” is a type of excipient.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
  • a compound, salt and/or composition can be administered orally.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Some embodiments described herein relate to a method for treating a disease described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a disease described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof)
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disease described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a disease described herein.
  • Some embodiments described herein relate to a method for treating an autoimmune disorder described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having an autoimmune disorder described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof)
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating an autoimmune disorder described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating an autoimmune disorder described herein.
  • Some embodiments described herein relate to a method for treating an inflammatory condition described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having an inflammatory condition described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having an inflammatory condition described herein.
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating an inflammatory condition described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating an inflammatory condition described herein.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • Some embodiments described herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD can include contacting a cancer cell from a cancer described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting a YAP/TAZ- TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a cancer cell with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments disclosed herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein or a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions disclosed herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • Still other embodiments disclosed herein relate to a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
  • suitable cancers include, but are not limited to: mesothelioma, renal cell carcinoma, cervical squamous cell cancer, endocervical adenocarcinoma, hepatocellular carcinoma, medulloblastoma, oral squamous cell cancer, lung squamous cell cancer, lung adenocarcinoma, schwannoma, meningioma, ependymoma, epithelioid hemangioendothelioma, luminal A breast cancer, luminal B breast cancer, colorectal cancer, uveal melanoma, pancreatic adenocarcinoma, kidney renal papillary cell carcinoma, rectum adenocarcinoma, bladder urothelial carcinoma, esophageal carcinoma, head and neck squamous cell cancer, squamous cell cancers, including head and neck squamous cell cancer, cancers that are resistant to an EG
  • compounds of Formula (I), along with pharmaceutically acceptable salts thereof, can be used to treat cancers that have one or more of the following features: a hippo pathway alteration, YAP and/or TAZ amplification, mutation, gain of function fusions, a neurofibromatosis type 2 (NF2) mutation or deletion, and/or a LATS1/2 mutation.
  • a “subject” refers to an animal that is the object of treatment, observation or experiment.
  • “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • the subject can be human.
  • the subject can be a child and/or an infant, for example, a child or infant with a fever.
  • the subject can be an adult.
  • the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition.
  • treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
  • treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
  • therapeutically effective amount and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated.
  • a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated.
  • an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration.
  • the dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.
  • a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg.
  • a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day, or any amount in between.
  • the compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed.
  • effective dosage levels that is the dosage levels necessary to achieve the desired result
  • useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine) [0123]
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data.
  • Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. [0124] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration.
  • the severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods.
  • the dose and perhaps dose frequency will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line.
  • a cell line such as a mammalian, and preferably human, cell line.
  • the results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • Example 6 (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (6A) and (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3- yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (6B) [0165]
  • Example 6 was synthesized similarly to Example 5.
  • Example 7 (S)-3-Methyl-3- (5-(2-((5- (trifluoromethyl)pyridin-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol -2- yl) pyrrolidin-2-one (7A) and (R)-3-methyl-3-(5-(2-((5-(trifluoromethyl) pyridin-2-yl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (7B) [0168]
  • Example 7 was synthesized similarly to Example 5.
  • Example 8 (S)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (8A) and (R)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2- yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (8B) [0171]
  • Example 8 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 8A and 8B are assigned arbitrarily. [0172] Prep.
  • HPLC conditions Column/dimension: X SELECT C18-CSH-packed C8 (19 ⁇ 250 mm), 5 ⁇ Mobile phase A: 10MM AMM-bicarbonate in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/30, 1/30, 7/60, 12.9/60, 13.0/100, 17/100, 17.1/30, 20/30; Flow rate: 18 ml/min; Solubility: THF + acetonitrile+ water.
  • Example 9 (S)-3-(5-(1,5-Dimethyl-3-((4-(trifluoromethyl)phenyl)amino)-1H- pyrazol-4-yl)-1,3,4-oxadiazol- 2-yl)-3-methylpyrrolidin-2-one (9A) and (R)-3-(5-(1,5-dimethyl-3-((4-(trifluoromethyl) phenyl) amino)-1H-pyrazol-4-yl)- 1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin- 2-one (9B) [0175]
  • Example 9 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC.
  • Example 12 (R)-1-(hydroxymethyl)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (12) [0188]
  • Example 12 was synthesized similarly to Example 11.
  • Example 13 (S)-1-(hydroxymethyl)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (13) [0189]
  • Example 13 was synthesized similarly to Example 11.
  • Example 14 (R)-1-(Hydroxymethyl)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (14) [0190]
  • Example 14 was synthesized similarly to Example 11.
  • Example 16 (S)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (16) [0196] Example 16 was synthesized similarly to Example 15.
  • Example 17 (S)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (17) [0197]
  • Example 17 was synthesized similarly to Example 15.
  • Example 18 (S)-3-Methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-3-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (18) [0198]
  • Example 18 was synthesized similarly to Example 15.
  • Example 19 3-Methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-3-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (19) [0199]
  • Example 19 was synthesized similarly to Example 15.
  • Example 20 (S)-3-methyl-3-(5-(1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazol-3-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (20) [0200] To a solution of methyl 4-bromo-1H-indazole-3-carboxylate (1.06 g, 4.14 mmol) in DMF (6 mL) was added K 2 CO 3 (1.72 g, 12.4 mmol). The mixture was stirred at rt for 1 h, and then iodomethane (0.881 g, 6.21 mmol) in DMF (1 mL) was added.
  • Example 22 (S)-3-Methyl-3-(5-(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (22) [0211]
  • Example 22 was synthesized similarly to Example 21.
  • Example 23 (S)-3-Methyl-3-(5-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (23) [0212]
  • Example 23 was synthesized similarly to Example 21.
  • the mixture was degassed by a flow of nitrogen for 10 min, followed by the addition of Pd(OAc) 2 (0.531 g, 2.36 mmol) and Xantphos (1.37 g, 2.36 mmol). After stirring at 100 °C for 16 h, the mixture was diluted with EtOAc (100 mL) and filtered through a pad of celite. The filter cake washed with EtOAc (2 x 30 mL). The combined filtrates were concentrated under reduced pressure.
  • Examples 32-47 were prepared using similar procedures as shown for Examples 1, 2, 5 and 15 using the appropriate the starting materials that are readily commercially available or prepared by known and published procedures.
  • Examples 48 and 49 (R)-2-(2-oxo-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-3-yl)acetonitrile (48) and (S)-2-(2-oxo-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)acetonitrile (49) [0241] To a stirred solution of 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (841 mg, 3.38 mmol) in DMF (8 mL) were
  • Example 54 (R)-3-(5-(3-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3- vinylpyrrolidin-2-one (54) [0265] Compound 54 was made in a similar fashion to that of Compounds 51 and 52.
  • Compounds 58 and 59 are stereoisomers, and the shown stereochemistry is relative. The stereochemistry of 58 and 59 are assigned arbitrarily.
  • Compounds 60 and 61 are stereoisomers, and the shown stereochemistry is relative. The stereochemistry of 60 and 61 are assigned arbitrarily.
  • TEAD luciferase Reporter Assay MCF-7 (BPS Bioscience, Cat#60618) cells were plated, and the following day were treated with inhibitors and 0.1% v/v DMSO. After 24 h incubation with the inhibitor, luciferase activity was evaluated using Firefly luciferase reagent (Promega, E1501). Plates were read on a M5e plate reader (Molecular Devices) using luciferase assay protocol. The potency of compounds was determined by IC 50 value generated with GraphPad Prism software. The results are provided in Table 1, and demonstrate that Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are inhibitors of TEAD.

Abstract

Compounds of Formula (I) are provided herein. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions, including autoimmune diseases, inflammatory conditions and/or cancers.

Description

AZOLE COMPOUNDS INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS [0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application Nos. 63/261,612, filed September 24, 2021 and 63/267,773, filed February 9, 2022, each of which is incorporated by reference in there entireties. Field [0002] The present application relates to compounds that are TEAD inhibitors and methods of using them to treat conditions, such autoimmune disorders, inflammatory conditions and cancer. Description [0003] Transcriptional enhanced associate domain (TEAD) transcription factors are key components of the Hippo signaling pathway. The human TEAD proteins include four paralogous transcription factors, each with an N-terminal TEA domain, DNA-binding domain, proline-rich region, and C-terminal YAP/TAZ-binding domain. TEAD proteins have been implicated as playing a role in development, cell proliferation, regeneration and tissue homeostasis. SUMMARY [0004] Some embodiments provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof. [0005] Some embodiments disclosed herein relate to a pharmaceutical composition that can include an effective amount of one or more of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. [0006] Some embodiments described herein relate to a method for treating a disorder, a condition and/or a disease described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a disorder, a condition and/or a disease described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disorder, a condition and/or a disease described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a disorder, a condition and/or a disease described herein. In some embodiments, the disorder, the condition and/or the disease can be selected from an autoimmune disorder, an inflammatory condition and a cancer. [0007] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. [0008] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. [0009] Some embodiments described herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD in a cell that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. [0010] Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting a YAP/TAZ- TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. DETAILED DESCRIPTION Definitions [0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0012] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, an amino, a mono-substituted amine, a di-substituted amine and an amine(C1-C6 alkyl). [0013] As used herein, “Ca to Cb” in which “a” and “b” are integers refer to the number of carbon atoms in a group. The indicated group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed. [0014] As used herein, the term “alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted. [0015] The term “alkenyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. An alkenyl group may be unsubstituted or substituted. [0016] The term “alkynyl” used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstituted or substituted. [0017] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane. [0018] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted. [0019] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. [0020] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted. [0021] As used herein, “heterocyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged heterocyclyl” refers to compounds wherein the heterocyclyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Heterocyclyl group can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogens in a heterocyclyl may be quaternized. Heterocyclyl groups may be unsubstituted or substituted. Examples of such “heterocyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2- dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3- dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N- Oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of spiro heterocyclyl groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6- azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and 2- azaspiro[3.4]octane. [0022] As used herein, “cycloalkyl(alkyl)” refer to a cycloalkyl group connected, as a substituent, via a lower alkylene group. The lower alkylene and cycloalkyl group of a cycloalkyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to cyclopropyl(alkyl), cyclobutyl(alkyl), cyclopentyl(alkyl) and cyclohexyl(alkyl). [0023] As used herein, “aryl(alkyl)” refers to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl. [0024] As used herein, “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to 2- thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs. [0025] A “heterocyclyl(alkyl)” refer to a heterocyclic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H- thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl). [0026] As used herein, “lower alkylene groups” are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- ) and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a cycloalkyl group (e.g.,
Figure imgf000010_0001
). [0027] As used herein, the term “hydroxy” refers to a –OH group. [0028] As used herein, “alkoxy” refers to the Formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted. [0029] As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted. [0030] A “cyano” group refers to a “-CN” group. [0031] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine. [0032] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted. [0033] An “O-carbamyl” group refers to a “-OC(=O)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted. [0034] An “N-carbamyl” group refers to an “ROC(=O)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted. [0035] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted. [0036] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted. [0037] A “C-amido” group refers to a “-C(=O)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted. [0038] An “N-amido” group refers to a “RC(=O)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted. [0039] An “S-sulfonamido” group refers to a “-SO2N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted. [0040] An “N-sulfonamido” group refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted. [0041] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted. [0042] The term “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. A C-carboxy may be substituted or unsubstituted. [0043] A “nitro” group refers to an “–NO2” group. [0044] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted. [0045] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted. [0046] A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted. [0047] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl and polyhaloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl and pentafluoroethyl. A haloalkyl may be substituted or unsubstituted. [0048] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted. [0049] The term “amino” as used herein refers to a –NH2 group. [0050] A “mono-substituted amine” group refers to a “-NHRA” group in which RA can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. The RA may be substituted or unsubstituted. Examples of mono-substituted amino groups include, but are not limited to, −NH(methyl), −NH(phenyl) and the like. [0051] A “di-substituted amine” group refers to a “-NRARB” group in which RA and RB can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. RA and RB can independently be substituted or unsubstituted. Examples of di-substituted amino groups include, but are not limited to, −N(methyl)2, −N(phenyl)(methyl), −N(ethyl)(methyl) and the like. [0052] As used herein, “hydroxyalkyl” refer to an alkyl as described herein that includes 1, 2 or 3 hydroxy (–OH) groups attached to the alkyl. The alkyl portion of the hydroxyalkyl can be straight-chained or branched. Additionally, the alkyl portion can be a lower alkyl. Examples of hydroxyalkyl include, but are not limited to, –CH2-OH, –CH2CH2-OH, – CH(CH3)OH, –C(CH3)2OH and –C(CH2CH2)OH. [0053] As used herein, “aminoalkyl” refer to an alkyl as described herein that includes 1, 2 or 3 amino (–NH2) groups attached to the alkyl. The alkyl portion of the aminoalkyl can be straight-chained or branched. Additionally, the alkyl portion can be a lower alkyl. Examples of heteroaryl rings include, but are not limited to, –CH2-NH2, –CH2CH2-NH2, –CH(CH3)NH2, – C(CH3)2NH2 and –C(CH2CH2)NH2. [0054] Where the number of substituents is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms. [0055] As used herein, a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term “radical” can be used interchangeably with the term “group.” [0056] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p- toluenesulfonic, trifluoroacetic, benzoic, salicylic, 2-oxopentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine. For compounds of Formula (I), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH2), the nitrogen-based group can be associated with a positive charge (for example, NH2 can become NH3+) and the positive charge can be balanced by a negatively charged counterion (such as Cl-). [0057] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. [0058] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium). [0059] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half- life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. [0060] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [0061] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. [0062] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. [0063] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope. Compounds [0064] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
Figure imgf000017_0001
wherein: Ring A can be an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted bicyclic heteroaryl or an unsubstituted or a substituted bicyclic heterocyclyl, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C1-6 alkyl, a deuterium- substituted C1-6 alkyl, hydroxy, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkyl; X1 can be absent, –(CH2)n–NR3a–, –O–, –S–, –S(O)–, –S(=O)2–, –CH2–, –CH(an unsubstituted C1- C6 alkyl)– or –C(R4R5)–; X2, X3, and X4 can be independently N (nitrogen), NR3b, O (oxygen), S (sulfur), or CR3c; R1 can be an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl, wherein when the cycloalkyl, the aryl, the heteroaryl and the heterocyclyl is substituted, the aryl, the heteroaryl and the heterocyclyl can be substituted with one or more substituents selected from –F, –Cl, –CF3, –CH2CF3, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkoxy; R2 can be an unsubstituted or a substituted C3-C10 cycloalkyl, an unsubstituted or a substituted C2-C10 heterocyclyl,
Figure imgf000017_0002
or
Figure imgf000017_0003
; R3a, R3b and R3c can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; R4 and R5 can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; or R4 and R5 can be taken together to form an unsubstituted or a substituted C3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl; R6 can be hydrogen, –F, –Cl, –CN, an unsubstituted or a substituted C3-6 cycloalkyl, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C2-C6 alkenyl, an unsubstituted or a substituted C2-6 alkynyl, an unsubstituted or a substituted C1-C6 haloalkyl, an unsubstituted or a substituted C1-6 alkoxy, an unsubstituted or a substituted hydroxyalkyl or an unsubstituted or a substituted aminoalkyl; R7 can be hydrogen, cyano, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C1-C6 haloalkyl or an unsubstituted or a substituted hydroxyalkyl; Y1 can be –CH2–, –CH2CH2–, –O–, –OCH2–, –CF2–, –CHF– or – C(CH3)2–; R8 can be hydrogen, –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl; and R9 can be hydrogen, –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl; or R8 and R9 can be taken together to form an unsubstituted or a substituted monocyclic cycloalkyl or an unsubstituted monocyclic heterocyclyl, wherein the substituted monocyclic cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl; and R10 and R11 can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; or R10 and R11 can be taken together to form an unsubstituted or a substituted 3- to 8-membered heterocyclyl; n can be 0 or 1; and provided that
Figure imgf000018_0001
is aromatic. [0065] R1, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9, R10 and R11 can be a substituted substituent as described herein. When R1, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9, R10 and/or R11 is substituted, R1, R2, R3a, R3b, R3c, R4, R5, R6, R7, R8, R9, R10 and/or R11 can be substituted one or more times (such as 1, 2, 3, 4 or more than 4 times) with groups independently selected from those provided for “optionally substituted.” [0066] As provided herein, R2 can be a variety of structures. In some embodiments, R2 can be an unsubstituted or a substituted C3-C10 cycloalkyl. In other embodiments, R2 can be an unsubstituted or a substituted C2-C10 heterocyclyl. In still other embodiments, R2 can be a cyclic amide, such as . In yet stil 2
Figure imgf000018_0003
Figure imgf000018_0002
l other embodiments, R can be . The C3- C10 cycloalkyl for R2 can be monocyclic or multicyclic (for example, bicyclic). Similarly, the unsubstituted or a substituted C2-C10 heterocyclyl for R2 can be monocyclic or multicyclic (such as bicyclic). In some embodiments, the unsubstituted or a substituted C2-C10 heterocyclyl for R2 can be a 4- to 12-membered heterocyclyl that includes 1, 2, 3, 4 or 5 heteroatoms selected from N (nitrogen), O (oxygen) and S (sulfur). When R2 is an unsubstituted or a substituted bicyclic C3- C10 cycloalkyl or an unsubstituted or a substituted bicyclic C2-C10 heterocyclyl, the two rings of C3-C10 cycloalkyl and/or C2-C10 heterocyclyl can be joined in a fused or spiro-fashion. [0067] When R2 is
Figure imgf000019_0001
, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure of Formula (Ia):
Figure imgf000019_0002
(Ia). [0068] The ring of R2, when R2 is
Figure imgf000019_0003
, can vary. In some embodiments, Y1 can be –CH2–, and
Figure imgf000019_0004
can be an optionally substituted pyrrolidinone. In other embodiments, Y1 can be –CH2CH2–, and R2 can be an optionally substituted piperidinone. In still other embodiments, R2 can be an optionally substituted oxazolidinone when Y1 is –O–. In yet still other embodiments, Y1 can be –OCH2–, and R2 can be an optionally substituted morpholinone having the structure
Figure imgf000019_0005
. The ring of R2 can be substituted with one or more fluoros. In some embodiments, R2 is
Figure imgf000020_0001
. In other embodiments, R2 is
Figure imgf000020_0002
. The ring of R2 can be also substituted with an unsubstituted alkyl. In some embodiments, Y1 can be –C(CH3)2–, and
Figure imgf000020_0003
can be
Figure imgf000020_0004
. [0069] As provided herein, R2 can be
Figure imgf000020_0005
, In some embodiments, R6 can be hydrogen. In other embodiments, R6 can be a halogen, such as –F or –Cl. In still other embodiments, R6 can be –CN. [0070] R6 can also be a saturated or unsaturated straight-chained or branched hydrogen carbon. For example, in some embodiments, R6 can be an unsubstituted or a substituted C1-C6 alkyl. Examples of C1-C6 alkyls for R6 include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched). In other embodiments, R6 can be an unsubstituted or a substituted C2-C6 alkenyl or an unsubstituted or a substituted C2-6 alkynyl. As an example, R6 can be –CH=CH2. Cyclic hydrocarbons can be present for R6. In some embodiments, R6 can be an unsubstituted or a substituted C3-6 cycloalkyl, such as an unsubstituted or a substituted monocyclic C3-6 cycloalkyl and an unsubstituted or a substituted bicyclic C3-6 cycloalkyl. Suitable C3-6 cycloalkyls for R6 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[1.1.1]pentyl. [0071] Various other groups can be present for R6. In some embodiments, R6 can be an unsubstituted or a substituted C1-C6 haloalkyl. Exemplary C1-C6 haloalkyls include the following: –CF3, –CCl3, –CHF2, –C(CH3)F2, –CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F and –CH2CH2CH2Cl. In other embodiments, R6 can be an unsubstituted or a substituted C1-6 alkoxy, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxyl, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched). In still other embodiments, R6 can be an unsubstituted or a substituted hydroxyalkyl. For example, R6 can be an unsubstituted or a substituted hydroxy-C1-6 alkyl. In yet still other embodiments, R6 can be an unsubstituted or a substituted aminoalkyl, sus as an unsubstituted or a substituted amino-C1-6 alkyl. The alkyl portion of a hydroxyalkyl and an aminoalkyl can be straight-chained or branched. Additionally, one or more hydroxy groups (such as 1, 2 or 3) can be present for a hydroxyalkyl, and one or more amino groups (for example, 1, 2 or 3) can be present for an aminoalkyl. A non-limiting list of hydroxyalkyls and aminoalkyls include the following: –CH2-OH, –CH2CH2-OH, –CH(CH3)OH, –C(CH3)2OH, –C(CH2CH2)OH, –CH2-NH2, –CH2CH2-NH2, –CH(CH3)NH2, –C(CH3)2NH2 and –C(CH2CH2)NH2. [0072] The various R6 substituents can be unsubstituted or substituted. In some embodiments, when R6 is substituted, one or more moieties (such as 1, 2, 3 or more than 3) can be present. Some moieties that can be present on a substituted C3-6 cycloalkyl, a substituted C1-C6 alkyl, a substituted C2-C6 alkenyl, a substituted C2-6 alkynyl, a substituted C1-C6 haloalkyl, a substituted C1-6 alkoxy, a substituted hydroxyalkyl and a substituted aminoalkyl for R6 are described herein. For example, the R6 groups provided herein can be substituted 1, 2, 3, or more than 3 times with moieties selected from deuterium and halogen, except for a substituted C1-C6 alkyl and a substituted C1-C6 haloalkyl, which can be substituted 1, 2, 3, or more than 3 times with deuterium. Those skilled in the art understand that the carbon to which R6 is attached can be a chiral center. In some embodiments, the carbon to which R6 is attached can be in the (R)- configuration. In other embodiments, the carbon to which R6 is attached can be in the (S)- configuration. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure
Figure imgf000021_0001
. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure
Figure imgf000021_0002
. [0073] Several groups can be attached to the nitrogen of
Figure imgf000022_0001
. In some embodiments, R7 can be hydrogen. In other embodiments, R7 can be cyano. In still other embodiments, R7 can be an unsubstituted C1-C6 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight- chained or branched). In yet still other embodiments, R7 can be an unsubstituted C1-C6 haloalkyl, including those described herein. In some embodiments, R7 can be an unsubstituted hydroxyalkyl. For example, R7 can be an unsubstituted hydroxy-C1-C6 alkyl. Suitable hydroxyalkyls are described herein, and include –CH2-OH, –CH2CH2-OH, –CH(CH3)OH, C(CH3)2OH and –C(CH2CH2)OH. As provided herein, R7 can be substituted, such as a substituted C1-C6 alkyl, a substituted C1-C6 haloalkyl or a substituted hydroxyalkyl (such as a substituted hydroxy-C1-C6 alkyl, for example, –CH(OH)CF3 and –CH(OH)CHF2). In some embodiments, a substituted C1- C6 alkyl can be substituted 1, 2, 3, or more than 3 times with deuterium, such as –CH2D, –CHD2, –CD3, –CD2CD3 and –C(CD3)3. A variety of substituents can be present when R7 is substituted, such as those described herein. [0074] Another option for R2 is
Figure imgf000022_0002
When R2 is
Figure imgf000022_0003
, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure of Formula (Ib):
Figure imgf000022_0004
( ) [0075] In some embodiments, R8 and R9 can be each hydrogen. In other embodiments, at least one of R8 and R9 can be a non-hydrogen group. As an example, one of R8 and R9 can be hydrogen, and the other of R8 and R9 can be –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl. As another example, one of R8 and R9 can be –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl, and the other of R8 and R9 can be –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl. In some embodiments, R8 and R9 can be taken together along with the carbon to which R8 and R9 are attached to form an unsubstituted or a substituted monocyclic cycloalkyl, wherein the substituted monocyclic cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen (such as F or Cl), hydroxy, an unsubstituted C1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), an unsubstituted C1-4 alkoxy (for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec- butoxy and tert-butoxy) and an unsubstituted C1-4 haloalkyl (such as –CF3, –CCl3, –CHF2, –C(CH3)F2, –CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F and –CH2CH2CH2Cl). The monocyclic cycloalkyl that can be formed by taking together R8 and R9 along with the carbon to which R8 and R9 are attached can include three to four carbons or three to six carbons. In other embodiments, R8 and R9 can be taken together along with the carbon to which R8 and R9 are attached to form unsubstituted monocyclic heterocyclyl. [0076] The groups coming off to the nitrogen of
Figure imgf000023_0001
can be such that –NR10R11 can be amino, a mono-substituted amine or a di-substituted amine. In some embodiments, R10 and R11 can be each hydrogen. In other embodiments, R10 can be hydrogen; and R11 can be an unsubstituted C1-C6 alkyl. In still other embodiments, R10 and R11 can be each an unsubstituted C1-C6 alkyl. Suitable C1-C6 alkyl are provided herein. In yet still other embodiments, R10 can be hydrogen; and R11 can be a substituted C1-C6 alkyl. In some embodiments, R10 and R11 can be each a substituted C1-C6 alkyl. When R10 and/or R11 are substituted, various moieties can substitute R10 and/or R11. Moieties that can substitute R10 and/or R11 include those described herein. For example, R10 and/or R11 can be substituted 1, 2, 3 or more than 3 times with moieties independently selected from deuterium, halogen and hydroxy. A cyclic moiety can be formed by taking R10 and R11 together along with the nitrogen to which R10 and R11 are attached. In some embodiments, R10 and R11 can be together along with the nitrogen to which R10 and R11 are attached to form an unsubstituted or a substituted 3- to 8-membered heterocyclyl, such as an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl. The 3- to 8- membered heterocyclyl can include additional heteroatoms besides the nitrogen to which R10 and R11 are attached. Exemplary heteroatoms that can be included in the cyclic ring from taking R10 and R11 together include a second nitrogen, oxygen and sulfur. The 3- to 8-membered heterocyclyl can be substituted. For example, the 3- to 8-membered heterocyclyl can be substituted 1, 2, 3, 4 or more than 4 times with moieties independently selected from deuterium, halogen and hydroxy. [0077] A compound of Formula (I), or a pharmaceutically acceptable salt thereof, includes a five-membered ring having the structure
Figure imgf000024_0001
. The five-membered ring,
Figure imgf000024_0002
, can be an azole, and can be an aromatic. In some embodiments,
Figure imgf000024_0004
can have the structure
Figure imgf000024_0003
. Examples of azoles include, but are not limited, to imidazole, pyrazole, oxazole, 1,3,4-oxadiazole, triazole and 1,3,4-thiadiazole. In some embodiments, X2 can be CR3c; X3 can be N; and X4 can be NR3b. In other embodiments, X2 can be CR3c; X3 can be N; and X4 can be O. In still other embodiments, X2 can be N; X3 can be CR3c; and X4 can be O. In yet still other embodiments, X2 can be N; X3 can be N; and X4 can be O. In some embodiments, X2 can be CR3c; X3 can be N; and X4 can be S. In other embodiments, X2 can be N; X3 can be N; and X4 can be S. In still other embodiments, X2 can be NR3b; X3 can be N; and X4 can be CR3c. In some of the embodiments of this paragraph, when X2; X3 and/or X4 can be NR3b, R3b can be hydrogen. In other of the embodiments of this paragraph, when X2; X3 and/or X4 can be NR3b, R3b can be an unsubstituted C1-C6 alkyl. In still other of the embodiments of this paragraph, when X2; X3 and/or X4 can be NR3b, R3b can be a substituted C1-C6 alkyl. [0078] Ring A can be joined to the rest of the molecule at two different positions (which may be two adjacent carbons in a 1,2-relationship, or a 1,3-relationship or a 1,4 relationship). Ring A can be an aromatic monocyclic ring or a non-aromatic monocyclic or bicyclic heterocyclyl. In some embodiments, Ring A can be an unsubstituted phenyl. In other embodiments, Ring A can be an unsubstituted monocyclic heteroaryl. In still other embodiments, Ring A can be an unsubstituted monocyclic heterocyclyl. In yet still other embodiments, Ring A can be an unsubstituted bicyclic heterocyclyl. In some embodiments, Ring A can be a substituted phenyl. In other embodiments, Ring A can be a substituted monocyclic heteroaryl. In still other embodiments, Ring A can be a substituted monocyclic heterocyclyl. In yet still other embodiments, Ring A can be a substituted bicyclic heterocyclyl. The heteroaryl and the heterocyclyl (monocyclic and bicyclic heterocyclyl) can include 1, 2, 3 or 4 heteroatoms. Suitable heteroatoms that can be present in a heteroaryl, a monocyclic heterocyclyl and a bicyclic heterocyclyl include O (oxygen), S (sulfur) and N (nitrogen). As described herein, Ring A can be substituted. For example, Ring A can be (including any nitrogens present of the monocyclic and/or bicyclic heterocyclyl, substituted one or more times (such as 1, 2, 3 or 4 times) with moieties independently selected from –F, –Cl, –CN, an unsubstituted C1-6 alkyl (such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched)), a-deuterium substituted C1-6 alkyl (for example, –CD3, –CD2CD3, –CD2CD2CD3, –CD(CD3)2, –CD2CD(CD3)2 and –CD2C(CD3)3), hydroxy, an unsubstituted C1-6 alkoxy (for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight- chained or branched)) and an unsubstituted C1-6 haloalkyl (such as –CF3, –CCl3, –CHF2, –C(CH3)F2, –CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F and –CH2CH2CH2Cl). Examples of Ring A moieties that include one or more heteroatoms (such as N (nitrogen), O (oxygen) and S (sulfur) include, but are not limited to, pyridine, pyrazole, triazole (such as 1,2,3-triazole), imidazole, 1H-indazole, pyrazolo[1,5- a]pyridine, pyridin-2-one and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, wherein each can be unsubstituted or substituted as described herein. Specific examples of what Ring A can be are below:
Figure imgf000025_0001
[0079] Exemplary cyclic groups for Ring A include, but are not limited to the following:
Figure imgf000026_0001
, , , , , , ,
Figure imgf000026_0002
, wherein the asterisk indicates the point of attachment to X1, and wherein each of these groups can be unsubstituted or substituted as described herein, including replacement of the hydrogen of a NH group with a moiety described herein (including those provided in the previous paragraph). [0080] A variety of rings can be present for R1, wherein R1 can be unsubstituted or substituted. The rings that can be present R1 can be non-aromatic or aromatic. In some embodiments, R1 can be an unsubstituted or a substituted cycloalkyl. Some examples of cycloalkyls that can be present for R1 include a 3- to 8-membered monocyclic cycloalkyl and a 5- to 10-membered bicyclic cycloalkyl. Suitable cycloalkyl for R1 can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and bicyclo[1.1.1]pentyl. In other embodiments, R1 can be an unsubstituted or a substituted aryl. For example, R1 can be an unsubstituted or a substituted phenyl or an unsubstituted or a substituted naphthyl. In some embodiments, R1 can be an unsubstituted or a substituted monocyclic heteroaryl. In other embodiments, R1 can be an unsubstituted or a substituted monocyclic heterocyclyl. In still other embodiments, R1 can be an unsubstituted or a substituted monocyclic heteroaryl. In yet still other embodiments, R1 can be an unsubstituted or a substituted monocyclic heterocyclyl. The heteroaryl and the heterocyclyl that can present for R1 can include one or more than one heteroatoms (such as 1, 2, 3 or 4 heteroatoms). Suitable heteroatoms include N (nitrogen), O (oxygen) and S (sulfur). When R1 is substituted, a variety of moieties can be present. In some embodiments, R1 can be a substituted with one or more substituents (for example, 1, 2, 3, or 4 substituents) selected from –F, –Cl, –CF3, –CH2CF3, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkoxy (such as –OCF3, –OCCl3, –OCHF2, –OC(CH3)F2, –OCHCl2, – OCH2F, –OCH(CH3)F, –OCH2CF3, –OCH2Cl, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, – OCH2CH2CH2Cl, –OCF2Cl and –OCFCl2). In other embodiments, R1 can be unsubstituted. [0081] One example of a ring structure of R1 is 1 2 3
Figure imgf000027_0001
, wherein Z , Z , Z , Z4 and Z5 can be independently CR12 or N; and each R12 can be hydrogen, –F, –Cl, an unsubstituted C1-C6 alkyl, –CF3, –CH2CF3, an unsubstituted C1-6 alkoxy or an unsubstituted C1-6 haloalkoxy. In some embodiments, Z1, Z2, Z3, Z4 and Z5 can be each CH. In some embodiments, Z1, Z2, Z3, Z4 and Z5 can be each CR12, wherein one or more R12’s (for example 1, 2 or 3 R12’s) can be selected from –F, –Cl, an unsubstituted C1-C6 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched)), an unsubstituted C1-6 alkoxy (for example, –methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched)), –CF3, –CH2CF3 or an unsubstituted C1-6 haloalkoxy (such as –OCF3, –OCHF2, –OCH2F, –OCH2CF3, –OCF2Cl and –OCFCl2). In other embodiments, at least one of Z1, Z2, Z3, Z4 and Z5 can be N (nitrogen). For example, one of Z1, Z2, Z3, Z4 and Z5 can be N (nitrogen); and the remaining four of Z1, Z2, Z3, Z4 and Z5 can be each CR12. As examples, Z1, Z2, Z3 and Z4 can each be hydrogen and Z5 can be N, or Z1, Z2, Z3 and Z5 can each be hydrogen and Z4 can be N. In still other embodiments, two of Z1, Z2, Z3, Z4 and Z5 can be N (nitrogen); and the remaining three of Z1, Z2, Z3, Z4 and Z5 are each CR12. [0082] Another example of a ring structure of R1 is
Figure imgf000027_0002
, wherein Z6, Z7, Z8, Z9 and Z10 can be independently CHR13 or N; and each R13 can be hydrogen, –F, –Cl, an unsubstituted C1-C6 alkyl, –CF3, –CH2CF3, an unsubstituted C1-6 alkoxy or an unsubstituted C1-6 haloalkoxy. In some embodiments, Z6, Z7, Z8, Z9 and Z10 can be each CH2. In some embodiments, Z6, Z7, Z8, Z9 and Z10 can be each CHR13, wherein one or more R13’s (for example 1, 2 or 3 R13’s) can be selected from –F, –Cl, an unsubstituted C1-C6 alkyl (such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched)), an unsubstituted C1-6 alkoxy (for example, –methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched) and hexoxy (straight-chained or branched)), –CF3, –CH2CF3 or an unsubstituted C1-6 haloalkoxy (such as –OCF3, –OCHF2, –OCH2F, –OCH2CF3, –OCF2Cl or –OCFCl2). [0083] Examples of rings for R1 include the following: , , , ,
Figure imgf000028_0001
[0084] R1 can be directly attached to a carbon of Ring A or through a linker. In some embodiments, X1 can be absent. In other embodiments, X1 can be –NH. In still other embodiments, X1 can be –N(an unsubstituted C1-C6 alkyl). In yet still other embodiments, X1 can be –N(a substituted C1-C6 alkyl). In some embodiments, X1 can be –(CH2)–NH–*, –(CH2)–N(an unsubstituted C1-C6 alkyl)–* or –(CH2)–N(a substituted C1-C6 alkyl)–*, wherein the “*” indicates the attachment point to Ring A. In other embodiments, X1 can be –O– or –S–. In still other embodiments, X1 can be –S(O)– or –S(=O)2–. In still other embodiments, X1 can be –CH2–. In yet still other embodiments, X1 can be –CH(an unsubstituted C1-C6 alkyl)–. In some embodiments, X1 can be –C(an unsubstituted C1-C6 alkyl)2–. In other embodiments, X1 can be –CH(an unsubstituted C1-C6 alkyl)–. In still other embodiments, X1 can be –C(a substituted C1-C6 alkyl)2– . In still other embodiments, X1 can be –C(R4R5)–, wherein R4 and R5 are taken together to form an unsubstituted C3-8 cycloalkyl. In yet still other embodiments, X1 can be –C(R4R5)–, wherein R4 and R5 are taken together to form a substituted C3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl. The cycloalkyl that can be formed by taking R4 and R5 together along with the carbon to which R4 and R5 attached can be a monocyclic C3-8 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexyl. In some embodiments, R4 and R5 are taken together to form a substituted C3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted 1 or 2 times with a substituent independently selected from –F, –Cl, –OH, –CH3, –OCH3 and –CF3. [0085] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where: Ring A can be an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted bicyclic heteroaryl or an unsubstituted or a substituted bicyclic heterocyclyl, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkyl; X1 can be absent, –NR3a–, –O–, –S–, –S(O)–, –S(=O)2– or –C(R4R5)–; X2, X3, and X4 can be independently N, NR3b, O, S, or CR3c; R1 can be an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl, wherein when the cycloalkyl, the aryl, the heteroaryl and the heterocyclyl is substituted, the aryl, the heteroaryl and the heterocyclyl can be substituted with one or more substituents selected from –F, –Cl, –CF3, an unsubstituted C1-6 alkyl and an unsubstituted C1-6 alkoxy; R2 can be an unsubstituted or a substituted C3-C10 cycloalkyl, an unsubstituted or a substituted C2-C10 heterocyclyl, 3a 3b 3c
Figure imgf000030_0001
or
Figure imgf000030_0002
; R , R and R can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; R4 and R5 can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; or R4 and R5 can be taken together to form an unsubstituted or a substituted C3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl; R6 can be hydrogen, –F, –Cl, –CN, an unsubstituted or a substituted C3-6 cycloalkyl, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C2-C6 alkenyl, an unsubstituted or a substituted C2-6 alkynyl, an unsubstituted or a substituted C1-C6 haloalkyl, an unsubstituted or a substituted C1-6 alkoxy, an unsubstituted or a substituted hydroxyalkyl or an unsubstituted or a substituted aminoalkyl; R7 can be hydrogen, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C1-C6 haloalkyl or an unsubstituted or a substituted hydroxyalkyl; Y1 can be –CH2–, –CH2CH2–, –O–, –OCH2–, –CF2–, –CHF– or –C(CH3)2–; R8 can be hydrogen, –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl; and R9 can be hydrogen, –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl; or R8 and R9 can be taken together to form an unsubstituted or a substituted monocyclic cycloalkyl or an unsubstituted monocyclic heterocyclyl, wherein the substituted monocyclic cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl; and R10 and R11 can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; or R10 and R11 can be taken together to form an unsubstituted or a substituted 3- to 8-membered heterocyclyl; and provided that
Figure imgf000030_0003
is aromatic; and provided that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be selected from (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, 3-methyl-3- {5-[3-(4-trifluoromethyl-phenylamino)-pyrazin-2-yl]-[1,3,4]oxadiazol-2-yl}-pyrrolidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-1,3,4-oxadiazol-2-yl]pyrrolidin-2- one and (3S)-3-Ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-1,3,4-oxadiazol-2- yl]pyrrolidin-2-one. [0086] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where: Ring A can be an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted bicyclic heteroaryl or an unsubstituted or a substituted bicyclic heterocyclyl, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkyl; X1 can be absent, –(CH2)n–NR3a–, –O–, –S–, –S(O)–, –S(=O)2– or –C(R4R5)–; X2, X3, and X4 can be independently N, NR3b, O, S, or CR3c; R1 can be an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl, wherein when the cycloalkyl, the aryl, the heteroaryl and the heterocyclyl is substituted, the aryl, the heteroaryl and the heterocyclyl can be substituted with one or more substituents selected from –F, –Cl, –CF3, an unsubstituted C1-6 alkyl and an unsubstituted C1-6 alkoxy; R2 can be an unsubstituted or a substituted C3-C10 cycloalkyl, an unsubstituted or a substituted C2-C10 heterocyclyl,
Figure imgf000031_0001
or ; R3a, R3b and R3c can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; R4 and R5 can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; or R4 and R5 can be taken together to form an unsubstituted or a substituted C3-8 cycloalkyl, wherein the substituted cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl; R6 can be hydrogen, –F, –Cl, –CN, an unsubstituted or a substituted C3-6 cycloalkyl, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C2-C6 alkenyl, an unsubstituted or a substituted C2-6 alkynyl, an unsubstituted or a substituted C1-C6 haloalkyl, an unsubstituted or a substituted C1-6 alkoxy, an unsubstituted or a substituted hydroxyalkyl or an unsubstituted or a substituted aminoalkyl; R7 can be hydrogen, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C1-C6 haloalkyl or an unsubstituted or a substituted hydroxyalkyl; Y1 can be –CH2–, –CH2CH2–, –O–, –OCH2–, –CF2–, –CHF– or –C(CH3)2–; R8 can be hydrogen, –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl; and R9 can be hydrogen, –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl; or R8 and R9 can be taken together to form an unsubstituted or a substituted monocyclic cycloalkyl or an unsubstituted monocyclic heterocyclyl, wherein the substituted monocyclic cycloalkyl can be substituted 1 to 6 times with a substituent independently selected from halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl; and R10 and R11 can be independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; or R10 and R11 can be taken together to form an unsubstituted or a substituted 3- to 8-membered heterocyclyl; n can be 0 or 1; and provided that
Figure imgf000032_0001
is aromatic; and provided that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be selected from (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin- 3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, 3-methyl-3- {5-[3-(4-trifluoromethyl-phenylamino)-pyrazin-2-yl]-[1,3,4]oxadiazol-2-yl}-pyrrolidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-1,3,4-oxadiazol-2-yl]pyrrolidin-2- one and (3S)-3-Ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-1,3,4-oxadiazol-2- yl]pyrrolidin-2-one. [0087] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where: Ring A can be an unsubstituted or a substituted monocyclic heteroaryl, when the monocyclic heteroaryl is substituted, the monocyclic heteroaryl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkyl; X1 can be –(CH2)n–NR3a–; X2 and X3 can be each N (nitrogen); X4 can be O (oxygen); R1 can be an unsubstituted or a substituted phenyl, wherein when the phenyl is substituted, the phenyl can be substituted with one or more substituents selected from –F, –Cl, –CF3, –CH2CF3, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkoxy; R2 can be
Figure imgf000033_0001
; R3a can be hydrogen; R6 can be an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted or a substituted C2-C6 alkenyl; R7 can be hydrogen, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C1-C6 haloalkyl or an unsubstituted or a substituted hydroxyalkyl; Y1 can be –CH2–; n can be 0; and provided that
Figure imgf000033_0002
is aromatic. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where: Ring A can be an unsubstituted or a substituted monocyclic heteroaryl, when the monocyclic heteroaryl is substituted, the monocyclic heteroaryl can be substituted with one or more substituents selected from –F, –Cl, –CN, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkyl; X1 can be –(CH2)n–NR3a–; X2 and X3 can be each N (nitrogen); X4 can be O (oxygen); R1 can be an unsubstituted or a substituted monocyclic cycloalkyl, wherein when the monocyclic cycloalkyl is substituted, the monocyclic cycloalkyl can be substituted with one or more substituents selected from –F, –Cl, –CF3, –CH2CF3, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkoxy; R2 can be
Figure imgf000033_0003
; R3a can be hydrogen; R6 can be an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted or a substituted C2-C6 alkenyl; R7 can be hydrogen, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C1-C6 haloalkyl or an unsubstituted or a substituted hydroxyalkyl; Y1 can be –CH2–; n can be 0; and provided that
Figure imgf000033_0004
is aromatic. In some embodiments of this paragraph, R6 can be an unsubstituted C1-C6 alkyl (such as methyl or ethyl). In other embodiments of this paragraph, R6 can be an unsubstituted or a substituted C2-C6 alkenyl (such as –CH=CH2). In some embodiments of this paragraph, Ring A can be an unsubstituted monocyclic heteroaryl that includes 1 or 2 nitrogens. In some embodiments of this paragraph, Ring A can be a substituted monocyclic heteroaryl that includes 1 or 2 nitrogens. In some embodiments of this paragraph, R7 can be hydrogen. In other embodiments of this paragraph, R7 can be an unsubstituted C1-C6 alkyl, an unsubstituted C1-C6 haloalkyl or an unsubstituted hydroxyalkyl. In some embodiments of this paragraph, R1 can be a substituted phenyl, for example, a mono- substituted phenyl (such as ortho-mono-substituted phenyl, meta-mono-substituted phenyl or para- mono-substituted phenyl). In some embodiments of this paragraph, R1 can be a substituted monocyclic cycloalkyl, for example, a mono-substituted monocyclic cycloalkyl, such as a mono- substituted cyclohexyl. [0088] Examples of compounds of Formula (I), and pharmaceutically acceptable salts thereof, include the following: , , ,
Figure imgf000034_0001
, , , , , , , ,
Figure imgf000035_0001
,
Figure imgf000036_0001
, , , , , ,
Figure imgf000037_0001
, , , , , , ,
Figure imgf000038_0001
,
Figure imgf000039_0001
, , and
Figure imgf000039_0002
, or a pharmaceutically acceptable salt of any of the foregoing. [0089] Further examples of compounds of Formula (I), and pharmaceutically acceptable salts thereof, include the following:
Figure imgf000039_0003
, , , , ,
Figure imgf000040_0001
, , , , , , ,
Figure imgf000041_0001
, , , , , , ,
Figure imgf000042_0001
, , , , , ,
Figure imgf000043_0001
,
Figure imgf000044_0001
, , , , ,
Figure imgf000045_0001
, , , , , , ,
Figure imgf000046_0001
, , , , , , ,
Figure imgf000047_0001
, , , , , , ,
Figure imgf000048_0001
, , , , , , ,
Figure imgf000049_0001
, , , , , , , , ,
Figure imgf000050_0001
, ,
Figure imgf000051_0001
, , , a pharmaceutically acceptable salt of any of the foregoing. [0090] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000051_0002
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000051_0003
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or
Figure imgf000051_0004
pharmaceutically acceptable salts thereof, can be
Figure imgf000052_0001
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000052_0002
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000052_0003
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000052_0004
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000052_0005
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or
Figure imgf000052_0006
pharmaceutically acceptable salts thereof, can be In some
Figure imgf000052_0007
embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000053_0001
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000053_0002
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000053_0003
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000053_0004
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000053_0005
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some
Figure imgf000053_0006
embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some embodiments, a compound of Formula (I), or
Figure imgf000053_0007
pharmaceutically acceptable salts thereof, can be
Figure imgf000054_0001
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000054_0002
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000054_0005
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000054_0003
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some
Figure imgf000054_0006
embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000054_0004
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be In some
Figure imgf000054_0007
embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000055_0001
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000055_0004
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000055_0002
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000055_0005
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000055_0003
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000055_0006
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000056_0001
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000056_0004
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000056_0002
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000056_0005
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000056_0003
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000056_0006
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000057_0004
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000057_0005
In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000057_0001
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000057_0002
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000057_0006
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000057_0003
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000057_0007
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000058_0001
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000058_0004
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000058_0002
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000058_0005
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be
Figure imgf000058_0003
. [0091] In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2021/102204. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be selected from (R)-3-methyl-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, (S)-3- methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin- 2-one, 3-methyl-3-(5-(2-((4-trifluoromethyl)phenyl)amino)pyridin-3-yl]-(1,3,4)oxadiazol-2-yl)- pyrrolidin-2-one, 3-methyl-3-{5-[3-(4-trifluoromethyl-phenylamino)-pyrazin-2-yl]- [1,3,4]oxadiazol-2-yl}-pyrrolidin-2-one, (3S)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3- pyridyl]-1,3,4-oxadiazol-2-yl]piperidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]- 3-pyridyl]-1,3,4-oxadiazol-2-yl]piperidin-2-one, (3R)-3-ethyl-3-[5-[2-[4- (trifluoromethyl)anilino]-3-pyridyl]-1,3,4-oxadiazol-2-yl]pyrrolidin-2-one, (3S)-3-Ethyl-3-[5-[2- [4-(trifluoromethyl)anilino]-3-pyridyl]-1,3,4-oxadiazol-2-yl]pyrrolidin-2-one, (S)-3-methyl-3-(5- (2-(( 4-( trifluoromethyl )phenyl )amino )pyridin-3-yl)-1,3,4-oxadiazol-2-yl)piperidin-2-one and (R)-3-methyl-3-(5-(2-(( 4-( trifluoromethyl )phenyl )amino )pyridin-3-yl)-1,3,4-oxadiazol-2- yl)piperidin-2-one, including any pharmaceutically acceptable salts of any of the foregoing. In some embodiments, R2 cannot be
Figure imgf000059_0001
, wherein Y1 is –CH2–; R6 is an unsubstituted C1- C6 alkyl; and R7 is hydrogen. In some embodiments, R2 cannot be
Figure imgf000059_0002
, wherein Y1 is – CH2CH2–; R6 is an unsubstituted C1-C6 alkyl; and R7 is hydrogen. In some embodiments, Ring A cannot be an unsubstituted monocyclic heteroaryl, such as
Figure imgf000059_0003
and
Figure imgf000059_0004
. In some embodiments, when R1 is a para-substituted phenyl (for example, a trifluoromethyl para- substituted phenyl and X1 is –NR3a (such as –NH–), then Ring A cannot be an unsubstituted monocyclic heteroaryl, such as
Figure imgf000059_0005
and In some embodiments, R1 cannot be a
Figure imgf000059_0006
para-substituted phenyl, such as a trifluoromethyl para-substituted phenyl). In some embodiments, when R2 is
Figure imgf000059_0007
, wherein Y1 is –CH2–; R6 is an unsubstituted C1-C6 alkyl; and R7 is hydrogen, then Ring A cannot be an unsubstituted monocyclic heteroaryl, such as
Figure imgf000059_0008
and . In some embodiments, when R2 is , wherein Y1 is – CH2CH2–; R6 is an unsubstituted C1-C6 alkyl; and R7 is hydrogen, then Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and . In some embodiments, when R2 is , wherein Y1 is –CH2–; R6 is an unsubstituted C1-C6 alkyl; R7 is hydrogen; and R1 is be a para- substituted phenyl (such as a trifluoromethyl para-substituted phenyl), then Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and . In some embodiments, when R2 is , wherein Y1 is – CH2CH2–; R6 is an unsubstituted C1-C6 alkyl; R7 is hydrogen; and R1 is be a para-substituted phenyl (such as a trifluoromethyl para-substituted phenyl), then Ring A cannot be an unsubstituted monocyclic heteroaryl, such as and . In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2019/222431. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be selected from: (R)-3-methyl-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, (S)-3-methyl-3- (5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one, 3- methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2- one, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino )phenyl)-1,3,4-oxadiazol-2-yl )cyclopentanol, 1- (5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)cyclopropyl 4- methylbenzenesulfonate, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)cyclobutanol, 3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)oxetan- 3-ol, 3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl )tetrahydrofuran-3- ol, (1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)cyclopropyl)carbamate, 2-(5-(1-aminocyclopropyl)-l,3,4-oxadiazol-2-yl)-N-(4- (trifluoromethyl)phenyl)aniline, N-(1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)cyclopropyl)acetamide, 1-(1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)- 1,3,4-oxadiazol-2-yl)cyclopropyl)urea, 2-(5-(1-aminocyclopropyl)-1,3,4-oxadiazol-2-yl)-N-(4- (trifluoromethyl)phenyl)aniline, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)cyclopropan-1-ol, 2-(5-(1-fluorocyclopropyl)-l,3,4-oxadiazol-2-yl)-N-(4- (trifluoromethyl)phenyl)aniline, 2-[5-(l-methylsulfonylcyclopropyl)-1,3,4-oxadiazol-2-yl]-N-[4- (trifluoromethyl)phenyl]aniline, 2-(5-(l-methoxycyclopropyl)-1,3,4-oxadiazol-2-yl)-N-(4- (trifluoromethyl)phenyl)aniline, 2-(5-(2-methyl-1,3-dioxolan-2-yl)-1,3,4-oxadiazol-2-yl)-N-(4- (trifluoromethyl)phenyl)aniline, N-(2-cyanoethyl)-2-methyl-2-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)propenamide, N-(cyanomethyl)-2- methyl-2-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)propenamide, N-(but-3-yn-l-yl)-2-methyl-2-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol- 2-yl)propenamide, 2-methyl-N-(prop-2-yn-l-yl)-2-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)propenamide, N-(2-cyanoethyl)-5- (2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazole-2-carboxamide, N- (cyanomethyl)-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazole-2-carboxamide, N-(but-3-yn-l-yl)-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazole-2- carboxamide, N-(prop-2-yn-l-yl)-5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazole-2-carboxamide, 2-(5-(oxiran-2-yl)-1,3,4-oxadiazol-2-yl)-N-(4- (trifluoromethyl)phenyl)aniline, 2-(5-(2-methyloxiran-2-yl)-1,3,4-oxadiazol-2-yl)-N-(4- (trifluoromethyl)phenyl)aniline, 2-(5-(1-((methylamino)methyl)cyclopropyl)-1,3,4-oxadiazol-2- yl)-N-(4-(trifluoromethyl)phenyl)aniline, tert-butyl methyl((l-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)cyclopropyl)methyl)carbamate, N- methyl-N-((1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)cyclopropyl)methyl)cyanamide, 2-(5-(1-(methylamino)cyclopropyl)-1,3,4-oxadiazol-2-yl)-N- (4-(trifluoromethyl)phenyl)aniline, tert-butyl methyl(l-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)cyclopropyl)carbamate, N-methyl- N-(1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)cyclopropyl)cyanamide, 2-methyl-2-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)propenamide, tert-butyl 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)cyclopropane-l-carboxylate, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)- 1,3,4-oxadiazol-2-yl)cyclopropane-l-carboxylic acid, 2-(5-(2-methyltetrahydrofuran-2-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(2-methyloxetan-2-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(tetrahydrofuran-2-yl)-1,3,4- oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(oxetan-2-yl)-1,3,4-oxadiazol-2-yl)- N-(4-(trifluoromethyl)phenyl)aniline, 2-(5-(3-methyloxetan-3-yl)-l ,3,4-oxadiazol-2-yl)-N-( 4- (trifluoromethyl)phenyl )aniline, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)cyclopropane-l-carbonitrile, N,N-dimethyl-1-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)cyclopropane-l-carboxamide, N- methyl-1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)cyclopropane-l- carboxamide, 1-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)cyclopropane-l-carboxamide. 2,2-dimethyl-5-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)-1,3-dioxan-5-ol and 4-bromo-2-(5- cyclopropyl-1,3,4-oxadiazol-2-yl)-N-(4-(trifluoromethyl)phenyl)aniline, along with any pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2018/231745. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2016/049586. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in U.S. 2009/0156592. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2012/135581. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2009/094445. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2004/113330. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be a compound, or pharmaceutically acceptable salts thereof, provided in WO 2004/056823. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where X1 is –S–, –S(O)– and/or –S(=O)2–. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where X1 is –S– , –S(O)– and/or –S(=O)2–; and Ring A is phenyl. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where X1 is –O–. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where X1 is –O–; and Ring A is phenyl. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where Ring A is phenyl. In some embodiments, Ring A cannot an unsubstituted or a substituted be 1H-pyrazolo[3,4-b]pyridine, such as an unsubstituted or a substituted
Figure imgf000063_0001
. In some embodiments, Ring A cannot be an unsubstituted or a substituted be 1H-pyrazolo[3,4-b]pyridine, such as an unsubstituted or a substituted
Figure imgf000063_0002
; and R1 is an unsubstituted or a substituted tetrahydropyran. In some embodiments, Ring A cannot an unsubstituted or a substituted be 1H-pyrazolo[3,4-b]pyridine, such as an unsubstituted or a substituted 1 3a 1
Figure imgf000063_0003
; when X is NR (such as NH); and R is an unsubstituted or a substituted tetrahydro-2H-pyran. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where Ring A is phenyl; and R1 is aryl, such as phenyl. In some embodiments,
Figure imgf000063_0004
cannot be
Figure imgf000063_0005
Figure imgf000064_0001
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where Ring A is phenyl; and
Figure imgf000064_0002
is
Figure imgf000064_0003
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where Ring A is phenyl; R1 is aryl (for example, phenyl); and
Figure imgf000064_0004
is
Figure imgf000064_0005
. In some embodiments, R1 cannot be an unsubstituted or a substituted C3-C10 cycloalkyl, for example, R1 cannot be an unsubstituted or a substituted cyclopropyl, an unsubstituted or a substituted cyclobutyl and/or an unsubstituted or a substituted cyclopentyl. In some embodiments R1 cannot be an unsubstituted or a substituted oxirane, an unsubstituted or a substituted oxetane, an unsubstituted or a substituted tetrahydrofuran, an unsubstituted or a substituted 1,3-dioxolane, an unsubstituted or a substituted tetrahydropyran and/or an unsubstituted or a substituted 1,3-dioxane. In some embodiments R1 cannot be an unsubstituted or a substituted pyrrolidine, an unsubstituted or a substituted piperidine and/or an unsubstituted or a substituted piperazine. In some embodiments, R1 cannot be an unsubstituted or a substituted pyrimidine-2,4(1H,3H)-dione. In some embodiments, R1 cannot be an unsubstituted or a substituted bicyclic heterocyclyl. In some embodiments, R1 cannot be an unsubstituted or a substituted isoindoline, an unsubstituted or a substituted 1,2,3,4-tetrahydroisoquinoline and/or an unsubstituted or a substituted 2H-benzo[b][1,4]oxazin-3(4H)-one. In some embodiments R2 cannot be an unsubstituted or a substituted pyrrolidine and/or an unsubstituted or a substituted piperidine. In some embodiments, R2 cannot be an unsubstituted or a substituted
Figure imgf000064_0006
. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be where R2 is
Figure imgf000065_0001
. In some embodiments, R10 and/or R11 cannot be an unsubstituted or a substituted C1-C6 alkyl. In some embodiments, R10 and/or R11 cannot be a substituted C1-C6 alkyl, such as an alkynyl substituted C1-C6 alkyl, a cyano substituted C1-C6 alkyl. In some embodiments, R10 and R11 cannot be each hydrogen. In some embodiments, a compound of Formula (I), or pharmaceutically acceptable salts thereof, cannot be selected from: ,
Figure imgf000065_0002
pharmaceutically acceptable salts thereof). Synthesis [0092] Compounds of the Formula (I), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein. General synthetic routes for preparing compounds of Formula (I), including pharmaceutically acceptable salts, and intermediates are shown and described herein along with some examples of starting materials used to synthesize compounds described herein. Compounds and intermediates disclosed herein can be obtained using commercially available starting materials and reagents. Synthetic procedures will depend on particular substituents present in the compounds or intermediates, and various protection, deprotection or other well-known organic synthesis steps may be required but not necessarily illustrated in the generic schemes. Any steps shown in the generic schemes may be used in any combination or in different order to achieve the desired compounds or intermediates. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein. Scheme 1:
Figure imgf000066_0001
[0093] In Scheme 1, R1, X1, Ring A and R6 can be as described herein. The carboxylic ester and reacting group (RG) can be in various relationships (such as 1,2, 1,3- 1,4-relationship, etc.). In Scheme 1, amine or halide of general Formula (1a) can be reacted with aryl halide, heteroaryl halide or boronate of general Formula (1b) to obtain a compound of general Formula (1c). Hydrazide formation of a compound of general Formula (1c) provides a compound of general Formula (1d) that can be reacted under amide coupling conditions with a compound of general Formula (1e) to obtain a compound of general Formula (1f). Cyclization of a compound of general Formula (1f) can provide a compound of general Formula (1g) that can be separated under chiral SFC or HPLC to obtain compounds of general Formulae (IA) and (IB). Alternatively, chirally pure acid of a compound of general Formula (1e) can be used in the amide coupling step to directly arrive in chirally pure compound of general Formula IA or compound of general Formula IB. Scheme 2:
Figure imgf000067_0001
[0094] In Scheme 2, R1, Ring A and R6 can be as described herein. In Scheme 2, hydrazide of general Formula (2a) can be reacted with an acid of general Formula (2b) (wherein PG indicates a suitable protecting group) to obtain a compound of general Formula (2c). Cyclization of a compound of general Formula (2c) can provide a compound of general Formula (2d) that can undergoes deprotonation and a substitution to form a compound of general Formula (2e). Deprotection of a compound of general Formula (2e) can provide a compound of general Formula (2f) that can be separated under chiral SFC or HPLC to obtain compounds of general Formulae (IIA) and (IIB).
Scheme 3:
Figure imgf000068_0001
[0095] In Scheme 3, R1, Ring A and R6 can be as described herein. The carboxylic ester and bromide can be in various relationships (such as 1,2, 1,3- 1,4-relationship, etc.). In Scheme 3, amide coupling of an acid of general Formula (3a) and hydrazide of general Formula (3b) can provide a compound of general Formula (3c). Cyclization of a compound of general Formula (3c) can provide a compound of general Formula (3d) that can undergo a coupling reaction with a reagent (such as aryl amine, heteroaryl amine, aliphatic amine, aryl boronic acid or heteroaryl boronic acid) to provide a compound of general Formula (3e). Deprotection and chiral SFC or HPLC separation provides compounds of general Formulae (IIIA) and (IIIB). Alternatively, chirally pure hydrazide of general Formula (3b) can be used in the amide coupling step to arrive in chirally pure compounds of general Formulae (IIIA) or (IIIB). Pharmaceutical Compositions [0096] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. [0097] The term “pharmaceutical composition” refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. [0098] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended. [0099] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject. [0100] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood. [0101] As used herein, an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. For example, stabilizers such as anti-oxidants and metal-chelating agents are excipients. In an embodiment, the pharmaceutical composition comprises an anti-oxidant and/or a metal-chelating agent. A “diluent” is a type of excipient. [0102] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. [0103] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions. [0104] Multiple techniques of administering a compound, salt and/or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally. [0105] One may also administer the compound, salt and/or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable. [0106] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Uses and Methods of Treatment [0107] Some embodiments described herein relate to a method for treating a disease described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a disease described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disease described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a disease described herein. [0108] Some embodiments described herein relate to a method for treating an autoimmune disorder described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having an autoimmune disorder described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating an autoimmune disorder described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating an autoimmune disorder described herein. [0109] Some embodiments described herein relate to a method for treating an inflammatory condition described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having an inflammatory condition described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating an inflammatory condition described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating an inflammatory condition described herein. [0110] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. [0111] Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. [0112] Some embodiments described herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. Some embodiments described herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD that can include contacting a cancer cell from a cancer described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. [0113] Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting a YAP/TAZ- TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a cancer cell with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. [0114] Some embodiments disclosed herein relate to a method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein or a cancer cell from a cancer described herein. Other embodiments disclosed herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. Still other embodiments disclosed herein relate to a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD. [0115] Examples of suitable cancers include, but are not limited to: mesothelioma, renal cell carcinoma, cervical squamous cell cancer, endocervical adenocarcinoma, hepatocellular carcinoma, medulloblastoma, oral squamous cell cancer, lung squamous cell cancer, lung adenocarcinoma, schwannoma, meningioma, ependymoma, epithelioid hemangioendothelioma, luminal A breast cancer, luminal B breast cancer, colorectal cancer, uveal melanoma, pancreatic adenocarcinoma, kidney renal papillary cell carcinoma, rectum adenocarcinoma, bladder urothelial carcinoma, esophageal carcinoma, head and neck squamous cell cancer, squamous cell cancers, including head and neck squamous cell cancer, cancers that are resistant to an EGFR inhibitor and cancers that are resistant to a MEK inhibitors. Further, compounds of Formula (I), along with pharmaceutically acceptable salts thereof, can be used to treat cancers that have one or more of the following features: a hippo pathway alteration, YAP and/or TAZ amplification, mutation, gain of function fusions, a neurofibromatosis type 2 (NF2) mutation or deletion, and/or a LATS1/2 mutation. [0116] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human. In some embodiments, the subject can be a child and/or an infant, for example, a child or infant with a fever. In other embodiments, the subject can be an adult. [0117] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance. [0118] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. [0119] The amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions. [0120] In general, however, a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day, or any amount in between. The compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form. [0121] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. [0122] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine) [0123] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. [0124] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine. [0125] Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime. EXAMPLES [0126] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.
Example 1 (S)-3-(Hydroxymethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl) amino)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (1A) and (R)-3-(hydroxymethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl) amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (1B)
Figure imgf000080_0001
[0127] To a stirred degassed solution of methyl 2-aminobenzoate (2.50 g, 16.5 mmol) in PhMe (50 mL), were added 1-iodo-4-(trifluoromethyl)benzene (5.40 g, 19.9 mmol), Cs2CO3 (8.06 g, 24.8 mmol), Pd2(dba)3 (1.50 g, 1.65 mmol) and BINAP (0.31g, 0.50 mmol). After stirring at 100 °C for 16 h, the mixture was cooled to room temperature (rt), filtered through a pad of celite. The filter cake washed with PhMe (3x). The combined filtrates were concentrated, and the residue was purified by silica chromatography eluting with 7-10% EtOAc in petroleum ether to afford methyl 2-((4-(trifluoromethyl)phenyl)amino)benzoate (2.7 g, 9.1 mmol, 55%). MS (LCMS): m/z 296.50 [M+H]+. [0128] To a stirred solution of methyl 2-((4-(trifluoromethyl)phenyl)amino)benzoate (3.50 g, 11.9 mmol) in MeOH (7 mL) was added NH2NH2 (7.70 g, 15.4 mmol) at rt, and the mixture was stirred at 80 °C for 16 h. The mixture was concentrated, triturated with water, filtered and dried under reduced pressure to afford 2-((4-(trifluoromethyl)phenyl)amino)benzohydrazide (3.4 g, 97 %), which was used directly in the next step. MS (LCMS): m/z 296.50 [M+H]+. [0129] To a stirred solution of 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (1.10 g, 4.41 mmol) in DMF (11 ml) were added HOBt (1.70 g, 8.82 mmol), EDC•HCl (1.10 g, 8.83 mmol) and Et3N (2.45 mL, 17.6 mmol) at 0 °C. After 10 min, 2-((4- (trifluoromethyl)phenyl)amino)benzohydrazide (1.04 g, 3.53 mmol) was added. After stirring at rt for 16 h, water (40 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica chromatography using 5% MeOH:DCM to afford 1-(4- methoxybenzyl)-2-oxo-N'-(2-((4-(trifluoromethyl)phenyl)amino)benzoyl)pyrrolidine-3- carbohydrazide (1.2 g, 52%). MS (LCMS): m/z 525.42 [M-H]-. [0130] To a stirred solution of 1-(4-methoxybenzyl)-2-oxo-N'-(2-((4-(trifluoromethyl) phenyl)amino) benzoyl)pyrrolidine-3-carbohydrazide (1.20 g, 2.28 mmol) in DCM (24 mL) were added TEA (0.95 mL, 6.8 mmol) and p-TsCl (521 mg, 2.73 mmol). After stirring at rt for 16 h, water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography using 80% EtOAc in petroleum ether to afford 1- (4-methoxybenzyl)-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (800 mg, 68%). [0131] To a solution of 1-(4-methoxybenzyl)-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (1.5 g, 2.9 mmol) in CH3CN (30 mL), were added TEA (0.82 mL, 5.9 mmol), DMAP (72 mg, 0.59 mmol) and (Boc)2O (1.30 g, 5.90 mmol) at 0° C. The mixture was allowed to warm to rt and then stirred for 16 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (Hex:EtOAc, 1:2) to afford tert-butyl (2-(5-(2-((tert-butoxycarbonyl)oxy)-1-(4-methoxybenzyl)-4,5-dihydro-1H- pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (1.7 g, 81%). MS (LCMS): m/z 653.59 [M-56]+. [0132] To a solution of tert-butyl (2-(5-(2-((tert-butoxycarbonyl)oxy)-1-(4- methoxybenzyl)-4,5-dihydro-1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)(4- (trifluoromethyl)phenyl)carbamate (1.50 g, 1.41 mmol) in THF (20 mL) was added 2.5 N n-BuLi in hexane (0.98 mL) dropwise at -78 ℃. The mixture was allowed to stir for 10 min. A solution of paraformaldehyde (634 mg, 21.1 mmol) in THF (5 mL) was added dropwise at -78 ℃. The mixture was stirred for 1 h, whereupon it was warmed up to 0 ℃ over the course of 2 h. The reaction was quenched with water (20 mL) and then extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (Hex/EtOAc 1:3) to afford tert-butyl (2-(5-(3-(hydroxymethyl)-1-(4-methoxybenzyl)-2- oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)(4-(trifluoromethyl)phenyl)carbamate (500 mg, 55%). MS (LCMS): m/z 583.56 [M-56]+. [0133] To a stirred solution of tert-butyl (2-(5-(3-(hydroxymethyl)-1-(4- methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)phenyl)(4- (trifluoromethyl)phenyl)carbamate (500 mg, 54.0 mmol) in DCM (5 mL), were added TEA (0.30 mL, 2.3 mmol), DMAP (19.0 mg, 0.156 mmol) and Ac2O (0.20 mL, 2.0 mmol) dropwise at 0 ℃ and then stirring was continued at rt for 2 h. The mixture was diluted with water (15 mL) and extracted with DCM (3 x 25 mL). The combined organic layers were washed brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (Hex:EtOAc, 1:1) to afford (3-(5-(2-((tert-butoxycarbonyl)(4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-2- oxopyrrolidin-3-yl)methyl acetate (450 mg, 84%). MS (LCMS): m/z 625.63 [M-56]+. [0134] To a stirred solution of (3-(5-(2-((tert-butoxycarbonyl)(4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-2- oxopyrrolidin-3-yl)methyl acetate (0.600 g, 0.882 mmol) in DCM (3 mL), were added TFA (18 mL) and triflic acid (0.70 mL, 4.4 mmol) at 0 ℃. The mixture was allowed to warm to rt and then stirring was continued for 16 h. The mixture was concentrated and sat. NaHCO3 solution (20 ml) was added to the residue. The mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica chromatography (MeOH:DCM, 1:20) to afford a racemic mixture of 3- (hydroxymethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (300 mg), which was separated by chiral SFC to afford (S)-3- (hydroxymethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (1A) (40 mg; 8%) and (R)-3-(hydroxymethyl)-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (1B) (32 mg; 10%). The stereochemistry of 1A and 1B are assigned arbitrarily. Preparative Chiral SFC Conditions Column/dimensions : YMC-Pack Diol-120 (4.6 x 250 mm), 5μ % CO2 : 80% % Co solvent : 20% (MeOH) Total Flow : 60 g/min Back Pressure : 100 bar Temperature : 30 °C Solubility : MeOH UV : 220 nm [0135] Compound 1A: 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.64-7.52 (m, 4H), 7.32 (d, J = 8.4 Hz, 2H), 7.19-7.14 (m, 1H), 5.34 (t, J = 11.2 Hz, 1H), 3.98-3.92 (m, 2H), 3.36-3.31 (m, 2H), 2.69-2.62 (m, 1H), 2.57-2.50 (m, 1H); MS (LCMS): m/z 419.2 [M+H]+. HPLC: 98.30%; Chiral HPLC: 99.89% (RT: 4.69 min). [0136] Compound 1B: 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.64-7.52 (m, 4H), 7.32 (d, J = 8.4 Hz, 2H), 7.19-7.14 (m, 1H), 5.34 (t, J = 11.2 Hz, 1H), 3.98-3.92 (m, 2H), 3.36-3.31 (m, 2H), 2.69-2.62 (m, 1H), 2.57-2.50 (m, 1H); MS (LCMS): m/z 419.2 [M+H]+. HPLC: 97.49 %; Chiral HPLC: 98.92 % (RT: 6.54 min).
Example 2 (S)-3-(methyl-d3)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (2A) and (R)-3-(methyl-d3)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (2B)
Figure imgf000084_0002
Step-5 F
Figure imgf000084_0001
[0137] To a stirred solution of ethyl 1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carboxylate (10.0 g, 34.3 mmol) in MeOH (100 mL) was added NH2NH2·H2O (17.2g, 343 mmol). After heating at 70 °C for 16 h, the mixture was concentrated. The residue triturated with n- pentane, filtered and dried under reduced pressure to afford 1-(4-methoxybenzyl)-2- oxopyrrolidine-3-carbohydrazide (10.0 g, 98%). MS (LCMS): m/z 264.13 [M+H]+. [0138] To a solution of 3-bromopicolinic acid (10.0 g, 49.5 mmol) and 1-(4- methoxybenzyl)-2-oxopyrrolidine-3-carbohydrazide (12.9 g, 49.5 mmol) in DCM (100 mL) and DMF (30 mL) were added DIPEA (19.0 g, 147 mmol) and HATU (22.3 g, 58.8 mmol) at rt. The mixture was stirred for 16 h. The mixture was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography eluting with 5-10% MeOH in DCM to afford 3-bromo-N'-(1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carbonyl)picolinohydrazide (10.0 g, 46%). MS (LCMS): m/z 445.46 [M-H]-. [0139] To a stirred solution of 3-bromo-N'-(1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carbonyl) picolinohydrazide (3.00 g, 6.71 mmol) in DCM (30 mL) at 0 °C was added Et3N (2.00 g, 20.0 mmol) followed by pTsCl (1.36 g, 7.20 mmol). After stirring at rt for 16 h, the mixture was diluted with water (50 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica chromatography using 70-80% ethyl acetate in petroleum ether to afford 3-(5-(3-bromopyridin-2- yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (1.00 g, 34%). 1H NMR (400 MHz, DMSO-d6): δ 8.74-8.73 (m, 1H), 8.12 (dd, J=8.4 Hz, J= 1.2 Hz, 1H), 7.35-7.32 (m, 1H), 7.21 (d, J = 8.4, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.51-4.41 (m, 2H), 4.20 (t, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.53-3.47 (m, 1H), 3.40-3.34 (m, 1H), 2.68-2.61 (m, 1H), 2.58-2.52 (m, 1H). MS (LCMS): m/z 429.32 [M+H]+. [0140] To a stirred solution of ethyl 3-(5-(3-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)- 1-(4-methoxybenzyl)pyrrolidin-2-one (1.00 g, 2.33 mmol) in THF (10 ml) was added 1 M LiHMDS in THF (4.67 mL, 4.67 mmol) at -78 °C. After stirring for 30 min, CD3I (0.672 g, 4.67 mmol) was added at -78 °C. The mixture was allowed to warm to 0 °C and then stirred for 30 min. The reaction was quenched with sat. NH4Cl (10 mL) and extracted with EtOAc (3 x 15 ml). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica chromatography using EtOAc in hexane to afford 3-(5-(3-bromopyridin-2-yl)-1,3,4- oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-(methyl-d3)pyrrolidin-2-one (0.75 g, 72%). MS (LCMS): m/z 446.5 [M+H]+. [0141] To a stirred solution of 3-(5-(3-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4- methoxybenzyl)-3-(methyl-d3)pyrrolidin-2-one (0.750 g, 1.68 mmol) in toluene (10 mL) were added 4-(trifluoromethyl)aniline (0.326 g, 2.02 mmol) and Cs2CO3 (1.09 g, 3.36 mmol). The mixture was degassed with nitrogen for 15 min, and Pd2(dba)3 (0.153 g, 0.168 mmol) and DPEphos (0.090 g, 0.168 mmol) were added. The mixture was heated at 100 °C for 16 h, cooled down to rt and filtered through a pad of celite. The filter cake washed with toluene (3x). The combined filtrates were concentrated. The residue was purified by silica chromatography using EtOAc in petroleum ether to afford 1-(4-methoxybenzyl)-3-(methyl-d3)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (0.52 g, 59%). [0142] To a stirred solution of 1-(4-methoxybenzyl)-3-(methyl-d3)-3-(5-(3-((4- (trifluoromethyl) phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (0.600 g, 1.14 mmol) in DCM (6 mL) were added triflic acid (1.0 mL, 11 mmol) and TFA at 0 °C. After stirring at rt for 24 h, the reaction was quenched with sat. NaHCO3 (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give a racemic mixture, which was further separated by chiral SFC to obtain (S)-3-(methyl-d3)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (2A) (55 mg, 9%) and (R)-3-(methyl-d3)-3-(5-(3-((4-(trifluoromethyl)phenyl) amino)pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (2B) (45 mg, 8%). The stereochemistry of 2A and 2B are assigned arbitrarily. Preparative SFC Conditions Column/dimensions : CHIRALPAK- IG (30 × 250) mm,5μm % CO2 : 75% %Co solvent : 35 % (0.2% 7N ammonia in MeOH in ACN: MeOH) (1:1) Total Flow : 110 g/min Back Pressure : 100 bar Temperature : 30 °C UV : 215 nm Solubility : ACN + MeOH [0143] Compound 2A: 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.35-8.34 (m, 1H), 8.19 (s, 1H), 8.00-7.98 (m, 1H), 7.68 (d, J= 8.4 Hz, 2 H), 7.55-7.52 (m, 1H), 7.42 (d, J= 8.4 Hz, 2H), 3.42-3.37 (m, 2H), 2.72-2.67 (m, 1H), 2.25-2.21 (m, 1H). MS (LCMS): m/z 407.50 [M+H]+. HPLC: 98.78%; Chiral Purity: 98.77% (RT: 2.61 min). [0144] Compound 2B: 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.35-8.34 (m, 1H), 8.19 (s, 1H), 8.00-7.98 (m, 1H), 7.68 (d, J= 8.4 Hz, 2 H), 7.55-7.52 (m, 1H), 7.42 (d, J= 8.4 Hz, 2H), 3.42-3.35 (m, 2H), 2.74-2.67 (m, 1H), 2.27-2.20 (m, 1H). MS (LCMS): m/z 407.50 [M+H]+. HPLC: 99.36%; Chiral Purity: 96.76% (RT: 3.52 min). Example 3 (S)-3-(Aminomethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (3A) and (R)-3-(aminomethyl)-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (3B)
Figure imgf000087_0001
[0145] To a stirred solution of ethyl 1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carboxylate (5.00 g, 18.0 mmol) in DCM (125 mL), was added Cs2CO3 (17.6 g, 54.1 mmol) followed by tert-butyl ((phenylsulfonyl)methyl)carbamate (8.80 g, 32.5 mmol). After stirring at rt for 16 h, the reaction was quenched with water (50 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using 20% EtOAc:petroleum ether to afford ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carboxylate (3.6 g, 49%). MS (LCMS): m/z 351.41 [M-56]+. [0146] To a suspension of ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-1-(4- methoxybenzyl)-2-oxopyrrolidine-3-carboxylate (3.60 g, 8.86 mmol) in THF:EtOH:H2O (2:2:1, 36 mL) was added LiOH·H2O (1.12 g, 26.6 mmol). The mixture was stirred at rt for 24 h, and then concentrated under reduced pressure. Water (20 mL) was added. The mixture was acidified with 2N HCl and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 3-(((tert- butoxycarbonyl)amino)methyl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (2.9 g, 87%), which was used directly in next step without further purification. MS (LCMS): m/z 323.37 [M-56]+. [0147] To a stirred solution of 3-(((tert-butoxycarbonyl)amino)methyl)-1-(4- methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (1.7 g, 4.49 mmol) in DMF (34 mL), were added EDC•HCl (2.24 g, 8.99 mmol), HOBT (1.21g, 8.99 mmol), Et3N (2.50 mL, 18.0 mmol) and 2-((4-(trifluoromethyl)phenyl)amino)benzohydrazide (1.59 g, 5.39 mmol) at 0 °C. After stirring at rt for 16 h, water (40 mL) was added, and the mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica chromatography using 45% EtOAc:petroleum ether to afford tert- butyl((1-(4-methoxybenzyl)-2-oxo-3-(2-(2-((4- (trifluoromethyl)phenyl)amino)benzoyl)hydrazine-1-carbonyl)pyrrolidin-3-yl)methyl)carbamate (2.0 g, 68%). MS (LCMS): m/z 654.44 [M-H]+. [0148] To a stirred solution of tert-butyl ((1-(4-methoxybenzyl)-2-oxo-3-(2-(2-((4- (trifluoromethyl)phenyl)amino)benzoyl)hydrazine-1- carbonyl)pyrrolidin-3-yl)methyl) carbamate (3.00 g, 4.58 mmol) in DCM (30 mL) was added DIPEA (1.50 mL, 9.16 mmol) at 0 °C, followed by Burgess reagent (2.20 g, 9.16 mmol). After stirring at rt for 16 h, the reaction was quenched with water (30 mL) and extracted with DCM (2 x 40 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica chromatography using 40% EtOAc:petroleum ether to afford tert-butyl ((1-(4- methoxybenzyl)-2-oxo-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-3-yl)methyl)carbamate (2.2 g, 75%). MS (LCMS): m/z 638.46 [M+H]+. [0149] To a stirred solution of tert-butyl ((1-(4-methoxybenzyl)-2-oxo-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)methyl)carbamate (1.00 g, 1.57 mmol) in DCM (30 mL), was added TFA (30 mL) followed by triflic acid (0.48 mL, 5.5 mmol) at 0 °C. After stirring at rt for 16 h, the mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL), basified with sat. aq. NaHCO3 solution and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford a racemic mixture, which was separated by chiral SFC to afford (S)-3-(aminomethyl)-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (3A) (95 mg, 14%) and (R)-3-(aminomethyl)-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (3B) (96 mg, 15%). The stereochemistry of 3A and 3B are assigned arbitrarily. [0150] Prep HPLC method: Column/dimensions: GEMINI NX C-18 (21.2 x 250 mm x 5µ) Mobile phase A: 10 Mm ABC in water; Mobile phase B: Acetonitrile (ORG) Gradient (Time/%B): 0.01/25, 1/25, 10/50, 17/50, 17.1/100, 24/100, 24.1/25, 26/25. Flow rate: 18 mL/min; Solubility: THF. Preparative SFC Conditions Column/dimensions : DCPAK-P4VP (30 x 250 mm),5µ % CO2 : 60% % Co solvent : 40% (MeOH) Total Flow : 110 g/min Back Pressure : 100 bar Temperature : 30 °C UV : 215 nm Solubility : MeOH [0151] Compound 3A: 1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 7.90 (dd, J= 1.2 Hz, J= 7.6 Hz, 1H), 7.57 (d, J= 8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.41-7.37 (m, 3H), 6.98- 6.94 (m, 1H), 5.83 (s, 1H), 3.67-3.61 (m, 1H), 3.57-3.48 (m, 2H), 3.36 (d, J= 13.2 Hz, 1H), 2.89- 2.83 (m, 1H), 2.67-2.60 (m, 1H), 1.25 (s, 2H). LC-MS: m/z 418.38 [M+H]+. HPLC: 98.88%; Chiral Purity: 99.90% (RT: 2.11 min). [0152] Compound 3B: 1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 7.90 (dd, J= 1.2 Hz, J= 7.6 Hz, 1H), 7.57 (d, J= 8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.41-7.37 (m, 3H), 6.98- 6.94 (m, 1H), 5.83 (s, 1H), 3.67-3.61 (m, 1H), 3.57-3.48 (m, 2H), 3.36 (d, J= 13.2 Hz, 1H), 2.89- 2.83 (m, 1H), 2.67-2.60 (m, 1H), 1.25 (s, 2H). LC-MS: m/z 418.38 [M+H]+. HPLC: 98.92%; Chiral Purity: 99.58% (RT: 3.13 min). Example 4 (R)-3-methyl-3-(5-(2-(4-(trifluoromethyl)benzyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (4A) and (S)-3-methyl-3-(5-(2-(4-(trifluoromethyl)benzyl)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (4B)
Figure imgf000090_0001
[0153] To a stirred degassed solution of 2-(methoxycarbonyl)phenyl)boronic acid (1.00 g, 5.56 mmol) in 1,4-dioxane:H2O (4:1, 10 mL), were added 1-(bromomethyl)-4- (trifluoromethyl)benzene (1.59 g, 6.67 mmol), K2CO3 (1.54 g, 11.1 mmol) and Pd(dppf)Cl2.DCM (453 mg, 0.556 mmol). After heating at 100 °C for 16 h, the mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was purified by silica chromatography (5% EtOAc:petroleum ether) to afford methyl 2-(4-(trifluoromethyl)benzyl)benzoate (800 mg, 49%). MS (LCMS): 295.22 m/z [M+H]+. [0154] To a stirred solution of methyl 2-(4-(trifluoromethyl)benzyl)benzoate (0.800 g, 2.72 mmol) in MeOH (8 mL) was added NH2NH2 (2.72 g, 54.4 mmol) at rt. After heating at 80 °C for 16 h, the mixture was concentrated under reduced pressure, washed with water (35 mL) and dried under reduced pressure to afford 2-(4-(trifluoromethyl)benzyl)benzohydrazide (600 mg, 75 %). 1H NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.40-7.24 (m, 4H), 4.44 (s, 2H), 4.18 (s, 2H). MS (LCMS): m/z 295.23 [M+H]+. [0155] To a stirred solution of 2-(4-(trifluoromethyl)benzyl)benzohydrazide (800 mg, 2.72 mmol) in DMF (8 mL) were added 3-methyl-2-oxopyrrolidine-3-carboxylic acid (467 mg, 3.26 mmol), HOBt (735 mg, 5.44 mmol), EDC•HCl (1.00 g, 5.44 mmol) and TEA (1.50 mL, 10.9 mmol) at 0 °C. After stirring at rt for 16 h, the reaction was quenched with water (15 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica chromatography using 80% EtOAc in petroleum ether to afford 3-methyl-2-oxo-N'-(2-(4- (trifluoromethyl)benzyl)benzoyl)pyrrolidine-3-carbohydrazide (360 mg, 32% yield). MS (LCMS): m/z 420.39 [M+H]+. [0156] To a stirred solution of 3-methyl-2-oxo-N'-(2-(4- (trifluoromethyl)benzyl)benzoyl)pyrrolidine-3-carbohydrazide (0.150 g, 0.357 mmol) in DCM (4 mL) were added TEA (0.15 mL, 1.1 mmol) and pTsCl (0.147 g, 0.77 mmol) at rt. After stirring at rt for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica chromatography using 80% EtOAc in petroleum ether to afford a racemic mixture, which was separated by chiral SFC to afford (R)-3-methyl-3-(5-(2-(4-(trifluoromethyl)benzyl)phenyl)- 1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (4A) (15.4 mg, 11%) and (S)-3-methyl-3-(5-(2-(4- (trifluoromethyl)benzyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (4B) (9 mg, 6%). The stereochemistry of 4A and 4B are assigned arbitrarily. Preparative SFC Conditions Column/dimensions : CHIRALPAK ADH (30 x 250 mm), 5µ % CO2 : 70% % Co solvent : 30% (MeOH) Total Flow : 100 g/min Back Pressure : 100 bar Temperature : 300C UV : 215 nm Solubility : MeOH [0157] Compound 4A: 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.63-7.57 (m, 3H), 7.52-7.45 (m, 2H), 7.33 (d, J = 7.6 Hz, 2H), 4.51 (s, 2H), 3.37- 3.32 (m, 2H), 2.67-2.59 (m, 1H), 2.21-2.14 (m, 1H), 1.55 (s, 3H); MS (LCMS): m/z 400.28 [M- H]-. LCMS Purity: 99.79%; HPLC Purity: 99.15%; Chiral Purity: 97.92% (RT: 2.05 min). [0158] Compound 4B: 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.63-7.57 (m, 3H), 7.52-7.45 (m, 2H), 7.33 (d, J = 7.6 Hz, 2H), 4.51 (s, 2H), 3.37- 3.32 (m, 2H), 2.67-2.59 (m, 1H), 2.21-2.14 (m, 1H), 1.55 (s, 3H); MS (LCMS): m/z 400.28 [M- H]-. LCMS Purity: 98.52%; HPLC Purity: 97.09%; Chiral Purity: 99.79% (RT: 3.68 min). Example 5 (R)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (5A) and (S)-3-methyl-3-(5-(2-(4-(trifluoromethyl)benzyl)phenyl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (5B)
Figure imgf000092_0001
[0159] A stirred solution of methyl 3-bromopicolinate (1.0 g, 6.3 mmol) in PhMe (10mL) was degassed and 4-(trifluoromethyl)aniline (1.75 g, 8.07 mmol), K2CO3 (1.7 g, 12.6 mmol), Xantphos (364 mg, 0.63 mmol) and Pd(OAc)2 (141 mg, 0.63 mmol) were added at rt. The mixture was heated at 100 °C for 16 h. The mixture was filtered through a pad of celite, and the filter cake washed with PhMe (3x). The combined filtrates were concentrated. The residue was purified by silica chromatography using 20% EtOAc in petroleum ether as the eluent to afford methyl 3-((4-(trifluoromethyl)phenyl)amino)picolinate (1.02 g, 74%). MS (LCMS): 297.30 m/z [M+H]+. [0160] To a stirred solution of methyl 3-((4-(trifluoromethyl)phenyl)amino)picolinate (1.00 g, 3.33 mmol) in MeOH (3mL) was added NH2NH2 (2.0 mL, 33 mmol) at rt. After stirring at 80 °C for 16 h, the mixture was concentrated under reduced pressure. The mixture was filtered, washed with water (35 mL) and dried under reduced pressure to afford 3-((4- (trifluoromethyl)phenyl)amino)picolinohydrazide (960 mg, 96 %). MS (LCMS): m/z 297.123 [M+H]+. [0161] To a stirred solution of 3-((4-(trifluoromethyl)phenyl)amino)picolinohydrazide (500 mg, 1.69 mmol) in DMF (8 mL) were added 3-methyl-2-oxopyrrolidine-3-carboxylic acid (600 mg, 4.22 mmol), HOBt (456 mg, 3.37 mmol), EDC•HCl (648 mg, 3.37 mmol) and TEA (0.70 mL, 6.7 mmol) at 0 °C. After stirring at rt for 16 h, the reaction was quenched with water (15 mL), and then extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica chromatography using 80% EtOAc in petroleum ether to afford N'-(3-methyl-2-oxopyrrolidine-3- carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)picolinohydrazide (400 mg, 57% yield). MS (LCMS): m/z 422.39 [M+H]+. [0162] To a stirred solution of N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-3-((4- (trifluoromethyl)phenyl)amino)picolinohydrazide (800 mg, 1.90 mmol) in DCM (2 mL) were added TEA (0.60 mL, 5.7 mmol) and pTsCl (435 mg, 2.28 mmol) at rt. After stirring at rt for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica chromatography using 80% EtOAc in petroleum ether to give a racemic mixture, which was further separated by chiral SFC to afford (R)-3-methyl-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (5A) (80 mg, 10 %) and (S)-3-methyl-3-(5-(2-(4-(trifluoromethyl)benzyl)phenyl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (5B) (100 mg, 13%). The stereochemistry of 5A and 5B are assigned arbitrarily. Preparative SFC Conditions Column/dimensions : CHIRALPAK-IC (30 x 250 mm), 5µ % CO2 : 60% % Co solvent : 40% (ACN:IPA) (1:1) Total Flow : 100 g/min Back Pressure : 100 bar Temperature : 30 °C UV : 215 nm Solubility : ACN [0163] Compound 5A: 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.35 (d, J = 3.6 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.43-3.36 (m, 2H), 2.75-2.66 (m, 1H), 2.27-2.20 (m, 1H), 1.62 (s, 3H). MS (LCMS): m/z 404.33 [M+H]+; LCMS Purity: 98.35%; HPLC Purity: 95.03%; Chiral Purity: 99.97% (RT: 2.17 min). [0164] Compound 5B: 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.35 (d, J = 3.6 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.43-3.36 (m, 2H), 2.75-2.66 (m, 1H), 2.27-2.20 (m, 1H), 1.62 (s, 3H). MS (LCMS): m/z 404.33 [M+H]+; LCMS Purity: 95.54%; HPLC Purity: 95.08%; Chiral Purity: 99.82% (RT: 2.98 min). Example 6 (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (6A) and (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3- yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (6B)
Figure imgf000094_0001
[0165] Example 6 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 6A and 6B are assigned arbitrarily. Preparative SFC Conditions Column/dimensions : LUX-CELLULOSE-4 (21 x 250 mm), 5µ % CO2 : 70% % Co solvent : 30% (MeOH) Total Flow : 100 g/min Back Pressure : 100 bar Temperature : 30 °C UV : 215 nm Solubility : MeOH+ACN [0166] Compound 6A: 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 8.29 (dd, J = 7.6, 1.6 Hz, 1H), 8.21 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.13 (dd, J = 8.0, 5.2 Hz, 1H), 3.49-3.39 (m, 2H), 2.83-2.75 (m, 1H), 2.29-2.21 (m, 1H), 1.64 (s, 3H). MS (LCMS): m/z 404.33 [M+H]+; LCMS Purity: 99.67 %; HPLC Purity: 99.41 %; Chiral Purity: 99.94% (RT: 1.88 min). [0167] Compound 6B: 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 8.29 (dd, J = 7.6, 1.6 Hz, 1H), 8.21 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.13 (dd, J = 8.0, 5.2 Hz, 1H), 3.49-3.39 (m, 2H), 2.83-2.75 (m, 1H), 2.29-2.21 (m, 1H), 1.64 (s, 3H). MS (LCMS): m/z 404.33 [M+H]+; LCMS Purity: 99.22 %; HPLC Purity: 99.74 %; Chiral Purity: 99.67% (RT: 2.95 min). Example 7 (S)-3-Methyl-3- (5-(2-((5- (trifluoromethyl)pyridin-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol -2- yl) pyrrolidin-2-one (7A) and (R)-3-methyl-3-(5-(2-((5-(trifluoromethyl) pyridin-2-yl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (7B)
Figure imgf000095_0001
[0168] Example 7 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 7A and 7B are assigned arbitrarily. Preparative Chiral SFC Conditions Column/dimensions : CHIRALPAK-IC (30 × 250 mm), 5µm % CO2 : 60% % Co solvent : 40% (MeOH) Total Flow : 100 g/min Back Pressure : 100 bar Temperature : 30 °C Solubility : MeOH UV : 215 nm [0169] Compound 7A: 1H NMR (400 MHz, DMSO-d6) δ 10.95 (br s, 1H), 8.72-8.67 (m, 2H), 8.58-8.57 (m, 1H), 8.36 (dd, J =7.6 Hz, J =1.6 Hz, 1H), 8.21-8.19 (m, 2H), 7.26-7.23 (m, 1H), 3.48-3.36 (m, 2H), 2.80-2.74 (m, 1H), 2.27-2.21 (m, 1H), 1.63 (s, 3H); MS (LCMS): m/z 403.24 [M-H]-; HPLC: 99.15%; Chiral HPLC: 99.9% (RT: 3.36 min). [0170] Compound 7B: 1H NMR (400 MHz, DMSO-d6) δ 10.95 (br s, 1H), 8.72-8.7 (m, 2H), 8.56-8.57 (m, 1H), 8.36 (dd, J =7.6 Hz, J =1.6 Hz, 1H), 8.21-8.19 (m, 2H), 7.26-7.23 (m, 1H), 3.48-3.39 (m, 2H), 2.81-2.74 (m, 1H), 2.27-2.21 (m, 1H), 1.63 (s, 3H). MS (LCMS): m/z 403.24 [M-H]-. HPLC: 98.64%. Chiral HPLC: 99.86% (RT: 4.64 min). Example 8 (S)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (8A) and (R)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2- yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (8B)
Figure imgf000096_0001
[0171] Example 8 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 8A and 8B are assigned arbitrarily. [0172] Prep. HPLC conditions: Column/dimension: X SELECT C18-CSH-packed C8 (19 × 250 mm), 5µ Mobile phase A: 10MM AMM-bicarbonate in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0/30, 1/30, 7/60, 12.9/60, 13.0/100, 17/100, 17.1/30, 20/30; Flow rate: 18 ml/min; Solubility: THF + acetonitrile+ water. Preparative Chiral SFC Conditions Column/dimensions : CHIRALCEL-OX-H (30 × 250 mm), 5µm % CO2 : 60% % Co solvent : 40% (MeOH) Total Flow : 100 g/min Back Pressure : 100 bar Temperature : 30 °C Solubility : MeOH UV : 295 nm [0173] Compound 8A: 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.75 (d, J =8.4 Hz, 2H), 3.48-3.38 (m, 2H), 2.76-2.72 (m, 1H), 2.31-2.24 (m, 1H), 1.65 (s, 3H); MS (LCMS): m/z 403.20 [M-H]-; HPLC: 99.83%; Chiral HPLC: 99.90% (RT: 3.60 min). [0174] Compound 8B: 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.75 (d, J =8.4 Hz, 2H), 3.45-3.38 (m, 2H), 2.79-2.72 (m, 1H), 2.31-2.24 (m, 1H), 1.65 (s, 3H); MS (LCMS): m/z 403.20 [M-H]-; HPLC: 99.51%; Chiral HPLC: 99.85% (RT: 5.42 min). Example 9 (S)-3-(5-(1,5-Dimethyl-3-((4-(trifluoromethyl)phenyl)amino)-1H- pyrazol-4-yl)-1,3,4-oxadiazol- 2-yl)-3-methylpyrrolidin-2-one (9A) and (R)-3-(5-(1,5-dimethyl-3-((4-(trifluoromethyl) phenyl) amino)-1H-pyrazol-4-yl)- 1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin- 2-one (9B)
Figure imgf000097_0001
[0175] Example 9 was synthesized similarly to Example 5. The racemic mixture was further separated by chiral SFC. The stereochemistry of 9A and 9B are assigned arbitrarily. [0176] Prep-HPLC method: Column/dimensions: X BRIDGE C18 (19 ×250, 5µm) Mobile phase A: 20 mM ABC in water pH Mobile phase B: 100% Acetonitrile Gradient (Time/%B): 0.01/35, 1/35, 10/65, 13/65, 13.1/100, 17/100, 17.1/35, 19/35. Flow rate: 18 ml/min Diluent: Acetonitrile +water + THF. Preparative Chiral SFC Conditions Column/dimensions : CHIRALCEL-OX-H (30 x 250 mm), 5μ % CO2 : 60% % Co solvent : 40% (ACN: IPA (1:1)) Total Flow : 110 g/min Back Pressure : 100 bar Temperature : 30 °C Solubility : MeOH UV : 293 nm [0177] Compound 9A: 1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.12 (s, 1H), 7.61-7.56 (m, 4H), 3.78 (s, 3H), 3.36-3.31 (m, 2H), 2.67-2.59 (m, 1H), 2.52-2.51 (m, 3H), 2.20- 2.14 (m, 1H), 1.54 (s, 3H); MS (LCMS): m/z 419.25 [M-H]-; HPLC: 99.55%; Chiral HPLC: 99.85% (RT: 2.16 min). [0178] Compound 9B: 1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.12 (s, 1H), 7.61-7.56 (m, 4H), 3.79 (s, 3H), 3.36-3.32 (m, 2H), 2.67-2.59 (m, 1H), 2.52-2.51 (m, 3H), 2.20- 2.14 (m, 1H), 1.54 (s, 3H); MS (LCMS): m/z 419.25 [M-H]-; HPLC: 99.56%; Chiral HPLC: 97.9% (RT: 4.01 min). Example 10 (R)-3-(5-(3-((4-(Trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3- vinylpyrrolidin-2-one (10A) and (S)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)- 1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (10B)
Figure imgf000098_0001
[0179] To a solution of ethyl 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylate (10.0 g, 36.1 mmol) in DMF (30mL) was added NaH (2.16 g, 54.09 mmol) at 0 °C. The mixture was stirred for 30 min, and then 1,2-dibromoethane (6.2 mL, 72.12 mmol) was added. Stirring was continued at rt for 6 h. The reaction was quenched with sat NH4Cl (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography using 40% EtOAc in petroleum ether as the eluent to afford ethyl 3-(2-bromoethyl)-1-(4- methoxybenzyl)-2-oxopyrrolidine-3-carboxylate (12 g, 65%). MS (LCMS): m/z 384.25 [M+H]+. [0180] To a stirred solution of ethyl 3-(2-bromoethyl)-1-(4-methoxybenzyl)-2- oxopyrrolidine-3-carboxylate (10.0 g, 26.0 mmol) in toluene (10 mL) was added DBU (7.7 mL, 52 mmol) at 0 °C. After heating at 80 °C for 16 h, the reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography using 50% EtOAc in petroleum ether to afford ethyl 1-(4-methoxybenzyl)-2-oxo- 3-vinylpyrrolidine-3-carboxylate (4.0 g, 44%). MS (LCMS): m/z 304.37 [M+H]+. [0181] To a stirred solution of ethyl 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3- carboxylate (1.00 g, 3.30 mmol) in THF:EtOH:H2O (1:1:1, 10 mL) was added LiOH•H2O (270 mg, 6.60 mmol) at 0 °C. After stirring at rt for 1 h, the organic solvents were removed. The residue acidified with 2 N HCl and then extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and dried under reduced pressure to afford 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylic acid (1.0 g), which was used directly in the next step without further purification. MS (LCMS): m/z 276.25 [M+H]+. [0182] To a stirred solution of 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3- carboxylic acid (1.00 g, 3.63 mmol) in DMF (10 mL) were added DIPEA (2.50 mL, 14.5 mmol), HATU (2.76 g, 7.28 mmol) and 3-((4-(trifluoromethyl)phenyl)amino)picolinohydrazide (650 mg, 2.19 mmol) at 0 °C. After stirring at rt for 16 h, the reaction was quenched with water (15 mL), and then extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica chromatography using EtOAc in petroleum ether to afford N’-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3- carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)picolinohydrazide (1.0 g, 61% ). MS (LCMS): m/z 554.60 [M+H]+. [0183] To a stirred solution of N'-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3- carbonyl)-3-((4-(trifluoromethyl)phenyl) amino)picolinohydrazide (1.00 g, 1.81 mmol) in DCM (10 mL) at 0 °C were added DIPEA (0.62 mL, 3.6 mmol) and Burgess reagent (0.86 g, 3.6 mmol). After stirring at rt for 16 h, the reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography using EtOAc in petroleum ether to afford 1-(4-methoxybenzyl)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (0.15 g, 13%). MS (LCMS): m/z 536.59 [M+H]+. [0184] To a stirred solution of 1-(4-methoxybenzyl)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (0.40 g, 0.75 mmol) in DCM (6 mL) were added triflic acid (0.35 mL, 3.7 mmol) and TFA (12 mL) at 0 °C. After stirring at rt for 16 h, the reaction was quenched with saturated NaHCO3 (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography using EtOAc in hexane to give a racemic mixture, which was further separated by chiral SFC to afford (R)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3- vinylpyrrolidin-2-one (10A) (30 mg, 9.6%) and (S)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (10B) (25 mg, 8%). The stereochemistry of 10A and 10B are assigned arbitrarily. Preparative Chiral SFC Conditions Column/dimensions : YMC PACK DIOL-120 (20 × 250 mm), 5µ % CO2 : 70% % Co solvent : 30% (MeOH) Total Flow : 60 g/min Back Pressure : 100 bar Temperature : 30 °C Solubility : MeOH + ACN UV : 298 nm [0185] Compound 10A: 1H NMR (400 MHz, DMSO-d6): δ 9.27 (br s, 1H), 8.35-8.32 (m, 2H), 7.99 (d, J= 8.0 Hz, 1H), 7.68 (d, J= 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.42 (d, J= 8.4 Hz, 2H), 6.30-6.23 (m, 1H), 5.47-5.41 (m, 2H), 3.44- 3.39 (m, 1H), 3.281 (m, 1H), 2.83- 2.76 (m, 1H), 2.57- 2.54 (m, 1H); MS (LCMS): m/z 414.22 [M-H]-; HPLC Purity: 99.25%; Chiral Purity: 99.96% (RT: 2.37 min). [0186] Compound 10B: 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.35-8.32 (m, 2H), 7.99 (d, J= 8.0 Hz, 1H), 7.68 (d, J= 8.4 Hz, 2H), 7.53 (dd, J= 8.4 Hz, J= 4.4 Hz, 1H), 7.43- 7.41 (m, 2H), 6.30-6.23 (m, 1H), 5.47-5.41(m, 2H), 3.44-3.32 (m, 1H), 3.28-3.27 (m, 1H), 2.79- 2.77 (m, 1H), 2.58-2.56 (m, 1H); MS (LCMS): m/z 414.22 [M-H]-; HPLC Purity: 99.%; Chiral Purity: 98.78% (RT: 3.40 min).
Example 11 (S)-1-(hydroxymethyl)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (11)
Figure imgf000101_0002
[0187] To a solution of (S)-3-methyl-3-(5-(2-((4- (trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (41.3 mg, 0.103 mmol) in THF (5 mL) was added potassium carbonate (284 mg, 2.053 mmol) and 37% formaldehyde aqueous solution (0.167 mL, 2.05 mmol). After stirring at rt overnight, water (20 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc:hexane to afford (S)-1- (hydroxymethyl)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4-oxadiazol- 2-yl)pyrrolidin-2-one (11) (13 mg, 29%). 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 7.91 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 1.0 Hz, 2H), 7.58-7.53 (m, 2H), 7.31 (d, J = 1.0 Hz, 2H), 7.19- 7.13 (m, 1H), 6.02 (t, J = 1.0 Hz, 1H), 4.70-4.56 (m, 2H), 3.63-3.49 (m, 2H), 2.72-2.57 (m, 1H), 2.20-2.10 (m, 1H), 1.58 (s, 3H). MS (LCMS): m/z 415.1 [M+H-18]+. Example 12 (R)-1-(hydroxymethyl)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (12)
Figure imgf000101_0001
[0188] Example 12 was synthesized similarly to Example 11. 1H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 7.90 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 1.0 Hz, 2H), 7.57-7.54 (m, 2H), 7.31 (d, J = 1.0 Hz, 2H), 7.20-7.13 (m, 1H), 6.02 (t, J = 1.0 Hz, 1H), 4.71-4.57 (m, 2H), 3.63-3.47 (m, 2H), 2.72-2.58 (m, 1H), 2.23-2.09 (m, 1H), 1.58 (s, 3H). MS (LCMS): m/z 415.1 [M+H-18]+. Example 13 (S)-1-(hydroxymethyl)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (13)
Figure imgf000102_0001
[0189] Example 13 was synthesized similarly to Example 11. 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.34 (dd, J = 4.4, 1.3 Hz, 1H), 7.99 (dd, J = 8.6, 1.2 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.53 (dd, J = 8.7, 4.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 6.04 (t, J = 7.1 Hz, 1H), 4.71-4.60 (m, 2H), 3.62-3.54 (m, 2H), 2.76-2.64 (m, 1H), 2.25-2.16 (m, 1H), 1.62 (s, 3H). MS (LCMS): m/z 416.1 [M+H-18]+. Example 14 (R)-1-(Hydroxymethyl)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (14)
Figure imgf000102_0002
[0190] Example 14 was synthesized similarly to Example 11. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.35 (dd, J = 4.3, 1.3 Hz, 1H), 8.00 (dd, J = 8.6, 1.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.6, 4.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 6.05 (t, J = 7.2 Hz, 1H), 4.73-4.59 (m, 2H), 3.66-3.55 (m, 2H), 2.74-2.64 (m, 1H), 2.26-2.16 (m, 1H), 1.63 (s, 3H). MS (LCMS): m/z 416.1 [M+H-18]+. Example 15 (S)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (15)
Figure imgf000103_0001
[0191] To a solution of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (568 mg, 3.15 mmol) in DMF (2 mL) was added NBS (673 mg, 3.78 mmol). After stirring at rt overnight, water (20 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica column chromatography to afford ethyl 3-bromo-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (806 mg, 99%). MS (LCMS): m/z 259, 261 [M+2]+. [0192] A mixture of ethyl 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylate (263 mg, 1.01 mmol), 4-(trifluoromethyl)aniline (196 mg, 1.22 mmol) and cesium carbonate (992 mg, 3.05 mmol) in dioxane (8 mL) was degassed by bubbling nitrogen for 1 min before adding Pd(dba)3 (93 mg, 0.102 mmol) and Xantphos (117 mg, 0.203 mmol). The mixture was heated at 95 °C for 4 h, and then cooled to rt. Water (20 mL) was added, and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography to afford ethyl 3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylate (160 mg, 46%). MS (LCMS): 340.1 m/z [M+H]+. [0193] To a solution of ethyl 3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-2-carboxylate (167 mg, 0.492 mmol) in anhydrous MeOH (2 mL) was added hydrazine monohydrate (1 mL, 19.98 mmol). After heating at 80 °C overnight, the mixture was concentrated, and the residue was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica chromatography eluted with 0-100% EtOAc:hexane to afford 3-((4- (trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbohydrazide (90 mg, 56%). MS (LCMS): m/z 326.1 [M+H]+. [0194] To a solution of 3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-2-carbohydrazide (90 mg, 0.277 mmol) in DMF (6 mL) were added (R)- 3-methyl-2-oxopyrrolidine-3-carboxylic acid (39.6 mg, 0.277 mmol), HATU (210 mg, 0.553 mmol), DMAP (33.8 mg, 0.277 mmol) and DIPEA (0.15 mL, 0.83 mmol). After stirring at rt overnight, the mixture was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc:hexane to afford (R)-N'-(3- methyl-2-oxopyrrolidine-3-carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-2-carbohydrazide (59 mg, 47%). MS (LCMS): m/z 451.1 [M+H]+. [0195] To a solution of (R)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-3-((4- (trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbohydrazide (59 mg, 0.13 mmol) in DCM (5 mL) was added tosyl-Cl (30 mg, 0.157 mmol) and TEA (0.050 mL, 0.359 mmol). After stirring at rt overnight, the mixture was treated with EtOAc (20 mL) and saturated NaHCO3 (20 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluting with 0- 100% EtOAc:hexane to afford the crude product. The residue was further purified by HPLC eluting with 0-100% MeCN:H2O containing 0.1% formic acid. The product fractions were combined, neutralized with sat. aq. NaHCO3 and extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was dissolved in 1,4-dioxane (1 mL), frozen and lyophilized overnight to afford (S)-3-methyl-3-(5-(3- ((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-1,3,4-oxadiazol- 2-yl)pyrrolidin-2-one (15) (9.4 mg, 16%). 1H NMR (400 MHz, CD3OD): δ 7.40 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.29-4.21 (m, 2H), 3.44-3.37 (m, 2H), 2.91-2.84 (m, 2H), 2.76-2.64 (m, 2H), 2.63-2.54 (m, 1H), 2.26-2.15 (m, 1H), 1.61 (s, 3H). MS (LCMS): m/z 433.1 [M+H]+. Example 16 (S)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (16)
Figure imgf000105_0001
[0196] Example 16 was synthesized similarly to Example 15. 1H NMR (400 MHz, CD3OD): δ 7.36 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.23 (t, J = 6.1 Hz, 2H), 3.41-3.32 (m, 2H), 2.68 (t, J = 6.4 Hz, 2H), 2.52-2.41 (m, 1H), 2.20-2.08 (m, 3H), 1.95-1.86 (m, 2H), 1.56 (s, 3H). MS (LCMS): m/z 447.2 [M+H]+.
Example 17 (S)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (17)
Figure imgf000106_0001
[0197] Example 17 was synthesized similarly to Example 15. 1H NMR (400 MHz, DMSO-d6): δ 8.86 (d, J = 7.0 Hz, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 7.58-7.51 (m, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.38-7.32 (m, 1H), 7.14 (dt, J = 6.9, 1.3 Hz, 1H), 6.70 (d, J = 8.6 Hz, 2H), 3.32-3.24 (m, 2H), 2.49-2.44 (m, 1H), 2.20-2.09 (m, 1H), 1.51 (s, 3H). MS (LCMS): m/z 443.2 [M+H]+.
Example 18 (S)-3-Methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-3-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (18)
Figure imgf000107_0001
[0198] Example 18 was synthesized similarly to Example 15. 1H NMR (400 MHz, DMSO-d6): δ 8.93 (s, 1H), 8.77 (d, J = 6.8 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.79- 7.75 (m, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.60-7.53 (m, 1H), 7.07-7.01 (m, 1H), 3.40-3.31 (m, 2H), 2.78-2.66 (m, 1H), 2.22-2.12 (m, 1H), 1.56 (s, 3H). MS (LCMS): m/z 443.1 [M+H]+.
Example 19 3-Methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyrazolo[1,5-a]pyridin-3-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (19)
Figure imgf000108_0001
[0199] Example 19 was synthesized similarly to Example 15. 1H NMR (400 MHz, CD3OD): δ 8.62-8.60 (m, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.89-7.85 (m, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.56-7.49 (m, 1H), 7.05-6.98 (m, 1H), 3.64-3.50 (m, 2H), 2.98-2.89 (m, 1H), 2.41-2.33 (m, 1H), 1.76 (s, 3H). MS (LCMS): m/z 443.1 [M+H]+.
Example 20 (S)-3-methyl-3-(5-(1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazol-3-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (20)
Figure imgf000109_0001
[0200] To a solution of methyl 4-bromo-1H-indazole-3-carboxylate (1.06 g, 4.14 mmol) in DMF (6 mL) was added K2CO3 (1.72 g, 12.4 mmol). The mixture was stirred at rt for 1 h, and then iodomethane (0.881 g, 6.21 mmol) in DMF (1 mL) was added. After stirring at rt overnight, the mixture was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography to afford methyl 4-bromo-1-methyl-1H-indazole-3-carboxylate (755 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 7.83 (dd, J = 8.5, 0.7 Hz, 1H), 7.56 (dd, J = 7.4, 0.7 Hz, 1H), 7.44-7.37 (m, 1H), 4.14 (s, 3H), 3.91 (s, 3H). MS (LCMS): m/z 270.0 [M+2]+. [0201] The mixture of methyl 4-bromo-1-methyl-1H-indazole-3-carboxylate (755 mg, 2.81 mmol), 4-(trifluoromethyl)aniline (542 mg, 3.37 mmol), and cesium carbonate (2.74 g, 8.42 mmol) in dioxane (8 mL) was degassed by bubbling nitrogen for 1 minute before adding Pd2(dba)3 (257 mg, 0.281 mmol) and Xantphos (162 mg, 0.281 mmol). After heating at 95 °C for 4 h, the mixture was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography to afford methyl 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazole-3- carboxylate (620 mg, 63%). MS (LCMS): m/z 350.1 [M+H]+. [0202] To a solution of methyl 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H- indazole-3-carboxylate (620 mg, 1.77 mmol) in anhydrous MeOH (3 mL) was added hydrazine monohydrate (1.0 mL, 20 mmol). After heating at 80 °C overnight, the mixture was concentrated, and the residue was treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica chromatography eluting with 0-100% EtOAc:hexane to afford 1-methyl-4-((4- (trifluoromethyl)phenyl)amino)-1H-indazole-3-carbohydrazide (534 mg, 86%). MS (LCMS): m/z 350.1 [M+H]+. [0203] To a solution of 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazole- 3-carbohydrazide (78.0 mg, 0.223 mmol) in DMF (6 mL), were added (R)-3-methyl-2- oxopyrrolidine-3-carboxylic acid (32.0 mg, 0.223 mmol), DMAP (27.3 mg, 0.223 mmol), HATU (127 mg, 0.335 mmol) and DIPEA (0.12 mL, 0.68 mmol). After stirring at rt overnight, the mixture was treated with EtOAc (20 mL) and saturated NaHCO3 (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by silica chromatography eluting with 0-100% EtOAc:hexane to afford (R)-1-methyl-N'-(3-methyl- 2-oxopyrrolidine-3-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)-1H-indazole-3- carbohydrazide (96 mg, 91%). MS (LCMS): m/z 475.2 [M+H]+. [0204] To a solution of (R)-1-methyl-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-4- ((4-(trifluoromethyl)phenyl)amino)-1H-indazole-3-carbohydrazide (96.0 mg, 0.202 mmol) in DCM (5 mL), were added tosyl-Cl (46.3 mg, 0.243 mmol) and TEA (0.10 mL, 0.72 mmol). After stirring at rt overnight, the mixture was treated with EtOAc (20 mL) and saturated NaHCO3 (20 mL). The organic layer was separated, and the aqueous was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The crude product was purified by HPLC eluting with 0-100% MeCN:H2O containing 0.1% formic acid. The product fractions were combined and concentrated. The residue extracted with sat NaHCO3/EtOAc. The combined organic layers were dried over Na2SO4, concentrated and dried under reduced pressure to afford (S)-3-methyl-3-(5-(1-methyl-4-((4- (trifluoromethyl)phenyl)amino)-1H-indazol-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (20) (35.0 mg, 36.4%). 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.22 (s, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.51-7.39 (m, 3H), 7.31 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 4.18 (s, 3H), 3.46- 3.37 (m, 2H), 2.80-2.69 (m, 1H), 2.25 (ddd, J = 5.3, 7.4, 12.9 Hz, 1H), 1.63 (s, 3H). MS (LCMS): m/z 457.2 [M+H]+. Example 21 (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (21)
Figure imgf000111_0001
[0205] To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (0.85 g, 5.6 mmol) in MeOH (12 mL) was added 2M (diazomethyl)trimethylsilane in diethyl ether (10 mL, 20 mmol). After stirring at rt overnight, the reaction was quenched with brine. The mixture was extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated and dried under reduced pressure to afford methyl 5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (0.70 g, 75%). MS (LCMS): m/z 167.1 [M+H]+. [0206] To a solution of methyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (1.40 g, 8.42 mmol) in MeCN (5 mL) was added Br2 (0.65 mL, 13 mmol) and acetic acid (3.0 mL, 13 mmol) at rt. After heating at 80 °C for 16 h, the mixture was treated with EtOAc (20 mL) and 1M NaOH (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated. The residue was purified by silica chromatography eluting with 0-100% EtOAc:hexane to afford methyl 2-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (1.39 g, 67%). MS (LCMS): m/z 245.0 [M], 247.0 [M+2]. [0207] To a solution of methyl 2-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- carboxylate (175 mg, 0.714 mmol) and 4-(trifluoromethyl)aniline (138 mg, 0.857 mmol) in dioxane (8 mL), was added Cs2CO3 (698 mg, 2.14 mmol). The mixture was degassed by bubbling nitrogen for 1 minute before adding BrettPhos Pd G3 (64.7 mg, 0.07 mmol) and BrettPhos (77 mg, 0.143 mmol). After heating at 95 °C for 4 h, the mixture was cooled to rt and brine (20 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica chromatography eluting with 0-100% EtOAc:hexane to afford methyl 2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (182 mg, 78%). MS (LCMS): m/z 326.1 [M+H]+. [0208] To a solution of methyl 2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-3-carboxylate (182 mg, 0.56 mmol) in anhydrous MeOH (2 mL) was added hydrazine monohydrate (1 mL). After heating at 80 °C for 16 h, the mixture was concentrated, and the residue treated with EtOAc (20 mL) and brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica column chromatography eluting with 0-100% EtOAc:hexane to afford 2-((4- (trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbohydrazide (63 mg, 35%). MS (LCMS): m/z 326.1 [M+H]+. [0209] To a solution of 2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-3-carbohydrazide (63 mg, 0.19 mmol) in DMF (2 mL) were added (R)-3- methyl-2-oxopyrrolidine-3-carboxylic acid
Figure imgf000113_0001
mg, 0.194 mmol), DMAP (24 mg, 0.19 mmol), HATU (147 mg, 0.387 mmol) and DIPEA (0.10 mL, 0.58 mmol). After stirring at rt for 16 h, the mixture was treated with brine (20 mL) and EtOAc (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography eluting with 0-100% EtOAc:hexane to afford (R)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2- ((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbohydrazide (70.5 mg, 81%). MS (LCMS): m/z 451.2 [M+H]+. [0210] To a solution of (R)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((4- (trifluoromethyl)phenyl)amino)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbohydrazide (70 mg, 0.15 mmol) in DCM (1 mL) were added tosyl-Cl (44.4 mg, 0.233 mmol) and TEA (0.043 mL, 0.31 mmol). After stirring at rt for 16 h, the mixture was diluted with sat. NaHCO3 (20 mL) and then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography eluting with 0-100% EtOAc:hexane to afford (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (21) (23 mg, 34%). 1H NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.12 (s, 1H), 7.69-7.55 (m, 4H), 4.17 (t, J = 7.2 Hz, 2H), 3.40-3.35 (m, 2H), 3.14-3.04 (m, 2H), 2.66-2.55 (m, 3H), 2.22-2.12 (m, 1H), 1.55 (s, 3H). MS (LCMS): m/z 433.1 [M+H]+. Example 22 (S)-3-Methyl-3-(5-(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (22)
Figure imgf000113_0002
[0211] Example 22 was synthesized similarly to Example 21. 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.46 (dd, J = 1.6, 0.9 Hz, 1H), 8.09 (s, 1H), 8.04 (dd, J = 8.9, 2.4 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 4.19 (t, J = 7.3 Hz, 2H), 3.31-3.25 (m, 2H), 3.15-3.05 (m, 2H), 2.66- 2.56 (m, 2H), 2.48-2.43 (m, 1H), 2.17-2.05 (m, 1H), 1.48 (s, 3H). MS (LCMS): m/z 434.1 [M+H]+. Example 23 (S)-3-Methyl-3-(5-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (23)
Figure imgf000114_0001
[0212] Example 23 was synthesized similarly to Example 21. 1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.68 (d, J = 2.6 Hz, 1H), 8.09 (dd, J = 2.4, 8.6 Hz, 1H), 8.05 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 4.11 (t, J = 7.3 Hz, 2H), 3.32-3.27 (m, 2H), 3.07-2.99 (m, 2H), 2.58-2.48 (m, 3H), 2.16-2.07 (m, 1H), 1.48 (s, 3H). MS (LCMS): m/z 434.1 [M+H]+.
Examples 24 and 25 (R)-3-cyclopropyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (24) and (S)-3-cyclopropyl-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (25)
Figure imgf000115_0001
[0213] To a stirred solution of 1-(4-methoxybenzyl)-3-(5-(3-((4- (trifluoromethyl)phenyl) amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (1.00 g, 1.87 mmol) in ACN (10 mL) at rt, was added triethylamine (0.78 mL, 5.6 mmol), DMAP (114 mg, 0.93 mmol) and Boc-anhydride (1.30 mL, 5.61 mmol) at rt. After stirring for 16 h, the mixture was diluted with EtOAc (20 mL) and then washed with water (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (2-(5-(1-(4- methoxybenzyl)-2-oxo-3-vinylpyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4- (trifluoromethyl)phenyl)carbamate (860 mg, 72%). LC-MS: m/z 636.37 [M+H]+. [0214] To an ice-cold solution of 50% aq. KOH (180 mL), was added diethyl ether (360 mL) under stirring. N-methyl-N-nitrosourea (9.0 g, 87 mmol) was added in portions over 10 min while maintaining the reaction temperature at around 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was transferred into a separating funnel. The organic layer was separated and dried over solid KOH (9 g). The ether layer containing diazomethane was transferred to a round bottom flask and cooled to -5 °C. Tert-butyl (2-(5-(1-(4-methoxybenzyl)-2-oxo-3- vinylpyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (900 mg, 1.41 mmol) and Pd(OAc)2 (31.8 mg, 0.141 mmol) were added. The mixture was stirred at -5 °C for 1 h and then gradually allowed to warm to rt. The mixture was stirred at rt for 4 h, and then filtered through a pad of celite. The filter cake washed with diethyl ether (60 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel using 30% EtOAc in petroleum ether to afford tert-butyl (2- (5-(3-cyclopropyl-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3- yl)(4- (trifluoromethyl)phenyl)carbamate (720 mg, 78%). LC-MS: m/z 650.66 [M+H]+. [0215] To a stirred solution of tert-butyl (2-(5-(e-cyclopropyl-1-(4-methoxybenzyl)-2- oxopyrrolidinj-3-yl)1,3,4-oxadiazol-2-yl)pyridine-3-yl)(4-(trifluoromethyl) (700 mg, 1.08 mmol) in DCM (21 mL) at 0 °C were added TFA (21 mL) and triflic acid (0.47 mL, 5.4 mmol). After the mixture was slowly warmed up to rt, the mixture was stirred at rt for 16 h. The mixture was concentrated under reduced pressure. Water (20 mL) was added to the resulting residue. The mixture was basified with sat. aq. NaHCO3 and then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC followed by chiral SFC to afford (R)-3- cyclopropyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (24), (12.4 mg, 39%) and (S)-3-cyclopropyl-3-(5-(3-((4-(trifluoromethyl) phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (25), (12.2 mg, 38%). The stereochemistry of 24 and 25 are assigned arbitrarily. Preparative HPLC Conditions: Column/dimensions : X –bridge C18 (19 × 150 × 5µm) Mobile Phase A : 10 mm ammonium bicarbonate in water Mobile Phase B : ACN Gradient (T%B) : 0.01/25, 1/25, 8/45, 15.5/45, 15.6/100,22/100, 22.1/25, 24/25. Flow Rate : 17 ml/min Sample Diluent : Acetonitrile + THF + water. Preparative SFC Conditions Column/dimensions : Chiralcel OD-H (30 ×250)mm, 5μ %CO2 : 70% %Co solvent : 30% (MeOH) Total Flow : 100g/min Back Pressure : 100 bar Temperature : 30 °C UV : 298 nm Solubility : MeOH [0216] Compound 24: 1H NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 8.35 (dd, J = 4.0, 0.8 Hz, 1H), 8.19 (s, 1H), 7.99 (dd, J = 8.4, 0.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.35-3.28 (m, 2H), 2.64-2.57 (m,1H), 2.14-2.08 (m, 1H), 1.58-1.54 (m, 1H), 0.69-0.54 (m, 3H), 0.35-0.31 (m, 1H). LC-MS (ESI): 428.24 [M-H]-. LCMS Purity: 98.70. HPLC Purity: 98.13%. Chiral Purity: 99.92% (RT: 1.88 min). [0217] Compound 25: 1H NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 8.35 (dd, J = 4.0, 0.8 Hz, 1H), 8.19 (s, 1H), 7.99 (dd, J = 8.4, 0.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.53 (dd, J = 8.4, 4.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.35-3.28 (m, 2H), 2.64-2.57 (m, 1H), 2.14-2.08 (m, 1H), 1.58-1.54 (m, 1H), 0.69-0.54 (m, 3H), 0.35-0.31 (m, 1H). LC-MS (ESI): 428.39 [M-H]- . LCMS Purity: 98.56. HPLC Purity: 97.70%. Chiral Purity: 99.59% (RT: 2.97 min).
Examples 26 and 27 (R)-3-(5-(1-Methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2- yl)-3-vinylpyrrolidin-2-one (26) and (S)-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)- 1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (27)
Figure imgf000118_0001
[0218] To a stirred solution of ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate (4.00 g, 23.6 mmol) in 1,4-dioxane (80 mL), were added 1-bromo-4-(trifluoromethyl)benzene (6.38 g, 28.4 mmol) and cesium carbonate (15.4 g, 47.3 mmol). The mixture was degassed by a flow of nitrogen for 10 min, followed by the addition of Pd(OAc)2 (0.531 g, 2.36 mmol) and Xantphos (1.37 g, 2.36 mmol). After stirring at 100 °C for 16 h, the mixture was diluted with EtOAc (100 mL) and filtered through a pad of celite. The filter cake washed with EtOAc (2 x 30 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 20% EtOAc in petroleum ether to give ethyl 1- methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carboxylate (5.8 g, 78%). LC-MS: m/z 314.23 [M+H]+. [0219] To a stirred solution of ethyl 1-methyl-3-((4-(trifluoromethyl)phenyl)amino)- 1H-pyrazole-4-carboxylate (4.00 g, 12.8 mmol) in methanol (40 mL) at rt was added hydrazine hydrate (6.14 mL, 192 mmol). After stirring at 80 °C for 16 h, the mixture was concentrated under reduced pressure. The residue triturated with toluene (2 x 20 mL). The residue was dissolved in EtOAc (30 mL) and cooled to 0 °C. Petroleum ether was added dropwise until a precipitate formed. The precipitate was filtered, washed with petroleum ether (30 mL) and dried under reduced pressure to give 1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4- carbohydrazide. LC-MS: m/z 300.28 [M+H]+. [0220] To a stirred solution of 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3- carboxylic acid (1.20 g, 4.36 mmol) in THF (12 mL) at rt, were added T3P (2.08 g, 6.54 mmol, 50% solution in EtOAc) and DIPEA (2.28 mL, 13.07 mmol). After 10 min, 1-methyl-3-((4- (trifluoromethyl) phenyl)amino)-1H-pyrazole-4-carbohydrazide (1.04 g, 3.49 mmol) was added. After stirring at rt for 16 h, the mixture was diluted with EtOAc (50 mL), washed with water (50 mL) and brine, separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 70% EtOAc in petroleum ether to afford N'-(1-(4-methoxybenzyl)-5-oxo-3-vinylpyrrolidine-3-carbonyl)-1- methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbohydrazide (1.32 g, 54%). LC- MS: m/z 557.62 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 9.86 (s, 1H), 9.08 (br s, 1H), 8.82 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.22 (dd, J = 17.2, 10.4 Hz, 1H), 5.43-5.31 (m, 2H), 4.60 (d, J = 14.4 Hz, 1H), 4.32 (d, J = 14.8 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 3.26-3.20 (m, 2H), 2.66-2.58 (m, 1H), 2.27- 2.22 (m, 1H). [0221] To a stirred solution of N'-(1-(4-methoxybenzyl)-5-oxo-3-vinylpyrrolidine-3- carbonyl)-1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbohydrazide (1.30 g, 2.34 mmol) in DCM (26 mL) at rt were added DIPEA (0.368 mL, 9.34 mmol) and Burgess reagent (2.22 g, 9.34 mmol) at rt. After stirring for 24 h, the mixture was diluted with DCM (30 mL), washed with water (50 mL), separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 70% EtOAc in petroleum ether to give 1-(4-methoxybenzyl)-3-(5-(1-methyl-3-((4- (trifluoromethyl) phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (1.23 g, 98%). LC-MS: m/z 539.60 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.37 (br s, 1H), 7.75 (s, 1H), 7.69 (d, J= 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.40 Hz, 2H), 6.31 (dd, J = 17.6, 10.8 Hz, 1H), 5.44-5.33 (m, 2H), 4.51 (d, J = 14.8 Hz, 1H), 4.36 (d, J = 14.4 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.46-3.40 (m, 1H), 3.33-3.27 (m, 1 H), 3.00-2.95 (m, 1H), 2.45-2.38 (m, 1H). [0222] To a stirred solution of 1-(4-methoxybenzyl)-3-(5-(1-methyl-3-((4- (trifluoromethyl) phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (1.20 g, 2.87 mmol) in DCM (36 mL) at rt, were added TFA (36 mL) and triflic acid (12 mL). After stirring for 16 h, the mixture was diluted with water (20 mL and basified with saturated aq. NaHCO3. The mixture extracted with DCM (2 x 100 mL). The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel using 8% methanol in dichloromethane to give a racemic mixture, which was further separated by chiral SFC to afford (R)-3-(5-(1-methyl-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (26) (150 mg, 16%) and (S)-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4- yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (27) (150 mg, 16%). The stereochemistry of 26 and 27 are assigned arbitrarily. Preparative SFC condition Column/dimensions : Chiralpak AS-H (30 × 250 × 5µ) %CO2 : 70% %Co solvent : 30% (MeOH) Total Flow : 100g/min Back Pressure : 100 bar Temperature : 30 °C UV : 274 nm Solubility : MeOH [0223] Compound 26: 1H NMR (400 MHz, DMSO-d6): δ 8.54 (br s, 1H), 8.42 (br s, 1H), 8.26 (s, 1H), 7.66-7.59 (m, 4H), 6.22 (dd, J = 17.2, 10.4 Hz, 1H), 5.42-5.36 (m, 2H), 3.88 (s, 3H), 3.40-3.35 (m, 1H), 3.32-3.26 (m, 1H), 2.77-2.70 (m, 1H), 2.49-2.46 (m, 1H). LC-MS: m/z 417.28 [M-H]+. LCMS Purity: 99.75. HPLC Purity: 99.34%. Chiral Purity: 99.99% (RT: 1.86 min). [0224] Compound 27: 1H NMR (400 MHz, DMSO-d6): δ 8.54 (br s, 1H), 8.42 (br s, 1H), 8.26 (s, 1H), 7.66-7.59 (m, 4H), 6.22 (dd, J = 17.2, 10.4 Hz, 1H), 5.42-5.36 (m, 2H), 3.88 (s, 3H), 3.40-3.35 (m, 1H), 3.32-3.26 (m, 1H), 2.77-2.70 (m, 1H), 2.50-2.46 (m, 1H). LC-MS: m/z 417.25 [M-H]+. LCMS Purity: 99.89. HPLC Purity: 99.37%. Chiral Purity: 99.19% (RT: 2.59 min). Example 28 (S)-1-Methyl-3-(5-(3-methyl-2-oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-4-((4- (trifluoromethyl)phenyl)amino)pyridin-2(1H)-one (28)
Figure imgf000121_0001
[0225] A suspension of 2-fluoro-4-iodonicotinic acid (3.0 g, 11 mmol) in 6M hydrochloric acid (60 mL) was heated at 100 °C for 1 h. After the mixture was cooled to rt, the precipitates were filtered, washed with cold water (2 x 20 mL), dried under reduced pressure to give 2-hydroxy-4-iodo nicotinic acid (2 g, crude). The residue was dissolved in DMF (20 mL) and cooled to 0 ℃. Potassium carbonate (2.0 g, 15 mmol) was added. After stirring for 30 min, methyl iodide (2.3 mL, 38 mmol) was added at 0 ℃. The mixture was allowed to warm to rt. The mixture was stirred for 16 h, and then poured into ice-cold water (200 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was triturated in pentane to afford methyl 4-iodo-1-methyl-2-oxo-1,2-dihydropyridine-3- carboxylate (1.1 g, 33%), which was used directly in the next step without further purification. MS (LCMS): 294.1 m/z [M+H]+. [0226] To a stirred solution of methyl 4-iodo-1-methyl-2-oxo-1,2-dihydropyridine-3- carboxylate (1.10 g, 3.76 mmol) in 1,4 dioxane (10 mL), was added 4-(trifluoromethyl)aniline (0.73 g, 4.5 mmol) and K2CO3 (1.0 g, 7.5 mol). After the mixture was degassed with argon for 15 min, Pd(OAc)2 (0.084 g, 0.37 mmol) and Xantphos (0.217 g, 0.37 mmol) were added. The mixture was stirred at 100 °C for 16 h. After cooling to rt, the mixture was diluted with EtOAc (50 mL) and then filtered through a pad of celite. The filtrates were concentrated under reduced pressure. The residue was purified by column chromatography using 5% MeOH in DCM as the eluent to afford methyl 1-methyl-2-oxo-4-((4-(trifluoromethyl)phenyl)amino)-1,2-dihydropyridine-3- carboxylate (0.98 g, 80%). MS (LCMS): 327.3 m/z [M+H]+. [0227] To a stirred solution of methyl 1-methyl-2-oxo-4-((4- (trifluoromethyl)phenyl)amino)-1,2-dihydropyridine (0.98 g, 3.0 mmol) in MeOH (10 mL) at rt, was added hydrazine hydrate (5 mL). The mixture was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure and co-evaporated with toluene (2 x 20 mL) to give 1-methyl- 2-oxo-4-((4-(trifluoromethyl)phenyl)amino)-1,2-dihydropyridine-3-carbohydrazide (0.87 g, 88%), which was used in the next step without further purification. MS (LCMS): m/z 327.3 [M+H]+. [0228] To a stirred solution of 1-methyl-2-oxo-4-((4-(trifluoromethyl)phenyl)amino)- 1,2-dihydropyridine-3-carbohydrazide (0.87 g, 2.6 mmol) in DMF (8.7 mL) at 0 °C, were added (R-3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.57 g, 3.9 mmol), HOBt (0.7 g, 5.3 mmol), EDC•HCl (1 g, 5.3 mmol) and TEA (1.1 mL, 8 mmol). After stirring at rt for 16 h, water (30 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel using 80% EtOAc in petroleum ether as the eluent to afford (R)-1-methyl-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)- 2-oxo-4-((4-(trifluoromethyl)phenyl)amino)-1,2-dihydropyridine-3-carbohydrazide (0.84 g, 70%). MS (LCMS): m/z 452.7 [M+H]+. [0229] To a stirred solution of (R)-1-methyl-N'-(3-methyl-2-oxopyrrolidine-3- carbonyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)amino)-1,2-dihydropyridine-3-carbohydrazide (0.200 g, 0.462 mmol) in DCM (8 mL) at 0 °C, were added DIPEA (0.3 mL, 1.38 mmol) and Burgess reagent (660 g, 2.76 mmol). After the mixture was allowed to warm to rt, the mixture was stirred for 16 h. Water (10 mL) was added, and the mixture was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by achiral prep-SFC (Chiralpak- IG (30 x 250 mm, 5 u; 60% CO2, 40% iPrOH, total flow 100 g/min, back pressure 100 bar, temperature 30 °C) to afford (S)-1-methyl-3-(5-(3-methyl-2-oxopyrrolidin-3-yl)-1,3,4-oxadiazol- 2-yl)-4-((4-(trifluoromethyl)phenyl)amino)pyridin-2(1H)-one (28) (50 mg, 25%). 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.12 (s, 1H), 7.77-7.73 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H), 6.21 (d, J = 7.6 Hz, 1H), 3.49-3.34 (m, 5H), 2.64-2.58 (m, 1H), 2.23 – 2.16 (m, 1H), 1.57 (s, 3H). MS (LCMS): 434.43 m/z [M+H]+. LCMS Purity: 98.9%. HPLC purity: 98.7%. Chiral Purity: 99.43% (RT: 3.95 min). Example 29 (S)-3-Methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-thiadiazol-2- yl)pyrrolidin-2-one (29A) and (S)-3-methyl-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin- 2-yl)-1,3,4-thiadiazol-2-yl)pyrrolidine-2-thione (29B)
Figure imgf000123_0001
Figure imgf000123_0002
[0230] To a stirred solution of (R)-3-methyl-2-oxopyrrolidine-3-carboxylic acid (348 mg, 2.43 mmol) in DMF (6 mL) at 0 °C were added HOBt (546 mg, 4.05 mmol), EDC•HCl (778 mg, 4.05 mmol), TEA (1.1 mL, 8.1 mmol) and 3-((4-(trifluoromethyl) phenyl)amino) picolinohydrazide (600 mg, 2.03 mmol). After the resulting suspension was stirred at rt for 16 h, water (15 mL) was added. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel using 3% methanol in DCM as the eluent to afford (S)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-3-((4- (trifluoromethyl)phenyl) amino)-picolinohydrazide (650 mg, 76%). MS (LCMS): 422.43 m/z [M+H]+. [0231] To a stirred solution of (S)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-3-((4- (trifluoromethyl) phenyl)amino)-picolinohydrazide (600 mg, 1.43 mmol) in THF (12 mL) at rt was added Lawesson’s reagent (693 mg, 1.71 mmol). After the resulting suspension was stirred at 60 °C for 3 h, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (XBridge C18 (19x150 mm, 5 μ; Mobile Phase A: 10 mM ammonium bicarbonate in water; Mobile Phase B: acetonitrile; Flow Rate: 18 mL/min) to afford (R)-3-methyl-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-thiadiazol -2-yl) pyrrolidin-2-one (29A) (5.7 mg, 0.72%) and (S)-3-methyl-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- thiadiazol-2-yl)pyrrolidine-2-thione (29B) (14.5 mg, 2.06%). [0232] Compound 29A: 1H NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 8.26 (d, J = 3.2 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.55-7.39 (m, 3H), 3.46-3.32 (m, 2H), 2.89-2.82 (m, 1H), 2.37-2.30 (m, 1H), 1.58 (s, 3H); MS (LCMS): m/z 418.23 [M-H]-. HPLC Purity: 96.84%. Chiral Purity: 99.63% (RT: 2.75 min). [0233] Compound 29B: 1H NMR (400 MHz, DMSO-d6): δ 10.67 (br s, 1H), 10.04 (s, 1H), 8.25 (dd, J =4.0, 1.2 Hz, 1H), 7.99 (dd, J = 8.8, 1.2 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.55- 7.39 (m, 3H), 3.64 (t, J = 6.8 Hz, 2H), 3.06-3.00 (m, 1H), 2.41-2.33 (m, 1H), 1.71 (s, 3H). MS (LCMS) m/z 434.21 [M-H]-. HPLC Purity: 99.23%; Chiral Purity: 99.86% (RT: 3.67 min).
Example 30 (S)-3-Methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5- yl)pyrrolidin-2-one (30)
Figure imgf000125_0001
[0234] The mixture of 3-bromopicolinonitrile (444 mg, 2.43 mmol), 4- (trifluoromethyl)aniline (469 mg, 2.91 mmol) and cesium carbonate (2.37 g, 7.28 mmol) in dioxane (20 mL) was bubbled with nitrogen for 1 minute before adding Pd(dppf)2Cl2 (355 mg, 0.485 mmol) and Xantphos (281 mg, 0.485 mmol). After stirring at 95 °C overnight, brine (50 mL) was added. The mixture was extracted with EtOAc (50 mL). After separation, the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography eluting with 0-70% EtOAc to afford 3-((4- (trifluoromethyl)phenyl)amino)picolinonitrile (404 mg, 63%). LC-MS exact mass calcd: 263.07 found: MS (APCI) m/z 264.1 [M+H]+. [0235] To a mixture of 3-((4-(trifluoromethyl)phenyl)amino)picolinonitrile (404 mg, 1.54 mmol), hydroxylamine hydrochloride (1.07 g, 15.4 mmol) in dioxane:water (30:20 mL), was added sodium bicarbonate (1.29 g, 15.35 mmol) portion-wise. After stirring at rt overnight, the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography eluted with EtOAc:hexane to afford (Z)-N'-hydroxy-3-((4- (trifluoromethyl)phenyl)amino)picolinimidamide. LC-MS exact mass calcd: 296.09 found: MS (APCI) m/z 297.1 [M+H]+. [0236] A mixture of (Z)-N'-hydroxy-3-((4- (trifluoromethyl)phenyl)amino)picolinimidamide (113 mg, 0.38 mmol), (R)-3-methyl-2- oxopyrrolidine-3-carboxylic acid (54.6 mg, 0.38 mmol), EDCI (110 mg, 0.57 mmol) and HOBt (88 mg, 0.57 mmol) in 1,4-dioxane (6 mL) was stirred at 70 °C overnight. After cooling to rt, the mixture was diluted with saturated aq. NaHCO3 and then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give (S)-3-methyl-3-(3-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-2-one (30) (12.2 mg, 7.9%). 1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 8.28-8.17 (m, 1H), 8.06 (s, 1H), 8.00-7.93 (m, 1H), 7.68 (d, J = 1.0 Hz, 2H), 7.55-7.41 (m, 1H), 7.32 (d, J = 1.0 Hz, 2H), 3.44-3.21 (m, 2H), 2.74 (ddd, J = 5.9, 8.3, 13.0 Hz, 1H), 2.05-2.00 (m, 1H), 1.43 (s, 3H). LC-MS exact mass calcd: 403.13 found: MS (APCI) m/z 404.1 [M+H]+. Example 31 (S)-3-Methyl-3-(3-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,2,4- oxadiazol-5-yl)pyrrolidin-2-one (31)
Figure imgf000126_0001
[0237] The mixture of methyl 5-bromo-1,2-dimethyl-1H-imidazole-4-carboxylate (263 mg, 2.15 mmol), 4-(trifluoromethyl)aniline (581 mg, 2.58 mmol) and cesium carbonate (2.1 g, 6.46 mmol) in dioxane (20 mL) was bubbled with nitrogen for 1 minute before adding BrettPhos Pd G3 (195 mg, 0.22 mmol) and BrettPhos (116 mg, 0.22 mmol). After stirring at 90 °C overnight, brine (50 mL) was added. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give methyl 1,2-dimethyl-5-((4-(trifluoromethyl)phenyl)amino)-1H- imidazole-4-carboxylate. LC-MS exact mass calcd: 266.08 found: MS (APCI) m/z 267.1 [M+H]+. [0238] To a mixture of 1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole- 4-carbonitrile (108 mg, 0.406 mmol) and hydroxylamine hydrochloride (282 mg, 4.06 mmol) in dioxane:water (30:20 mL), was added sodium bicarbonate (341 mg, 4.06 mmol) portion-wise. After stirring at rt overnight, the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography eluted with EtOAc:hexane containing 20% 7N NH3 in MeOH to afford (Z)-N'-hydroxy-1-methyl-3-((4-(trifluoromethyl)phenyl)amino)- 1H-pyrazole-4-carboximidamide (41 mg, 34%). LC-MS exact mass calcd: 299.1 found: MS (APCI) m/z 300.1 [M+H]+. [0239] A mixture of (Z)-N'-hydroxy-1-methyl-3-((4-(trifluoromethyl)phenyl)amino)- 1H-pyrazole-4-carboximidamide (41 mg, 0.137 mmol), (R)-3-methyl-2-oxopyrrolidine-3- carboxylic acid (19.6 mg, 0.137 mmol), EDCI (39.4 mg, 0.206 mmol) and HOBt (31.5 mg, 0.206 mmol) in 1,4-dioxane (2 mL) was stirred at 70 °C overnight. After cooling to rt, the mixture was diluted with saturated aq. NaHCO3 and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography to give (S)-3-methyl-3-(3-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)- 1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-2-one (31) (3.1 mg, 5.6%). 1H NMR (400 MHz, DMSO-d6): δ 8.80-8.70 (m, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 3.71 (s, 3H), 3.33 (s, 48H), 3.31-3.26 (m, 2H), 3.17 (d, J = 5.1 Hz, 1H), 2.19-2.03 (m, 1H), 1.49 (s, 3H). LC-MS exact mass calcd: 406.14 found: MS (APCI) m/z 407.1 [M+H]+. [0240] Examples 32-47 were prepared using similar procedures as shown for Examples 1, 2, 5 and 15 using the appropriate the starting materials that are readily commercially available or prepared by known and published procedures.
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Examples 48 and 49 (R)-2-(2-oxo-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-3-yl)acetonitrile (48) and (S)-2-(2-oxo-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)acetonitrile (49)
Figure imgf000133_0001
[0241] To a stirred solution of 1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carboxylic acid (841 mg, 3.38 mmol) in DMF (8 mL) were added 3-((4- (trifluoromethyl)phenyl)amino)picolinohydrazide (500 mg, 1.69 mmol), HOBt (456 mg, 3.37 mmol), EDC•HCl (648 mg, 3.37 mmol) and TEA (0.7 mL, 6.756 mmol) at 0 °C. After stirring at rt for 16 h, the mixture was diluted with water (15 mL), and then extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel column chromatography using 80% EtOAc in petroleum ether to afford N'-(1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonyl)-3-((4- (trifluoromethyl)phenyl) amino)picolinohydrazide (582 mg, 65%). MS (LCMS) m/z 528.58 [M+H]+. [0242] To a stirred solution of N'-(1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carbonyl)-3-((4-(trifluoromethyl)phenyl)amino)picolinohydrazide (10.0 g, 189 mmol) in DCM (80 mL) were added Burgess reagent (180 g, 759 mmol) and DIPEA (10.0 mL, 569 mmol). After stirring at rt for 16 h, the mixture was concentrated and the residue was purified by flash silica gel column chromatography using 80% EtOAc in petroleum ether to afford 1-(4-methoxybenzyl)-3- (5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (6.3 g, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.35 (d, J = 4.4 Hz, 1H), , 7.99 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.49-4.35 (m, 3H), 3.75 (s, 3H), 3.45-3.34 (m, 2H), 2.58- 2.54 (m, 1H), 2.50-2.34 (m, 1H); MS (LCMS) m/z 510.60 [M+H]+. [0243] To a solution of 1-(4-methoxybenzyl)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (2.40 g, 4.71 mmol) in CH3CN (48 mL) were added TEA (1.97 mL, 14.1 mmol), DMAP (0.288 g, 2.36 mmol) and (Boc)2O (5.14 g, 23.6 mmol) at 0 °C. After stirring at rt for 16 h, the mixture was diluted with water (100 mL) and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with Hex:EtOAc (1:2) to afford tert-butyl (2-(5-(2- ((tert-butoxycarbonyl)oxy)-1-(4-methoxybenzyl)-4,5-dihydro-1H-pyrrol-3-yl)-1,3,4-oxadiazol- 2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (2.4 g, 72%). 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J = 3.2 Hz, 1H), 7.99 (dd, J = 8.0,.2 Hz, 1H), 7.53-7.44 (m, 5H), 7.19 (d, J = 8.8, 2H), 6.84 (d, J = 8.8, 2H), 4.62 (d J = 14.4 Hz, 1H), 4.27 (d, J = 14.8 Hz, 1H),3.79 (s, 3H), 3.40-3.35 (m, 1H), 3.34-3.23 (m, 1H), 3.02-2.95 (m, 1H), 2.80-2.74 (m, 1H), 1.42 (s, 9H), 1.34 (s, 9H). MS (LCMS) m/z 710.86 [M+H]+. [0244] To a solution of tert-butyl (2-(5-(2-((tert-butoxycarbonyl)oxy)-1-(4- methoxybenzyl)-4,5-dihydro-1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4- (trifluoromethyl)phenyl)-carbamate (5.00 g, 7.04 mmol) in MeOH:THF:H2O (2:2:1) (50 mL) was added LiOH•H2O (0.889 g, 21.2 mmol) portion wise at 0 ℃. After stirring at rt for 2 h, the mixture was evaporated under reduced pressure, and the pH adjusted with 1N HCl to ~pH 4. The aqueous mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford tert-butyl (2-(5-(1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4- oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (4.0 g, 93%). MS (LCMS) m/z 554.60 [M-56]-. [0245] To a stirred solution of tert-butyl (2-(5-(1-(4-methoxybenzyl)-2-oxopyrrolidin- 3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (1.50 g, 2.46 mmol) in THF (15 mL) was added 1M LiHMDS in THF (7 mL, 7.38 mmol) dropwise at -78 ℃. The mixture was stirred at -78 ℃ for 30 min, and ethyl 2-bromoacetate (0.60 mL, 49 mmol) was added. After stirring at rt for 10 h, the reaction was quenched with sat. NH4Cl and then extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using petroleum ether:EtOAc (1:3) to afford ethyl 2-(3-(5-(3-((tert-butoxycarbonyl)(4(trifluoromethyl)phenyl) amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl) acetate (1.2 g, 70%). MS (LCMS) m/z 596.58 [M+H]+ [De Boc adduct]. [0246] To a solution of ethyl 2-(3-(5-(3-((tert- butoxycarbonyl)(4(trifluoromethyl)phenyl) amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4- methoxybenzyl)-2-oxopyrrolidin-3-yl) acetate (1.00 g, 1.44 mmol) in EtOH:THF:H2O (2:2:1, 10 mL), was added LiOH.H2O (0.910 g, 2.15 mmol) portion wise at 0 ℃. After stirring at rt for 16 h, the mixture was concentrated, and the pH was adjusted with 1N HCl to ~pH 4. The solution was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 2-(3-(5-(3-((tert-butoxycarbonyl)(4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-2- oxopyrrolidin-3-yl)acetic acid (0.90 g, 94%), which was used directly in the next step. MS (LCMS) m/z 666.31 [M-H]-. [0247] To a stirred solution of 2-(3-(5-(3-((tert-butoxycarbonyl)(4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-2- oxopyrrolidin-3-yl)acetic acid (500 mg, 0.749 mmol) in DCM (16 mL) were added NH4Cl (80 mg, 1.5 mmol), HATU (426 mg, 1.12 mmol) and DIPEA ( 1.5 ml, 8.6 mmol) at 0 °C. After stirring at rt for 16 h, the mixture was diluted with DCM (50 mL), washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using 5-10% MeOH in DCM to afford tert-butyl (2-(5-(3-(2-amino-2-oxoethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidin- 3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (350 mg, 70%). MS (LCMS) m/z 665.42 [M-H]-. [0248] To a stirred solution of tert-butyl (2-(5-(3-(2-amino-2-oxoethyl)-1-(4- methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4- (trifluoromethyl)phenyl)-carbamate (350 mg, 0.525 mmol) in DCM (3.5 mL) were added TFA (10.5 mL) and triflic acid (10.5 mL) dropwise at 0 °C sequentially. After stirring at rt for 16 h, the mixture was diluted with DCM (300 mL) and ice water (50 mL) and then neutralized with sat. NaHCO3. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue triturated with pentane (2 × 10 mL) to afford 2-(2-oxo-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)acetamide (180 mg, 66%). MS (LCMS) m/z 447.37 [M+H]+. [0249] To a stirred solution of 2-(2-oxo-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-yl)acetamide (100 mg, 0.220 mmol) in DCM (2 mL) were added triflic anhydride (1.0 mL) and Et3N (1.0 mL) at -50 °C. After stirring at rt for 16 h, the mixture was diluted with DCM (10 mL), washed with brine, dried over MgSO4 and concentrated. The residue was purified by prep-HPLC, followed by chiral SFC to afford (R)-3-(cyanomethyl)-2-oxo-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium (48) (3.0 mg, 3%) and (S)-3-(cyanomethyl)-2-oxo-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)- 1,3,4-oxadiazol-2-yl)pyrrolidin-1-ium (49) (3.0 mg, 3%). The stereochemistry of 48 and 49 are assigned arbitrarily. Preparative SFC Conditions Column/dimensions : CHIRALCEL-OX (30 × 250) mm, 5μ % CO2: : 60% % Co solvent: : 40% (MeOH) Total Flow : 100 g/min Back Pressure : 100 bar Temperature : 30 °C UV : 298 nm Solubility : MeOH [0250] Compound 48: 1H NMR (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 8.56 (s, 1H), 8.35 (dd, J = 4.4, 1.2 Hz, 1H), 7.98 (dd, J = 8.8, 1.2 Hz, 1H), 7.66 (d, J = 8.4, 2H), 7.56-7.53 (m, 1H), 7.42 (d, J = 8.4, 2H), 3.46 (t, J = 6.8, 2H), 3.39 (s, 2H), 2.82-2.76 (m, 1H), 2.46-2.44 (m, 1H); MS (LCMS) m/z 429.39 [M+H]+. [0251] Compound 49: 1H NMR (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 8.57-8.55 (br s, 1H), 8.36-8.35 (m, 1H), 7.99 (dd, J = 8.8,1.2 Hz, 1H), 7.66 (d, J = 8.4, 2H), 7.56-7.53 (m, 1H), 7.42 (d, J = 8.4, 2H), 3.46 (t, J = 6.4, 2H), 3.39 (s, 2H), 2.82-2.76 (m, 1H), 2.50-2.49 (m, 1H); MS (LCMS) m/z 429.39 [M+H]+. Example 50 (R)-2-oxo-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3- vinylpyrrolidine-1-carbonitrile (50)
Figure imgf000137_0001
[0252] To a stirred solution of (R)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin- 2-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (10B) (150 mg, 0.361 mmol) in acetonitrile (3 mL) was added Cs2CO3 (294 mg, 0.904 mmol) at rt. The mixture was stirred for 1 h, cooled to 0 °C and cyanogen bromide (96 mg, 0.90 mmol) was added. After stirring at rt for 16 h, the mixture was filtered and washed with dichloromethane. The combined filtrates were concentrated. The residue was purified by silica gel column chromatography using 55% ethyl acetate in petroleum ether as an eluent, followed by chiral SFC to afford (R)-2-oxo-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidine-1- carbonitrile (50) (10 mg, 6%). Preparative SFC Conditions Column/dimensions : Chiralcel OX-H (30 x 250) mm, 5μ %CO2 : 50% %Co solvent : 50% (ACN) Total Flow : 100g/min Back Pressure : 100 bar Temperature : 30 °C UV : 295 nm Solubility : ACN [0253] Compound 50: 1H NMR (400 MHz, DMSO-d6): δ 9.25 (br s, 1H), 8.34 (dd, J = 4.4, 1.2 Hz, 1H), 8.34 (dd, J = 8.8, 1.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.57-7.54 (m, 1H), 7.42 (d, J = 8.8 Hz, 2H), 6.27-6.20 (m, 1H), 5.56 (d, J = 10.8 Hz, 1H), 5.42 (d, J = 17.6 Hz, 1H), 4.03- 3.93 (m, 2H), 3.03-2.97 (m, 1H), 2.78-2.72 (m, 1H). MS (LCMS) m/z 439.24 [M-H]-. Examples 51 and 52 (R)-3-(5-(3-(((1S,3R)-3-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)- 3-vinylpyrrolidin-2-one (51) and (R)-3-(5-(3-(((1R,3S)-3- (trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (52)
Figure imgf000138_0001
[0254] To a stirred solution of ethyl 1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carboxylate (241 g, 0.869 mol) in MeOH (1.5 L) was added NH2NH2•H2O (435 g, 8.69 mol) at 20 °C. After stirring at 90 °C for 2 h, the mixture was concentrated. The residue was triturated with 1.0 L of n-heptane at t for 30 min and then filtered to afford 1-(4-methoxybenzyl)-2- oxopyrrolidine-3-carbohydrazide (223 g, 97%). 1H NMR (400 MHz, D2O): δ 7.15 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.31 (dd, J = 23.4, 14.8 Hz, 2H), 3.71 (s, 3H), 3.42 (m, 1H), 3.36- 3.22 (m, 2H), 2.22-2.04 (m, 2H). [0255] To a stirred mixture of 1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carbohydrazide (201 g, 763 mmol) and 3-bromopicolinic acid (140 g, 694 mmol) in MeCN (2.8 L), were added EDCI (200 g, 1.04 mol), HOBT (141 g, 1.04 mol) and TEA (140 g, 1.39 mol) at 20 ℃. After stirring at 20 ℃ for 16 h, the mixture was concentrated, and water (2L) added. The resulting precipitates were collected by filtration. The solids were suspended in EtOAc (2.0 L), 1N HCl (300 mL) was then added. The mixture was stirred for 45 min and filtered. The filter cake washed with 1M aq. HCl (2 X) and dried to afford solid A. The combined filtrates were saturated with solid NaCl, extracted with EtOAc (4x). The combined organic layers were washed with 1N HCl (3x), dried over MgSO4, filtered, and concentrated to give solid B. The combined solids (solids A and B) were triturated with n-heptane (1.0 L) at rt for 30 min, filtered and dried to afford 3-bromo-N'-(1-(4-methoxybenzyl)-2-oxopyrrolidine-3-carbonyl)picolinohydrazide (268 g, 86%). 1H NMR (400 MHz, CDCl3): δ 10.11-10.01 (m, 2H), 8.55-8.54 (m, 1H), 8.07-8.05 (m, 1H), 7.34-7.28 (m, 1H), 7.20-7.17 (m, 2H), 6.89-6.86 (m, 2H), 4.43 (dd, J = 26.8, 14.5 Hz, 2H), 3.81 (s, 3H), 3.64-3.59 (m, 1H), 3.35-3.24 (m, 2H), 2.49-2.32 (m, 2H). [0256] To a stirred solution of 3-bromo-N'-(1-(4-methoxybenzyl)-2-oxopyrrolidine-3- carbonyl)picolinohydrazide (268 g, 598 mmol) in DCM (2.6 L) at 0 °C were added TEA (182 g, 1.80 mol) and TsCl (137 g, 718 mmol) portion wise. After stirring at 20 °C for 16 h, the reaction was quenched with water (1.0 L). The mixture was extracted with DCM (3x), and the combined organic layers washed with brine, dried over MgSO4, filtered and concentrated. The resulting concentrate was triturated with n-heptane:EtOAc (2:1, 1.0 L), filtered and dried to afford 3-(5-(3- bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (241 g, 94%). 1H NMR (400 MHz, CDCl3): δ 8.75 (dd, J = 4.5, 1.4 Hz, 1H), 8.13 (dd, J = 8.2, 1.4 Hz, 1H), 7.35 (dd, J = 8.2, 4.6 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 6.90-6.87 (d, J = 7.8 Hz, 2H), 4.52-4.42 (dd, J = 24.0, 14.5 Hz, ,2H), 4.22 (t, J = 8.5 Hz, 1H), 3.82 (s, 3H), 3.53-3.48 (m, 1H), 3.41-3.35 (m, 1H), 2.67-2.54 (m, 2H). [0257] To a stirred solution of 3-(5-(3-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4- methoxybenzyl)pyrrolidin-2-one (119 g, 278 mmol) in DMF (1.2 L) at 0 °C was added NaH (22.2 g, 555 mmol, 60% by wt) portion wise. The mixture was stirred for 30 min, and then 1,2- dibromoethane (104 g, 554 mmol) was added. After stirring at 20 °C for 16 h, the reaction was quenched with water (1.2 L) and extracted with EtOAc (6 x 500 mL). The combined organic layers were washed with brine (3x), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (heptane:EA=3:1 to 1:3) to afford 3-(2-bromoethyl)- 3-(5-(3-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (94.8 g, 64%). This material was used directly in the subsequent step. [0258] To a stirred solution of 3-(2-bromoethyl)-3-(5-(3-bromopyridin-2-yl)-1,3,4- oxadiazol-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (94.8 g, 177 mmol) in toluene (900 mL) at 0 °C was added DBU (53.8 g, 353 mmol) dropwise. After stirring at 80 °C for 16 h, the mixture was diluted with water (500 mL) and then extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2x), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (heptane:EtOAc = 3:1 to 1:3) to afford 3-(5-(3-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-vinylpyrrolidin-2-one (44.6 g, 55%). 1H NMR (400 MHz, CDCl3): δ 8.74 (d, J = 4.6, 1.4 Hz, 1H), 8.11 (d, J = 8.2, 1.4 Hz, 1H), 7.36-7.33 (m, 1H), 7.19 (d, J = 6.7 Hz, 2H), 6.86 (d, J = 6.6 Hz, 2H), 6.42 (dd, J = 17.4, 10.6 Hz, 1H), 5.46 (d, J = 10.6 Hz, 1H), 5.43 (d, J = 17.4 Hz, 1H), 4.54 (d, J = 14.6 Hz, 1H), 4.38 (d, J = 14.6 Hz, 1H), 3.81 (s, 3H), 3.45-3.44 (m, 1H), 3.33-3.31 (m, 1H), 3.00-2.98 (m, 1H), 2.48 (m, 1H). MS (LCMS) m/z 454.8 [M+H]+. [0259] 3-(5-(3-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-3- vinylpyrrolidin-2-one (40 g) was subjected to chiral SFC to afford (S)-3-(5-(3-bromopyridin-2- yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)-3-vinylpyrrolidin-2-one (18 g, 98% ee, 99.7% chemical purity) and (R)-3-(5-(3-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1-(4-methoxybenzyl)- 3-vinylpyrrolidin-2-one (17 g, 97% ee, 97.2% chemical purity). Preparative SFC Conditions Instrument : Waters 200 preparative SFC Column/dimensions : CHIRALCEL OD (50 × 250) mm, 10 μm Mobile phase : A for CO2 and B for MeOH (0.1% NH3•H2O Gradient B 50% Flow rate 160 mL/min Back Pressure : 100 bar Column temperature : 40 °C Wavelength : 210 nm Cycle time : ~ 5 min Sample preparation Compound dissolved in 1000 mL of MeOH Injection :2.5 mL per injection Analytic Chiral Conditions Instrument : Agilent 1260 with DAD or the equivalent Column/dimensions : CHIRLPAK OD (4.6 × 250) mm, 5 μm Mobile phase : A: hexane, B: EtOH Isocratic elution A:B = 60:40 (v/v) Stop time 20 min Flow rate 1.0 mL/min Column temperature : 37 °C Wavelength : 254nm Injection :2 mL [0260] To a stirred solution of (R)-3-(5-(3-bromopyridin-2-yl)-1,3,4-oxadiazol-2-yl)- 1-(4-methoxybenzyl)-3-vinylpyrrolidin-2-one (0.300g, 0.659 mmol), rac-(1R,3S)-3- (trifluoromethyl)cyclohexan-1-amine hydrochloride (0.161 g, 0.791 mmol) in PhMe (3 mL), degassed with nitrogen for 15 min, were added Cs2CO3 (0.664 g, 1.98 mmol), DPEPhos (0.070 g, 0.13 mmol) and Pd2(dba)3 (0.033 g, 0.065 mmol). The mixture was then degassed again for 10 min. After stirring at 100 °C for 16 h, the mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the filtrates were concentrated. The residue was purified by silica gel column chromatography using 45% ethyl acetate in petroleum ether to afford rac-(R)- 1-(4-methoxybenzyl)-3-(5-(3-(((1S,3R)-3-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)- 1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (0.26 g, 99%). [0261] To a stirred solution of rac-(R)-1-(4-methoxybenzyl)-3-(5-(3-(((1S,3R)-3- (trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (0.260 g, 0.480 mmol) in DCM (2.6 ml,) at 0 °C, was added TFA (7.8 ml) and triflic acid (2.6 ml). After stirring at rt for 16 h, the mixture was concentrated, neutralized with sat. NaHCO3 and extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 100% ethyl acetate as an eluent, followed by chiral SFC to afford ((R)-3-(5-(3-(((1S,3R)-3- (trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-13,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (51) (0.050g, 25%) and (R)-3-(5-(3-(((1R,3S)-3-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)- 1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (52) (0.052g, 26%). The stereochemistry of 51 and 52 are assigned arbitrarily. Preparative SFC Conditions Column/dimensions : CHIRALCEL-OX-H (30 × 250) mm,5μ % CO2 : 60% % Co solvent : 40% (ACN:MeOH, 1:1) Total Flow : 100g/min Back Pressure : 100 bar Temperature : 30 °C UV : 215 nm Solubility : ACN + MeOH [0262] Compound 51: 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (br s, 1H), 8.01 (dd, J = 4.2, 1.0 Hz, 1H), 7.50-7.37 (m, 3H), 6.30-6.23 (m, 1H), 5.46-5.40 (m, 2H), 3.67-3.69 (m, 1H), 3.43-3.40 (m, 1H), 3.29-3.28 (m, 1H), 2.81-2.67 (m, 1H), 2.57-2.51 (m, 2H), 2.20-2.18 (m, 1H), 2.09-2.01 (m, 1H), 1.89-1.80 (m, 2H), 1.52-1.48 (m, 1H), 1.30-1.19 (m, 3H). LC-MS: m/z 422.38 [M+H]+. [0263] Compound 52: 1H-NMR (400 MHz, DMSO-d6): δ 8.31 (br s, 1H), 8.01 (dd, J = 4.4, 1.2 Hz, 1H), 7.49 (d, 8.0 Hz, 1H), 7.43-7.37 (m, 2H), 6.30-6.23 (m, 1H), 5.46-5.40 (m, 2H), 3.69-3.67 (m, 1H), 3.43-3.39 (m, 1H), 3.32-3.31 (m, 1H), 2.81-2.76 (m, 1H), 2.57-2.51 (m, 2H), 2.22-2.20 (m, 1H), 2.07-2.04 (m, 1H), 1.88-1.86 (m, 2H), 1.51-1.47 (m, 1H), 1.32-1.20 (m, 3H). LC-MS: m/z 422.38 [M+H]+. Example 53 (R)-3-(5-(3-((trans-4-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3- vinylpyrrolidin-2-one (53)
Figure imgf000142_0001
[0264] Compound 53 was prepared in a similar fashion to that of Compounds 51 and 52. 1H NMR (400 MHz, DMSO-d6): δ 8.31 (br s, 1H), 7.99 (d, J= 4.0, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.40-7.33 (m, 2H), 6.26-6.22 (m, 1H), 5.46-5.39 (m, 2H), 3.59-3.57 (m, 1H), 3.42-3.39 (m,
1H), 3.29-3.27 (m, 1H), 2.80-2.75 (m, 1H), 2.56-2.53 (m, 1H), 2.50-2.49 (m, 1H), 2.15-2.12 (m, 2H), 1.95-1.92 (m, 2H), 1.51-1.44 (m, 2H), 1.38- 1.32 (m, 2H). LCMS m/z 422.46 [M+H]+. Example 54 (R)-3-(5-(3-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-3- vinylpyrrolidin-2-one (54)
Figure imgf000143_0001
[0265] Compound 54 was made in a similar fashion to that of Compounds 51 and 52. 1H NMR (400 MHz, DMSO-d6): δ 8.32 (br s, 1H), 8.01 (t, J = 2.0, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.43-7.38 (m, 2H), 6.31-6.28 (m, 1H), 5.47-5.41 (m, 2H), 4.08-4.09 (m, 1H), 3.45-3.38 (m, 1H), 3.28-3.26 (m, 1H), 2.85-2.77 (m, 1H), 2.50-2.42 (m, 2H), 1.90-1.79 (m, 6H), 1.76-1.70 (m, 2H). LC-MS: m/z 422.50 [M+H]+. Examples 55 and 56 (S)-3-(5-(1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2- yl)-3-vinylpyrrolidin-2-one (55) and (R)-3-(5-(1-methyl-4-((4-(trifluoromethyl)phenyl)amino)- 1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (56)
Figure imgf000143_0002
142
Figure imgf000144_0001
[0266] To a stirred solution of 1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3- carboxylic acid (3.00 g, 10.9 mmol) in DCM (30 mL) were added tert-butyl hydrazinecarboxylate (2.16 g, 16.3 mmol), DIPEA (10.0 ml, 54.5 mmol) and HATU (4.97 g, 13.1 mmol) at rt. After stirring at rt for 16 h, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 50% ethyl acetate in petroleum ether as an eluent to afford tert-butyl 2-(1-(4-methoxybenzyl)-2-oxo-3- vinylpyrrolidine-3-carbonyl)hydrazine-1-carboxylate (3.0 g, 70%). MS (LCMS): m/z 388.32 [M- H]-. [0267] To a stirred solution of tert-butyl 2-(1-(4-methoxybenzyl)-2-oxo-3- vinylpyrrolidine-3-carbonyl)hydrazine-1-carboxylate (0.90 g, 3.1 mmol) in TFA (27 mL) was added triflic acid (4.5 mL, 2.6 mmol) at rt. After stirring at 80 °C for 2 h, the mixture was concentrated. The residue triturated with pentane (2 x 10 mL) to afford 2-oxo-3-vinylpyrrolidine- 3-carbohydrazide (1.2 g, crude), which was used directly in the next step without further purification. MS (LCMS): m/z 170.18 [M+H]+. [0268] To a stirred solution of 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H- pyrazole-3-carboxylic acid (0.300 g, 1.05 mmol) and 2-oxo-3-vinylpyrrolidine-3-carbohydrazide (1.2 g crude) in DMF (3 mL), were added DIPEA (3.88 ml, 21.0 mmol) and HATU (0.480 g, 1.26 mmol) at 0 °C. After stirring at rt for 16 h, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography using 10% methanol in DCM as an eluent to yield 1-methyl-N'-(5-oxo-3- vinylpyrrolidine-3-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3- carbohydrazide (0.40 g, 36% over two steps). MS (LCMS): m/z 435.45 [M-H]-. [0269] To a stirred solution of 1-methyl-N'-(5-oxo-3-vinylpyrrolidine-3-carbonyl)-4- ((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carbohydrazide (0.400 g, 0.917 mmol) in DCM (4 mL) were added DIPEA (0.676 g, 3.67 mmol) and Burgess reagent (0.874 g, 3.67 mmol) at rt. After stirring at rt for 16 h, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography using (5-10)% methanol in DCM, followed by chiral SFC to afford (S)-3-(5-(1- methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)-3- vinylpyrrolidin-2-one (55) (0.04 g, 10%), and (R)-3-(5-(1-methyl-4-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one, (56) (0.038 g, 9%). The stereochemistry of 55 and 56 are assigned arbitrarily. Preparative SFC Conditions Column/dimensions : CHIRALPAK-IC (30 × 250) mm, 5μ %CO2 : 55% %Co solvent : 45% (MeOH) Total Flow : 100g/min Back Pressure : 100 bar Temperature : 30 °C UV : 247 nm Solubility : MeOH + ACN [0270] Compound 55: 1H NMR (400 MHz, DMSO-d6): δ 8.24 (br s, 1H), 8.12-8.08 (m, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.20-6.13 (m, 1H), 5.39-5.32 (m, 2H), 3.97 (s, 3H), 3.29-3.22 (m, 2H), 2.67-2.59 (m, 1H), 2.49-2.46 (m, 1H); MS (LCMS) m/z 417.25 [M-H]-. [0271] Compound 56: 1H NMR (400 MHz, DMSO-d6): δ 8.24 (br s, 1H), 8.12-8.08 (m, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.20-6.13 (m, 1H), 5.39-5.33 (m, 2H), 3.97 (s, 3H), 3.29-3.22 (m, 2H), 2.67-2.59 (m, 1H), 2.49-2.42 (m, 1H); MS (LCMS) m/z 417.21 [M-H]-. [0272] To a stirred solution of methyl 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)- 1H-pyrazole-3-carboxylate (0.360 g, 1.20 mmol) in THF (2.2 mL), ethanol (2.2 mL) and H2O (2.2 mL) was added LiOH•H2O (0.151 g, 3.60 mmol) at rt. After stirring at 80 °C for 3h, the mixture was concentrated, diluted with water (10 mL), acidified with 2N HCl (~ 1.5 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carboxylic acid (0.34 g, 99%), which was used directly in the next step without further purification. MS (LCMS): m/z 284.22 [M-H]-. Example 57 (S)-3-(5-(5-fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-3-yl)-1,3,4- oxadiazol-2-yl)-3-methylpyrrolidin-2-one (57)
Figure imgf000146_0001
[0273] To a stirred solution of methyl 5-fluoro-1-methyl-1H-pyrazole-3-carboxylate (990 mg, 6.26 mmol) in DMF (5 mL) was added NBS (1.34 g, 7.51 mmol). After stirring at rt temperature, the reaction was quenched with brine (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography eluting with 0-100% EtOAc:hexane to afford methyl 4- bromo-5-fluoro-1-methyl-1H-pyrazole-3-carboxylate (1.4 g, 94%). MS (APCI) m/z 238.0 [M+H]+. [0274] To a stirred mixture of methyl 4-bromo-5-fluoro-1-methyl-1H-pyrazole-3- carboxylate (211 mg, 0.890 mmol), 4-(trifluoromethyl)aniline (172 mg, 1.07 mmol) in dioxane (5 mL) at rt were added Cs2CO3 (870 mg, 2.67 mmol), degassed with nitrogen for 1 minute, BrettPhos Pd G3 (81 mg, 0.089 mmol) and BrettPhos (47.8 mg, 0.089 mmol). After stirring at 90 °C overnight, the reaction was quenched with brine and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc:hexane to afford methyl 5- fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carboxylate (133 mg, 47%). MS (APCI) m/z 318.1 [M+H]+. [0275] To a solution of methyl 5-fluoro-1-methyl-4-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carboxylate (133 mg, 0.420 mmol) in anhydrous MeOH (5 mL) was added hydrazine hydrate (1 mL, 20 mmol). After stirring at 60 °C overnight, the mixture was concentrated, diluted with sat. NaHCO3 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc:hexane to afford 5-fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carbohydrazide (126 mg, 95%). MS (APCI) m/z 318.1 [M+H]+. [0276] To a solution of 5-fluoro-1-methyl-4-((4-(trifluoromethyl)phenyl)amino)-1H- pyrazole-3-carbohydrazide (56.0 mg, 0.177 mmol) in DMF (2 mL), were added (R)-3-methyl-2- oxopyrrolidine-3-carboxylic acid (25.3 mg, 0.177 mmol), DMAP (21.5 mg, 0.177 mmol), HATU (101 mg, 0.265 mmol) and DIPEA (0.10 mL, 0.57 mmol). After stirring at rt overnight, the mixture was diluted with sat. NaHCO3 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc:hexane to afford (R)-5-fluoro-1-methyl- N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole- 3-carbohydrazide (36 mg, 46%). MS (APCI) m/z 443.1 [M+H]+. [0277] To a stirred solution of (R)-5-fluoro-1-methyl-N'-(3-methyl-2-oxopyrrolidine- 3-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-3-carbohydrazide (36.2 mg, 0.082 mmol) in DCM (2 mL), were added 4-methylbenzene-1-sulfonyl chloride (18.7 mg, 0.10 mmol) and TEA (0.034 mL, 0.245 mmol). After stirring at rt overnight, the reaction was quenched with sat. NaHCO3 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc:hexane to afford (S)-3-(5-(5-fluoro-1-methyl-4-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2- one (57) (17.4 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ 8.13-8.08 (m, 1H), 8.08 (s, 1H), 7.48-7.38 (m, 2H), 6.77 (d, J = 8.6 Hz, 2H), 3.90 (s, 3H), 3.31-3.26 (m, 2H), 2.48-2.40 (m, 1H), 2.23-2.01 (m, 1H), 1.49 (s, 3H). MS (APCI) m/z 425.1 [M+H]+. Examples 58 and 59 (S)-3-Methyl-1-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (58) and (S)- 3-Methyl-1-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (59)
Figure imgf000148_0001
[0278] To a stirred solution of (S)-3-methyl-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (5B) (20.9 mg, 0.052 mmol) in THF (0.76 mL), were added K2CO3 (101 mg, 0.73 mmol) and 2,2,2-trifluoro- 1,1-ethanediol (0.58 mL, 5.12 mmol) at rt. After stirring at rt for 16 h, the mixture was extracted with EtOAc (3 x 15 mL), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (ACCQ, ACN/H2O/0.1% FA) to afford (S)-3-methyl-1-((S)- 2,2,2-trifluoro-1-hydroxyethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (58) (8.0 mg, 31%) and (S)-3-methyl-1-((R)-2,2,2-trifluoro-1- hydroxyethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (59) (9.5 mg, 36%). Compounds 58 and 59 are stereoisomers, and the shown stereochemistry is relative. The stereochemistry of 58 and 59 are assigned arbitrarily. [0279] Compound 58: 1H NMR (400 MHz, DMSO-d6): δ 9.26 (br s, 1H), 8.41-8.30 (m, 1H), 8.04-7.97 (m, 1H), 7.97-7.88 (m, 1H), 7.75-7.61 (m, J = 8.1 Hz, 2H), 7.60-7.48 (m, 1H), 7.47-7.35 (m, 2H), 5.77-5.65 (m, 1H), 3.73-3.58 (m, 2H), 2.79-2.68 (m, 1H), 2.33-2.23 (m, 1H), 1.65 (br s, 3H). MS (APCI) m/z 502.10 [M+H]+. [0280] Compound 59: 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.38-8.32 (m, 1H), 8.02-7.97 (m, 1H), 7.92 (br d, J = 5.7 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.6, 4.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 5.75-5.68 (m, 1H), 3.81-3.73 (m, 1H), 3.51-3.43 (m, 1H), 2.82-2.64 (m, 1H), 2.35-2.26 (m, 1H), 1.66 (s, 3H). MS (APCI) m/z 502.10 [M+H]+. Examples 60 and 61 (R)-3-(5-(1-Methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2- yl)-1-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3-vinylpyrrolidin-2-one (60) and (R)-3-(5-(1-Methyl- 3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-1-((R)-2,2,2- trifluoro-1-hydroxyethyl)-3-vinylpyrrolidin-2-one (61)
Figure imgf000149_0001
[0281] Compounds 60 and 61 were prepared in a similar fashion to that of Compounds 58 and 59 using Example 26 instead. Compounds 60 and 61 are stereoisomers, and the shown stereochemistry is relative. The stereochemistry of 60 and 61 are assigned arbitrarily. [0282] Compound 60: 1H NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.38 (s, 1H), 7.93 (d, J = 3.3 Hz, 1H), 7.66-7.57 (m, 4H), 6.22 (dd, J = 17.5, 10.7 Hz, 1H), 5.75-5.69 (m, 1H), 5.49-5.37 (m, 2H), 3.89 (s, 3H), 3.63-3.56 (m, J = 9.7 Hz, 1H), 3.46-3.43 (m, 1H), 2.76-2.65 (m, 2H). MS (APCI) m/z 517.10 [M+H]+. [0283] Compound 61: 1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 8.34 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.62-7.51 (m, 4H), 6.14 (dd, J = 17.5, 10.6 Hz, 1H), 5.71-5.63 (m, 1H), 5.42-5.37 (m, 1H), 5.32-5.24 (m, 1H), 3.81 (s, 3H), 3.70-3.62 (m, 1H), 3.32-3.31 (m, 1H), 2.80- 2.62 (m, 1H), 2.51-2.45 (m, 1H). MS (APCI) m/z 517.10 [M+H]+. Examples 62 and 63 (R)-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1H-pyrazol-5- yl)pyrrolidin-2-one (62) and (S)-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2- yl)-1H-pyrazol-5-yl)pyrrolidin-2-one (63)
Figure imgf000150_0001
[0284] To a stirred solution of ethyl 1-(4-methoxybenzyl)-3-methyl-2-oxopyrrolidine- 3-carboxylate (10.0 g, 34.3 mmol) and tert-butyl acetate (9.272 mL, 68.647 mmol) in anhydrous PhMe (50 mL) at -40 °C, was added 1M LiHMDS in THF (103 mL, 103 mmol) dropwise. After stirring at rt for 4 h, the mixture was cooled to 0 °C. The reaction was quenched with sat. NH4Cl (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford tert-butyl 3-(1-(4- methoxybenzyl)-3-methyl-2-oxopyrrolidin-3-yl)-3-oxopropanoate (12.0 g), which was used in the next step without further purification. MS (LCMS) m/z 360.27 [M-H]-. [0285] To a stirred solution of the tert-butyl 3-(1-(4-methoxybenzyl)-3-methyl-2- oxopyrrolidin-3-yl)-3-oxopropanoate (16.0 g, 44.3 mmol) in PhMe (80 mL) was added p-TSA (7.61 g, 44.3 mmol). After stirring at 90 °C for 16 h, the mixture was concentrated, neutralized with sat. NaHCO3 and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, concentrated and the residue was purified by silica gel flash column chromatography using 48% ethyl acetate in petroleum ether as an eluent to afford 3-acetyl-1-(4- methoxybenzyl)pyrrolidin-2-one (6.0 g, 51%). MS (LCMS) m/z 262.26 [M+H]+. [0286] To a solution of 3-acetyl-1-(4-methoxybenzyl)-3-methylpyrrolidin-2-one (5.00 g, 19.1 mmol) in anhydrous THF (50 mL) at -78 °C was added 1M LiHMDS in THF (57 mL, 57 mmol). The mixture was stirred at -78 °C for 20 min. Methyl 3-bromopicolinate (8.00 g, 38.3 mol) was added and the mixture was stirred at the same temperature for 30 min. After stirring at 0 °C for 2.5 h, the reaction was quenched with sat. NH4Cl (100 mL) and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 1-(3-bromopyridin-2-yl)-3-(1-(4-methoxybenzyl)-3- methyl-2-oxopyrrolidin-3-yl)propane-1,3-dione (10.0 g), which was used in the next step without further purification. MS (LCMS) m/z 447.39 [M+2+H]+. [0287] To a stirred solution of 1-(3-bromopyridin-2-yl)-3-(1-(4-methoxybenzyl)-3- methyl-2-oxopyrrolidin-3-yl)propane-1,3-dione (2.00 g, 4.50 mmol) in methanol (30 mL) at 0 °C were added hydrazine monohydrate (10 mL) and acetic acid (1 ml). After stirring at 70 °C for 16 h, the mixture was concentrated, diluted with ice water (50 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 55% ethyl acetate in petroleum ether to afford 3-(3-(3-bromopyridin-2-yl)-1H-pyrazol-5- yl)-1-(4-methoxybenzyl)-3-methylpyrrolidin-2-one (1.00 g, 50%). MS (LCMS) m/z 443.41 [M+H]+. [0288] To a stirred solution of 3-(3-(3-bromopyridin-2-yl)-1H-pyrazol-5-yl)-1-(4- methoxybenzyl)-3-methylpyrrolidin-2-one (550 mg, 1.24 mmol) in THF (11 mL) at 0 °C, was added 60% sodium hydride (74.0 mg, 3.12 mmol)). The mixture was allowed to warm to rt, stirred for 40 min, cooled to 0 °C, and (2-(chloromethoxy)ethyl)trimethylsilane (0.57 ml, 3.1 mmol) was added. After stirring at rt for 2 h, the reaction was quenched with ice water (30 mL) and the mixture extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 45% ethyl acetate in petroleum ether to afford a mixture of 3-(3-(3- bromopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1-(4-methoxybenzyl)- 3-methylpyrrolidin-2-one and 3-(5-(3-bromopyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-3-yl)-1-(4-methoxybenzyl)-3-methylpyrrolidin-2-one (0.25 g). MS (LCMS) m/z 571.86 [M+H]+. [0289] To a stirred solution of 3-(3-(3-bromopyridin-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1-(4-methoxybenzyl)-3-methylpyrrolidin-2-one (1.20 g, 2.10 mmol) and 4-(trifluoromethyl)aniline (0.338 g, 2.10 mmol) in 1,4-dioxane (18 mL), degassed with nitrogen for 15 min, were added Cs2CO3 (2.05 g, 6.29 mmol), Xantphos (0.243 g, 0.420 mmol) and Pd2(dba)3 (0.192 g, 0.210 mmol), degassed again for 10 min. After stirring at 100 °C for 16 h, the mixture was filtered through a pad of Celite and the filter cake washed with ethyl acetate (2 x 40 mL). The combined filtrates were dried over MgSO4, concentrated and the residue was purified by silica gel column chromatography using 40% ethyl acetate in petroleum ether to afford a mixture of 1-(4-methoxybenzyl)-3-methyl-3-(3-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)pyrrolidin-2-one and 1-(4-methoxybenzyl)-3-methyl-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3- yl)pyrrolidin-2-one (0.8 g). MS (LCMS) m/z 650.29 [M-H]-. [0290] To a stirred mixture of 1-(4-methoxybenzyl)-3-methyl-3-(3-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)pyrrolidin-2-one and 1-(4-methoxybenzyl)-3-methyl-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3- yl)pyrrolidin-2-one] (0.130 g, 0.200 mmol) in THF (1.3 ml) at rt was added tetrabutylammonium fluoride (1M solution in THF) (2.6 mL). After stirring at 80 °C for 16 h, the mixture was concentrated, diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 40% ethyl acetate in petroleum ether to afford 1-(4-methoxybenzyl)-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)- 1H-pyrazol-5-yl)pyrrolidin-2-one (0.050g, 48%). MS (LCMS) m/z 522.07 [M+H]+. [0291] To a stirred solution of 1-(4-methoxybenzyl)-3-methyl-3-(3-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1H-pyrazol-5-yl (0.0700 g, 0.134 mmol) in toluene (1.14 ml) at 0 °C was added p-TSA (0.300g, 2.01mmol). After stirring at 100 °C for 5 h, the mixture was concentrated, neutralized with 10% aq. NaHCO3 and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 7% methanol in dichloromethane, followed by chiral SFC to afford (R)-3-methyl-3-(3-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1H-pyrazol-5-yl)pyrrolidin-2-one (62) (9.4 mg, 17%) and (S)-3-methyl-3-(3-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1H-pyrazol-5- yl)pyrrolidin-2-one (63) (11.3 mg, 21% ). Compounds 62 and 63 are enantiomers, and the shown stereochemistry is relative. The stereochemistry of 62 and 63 are assigned arbitrarily. Preparative Chiral SFC Conditions Column/dimensions : CHIRALPAK-AD-H (30 × 250) mm, 5µ % CO2 : 70% % Co solvent : 30% (0.2% isopropylamine in isopropanol) Total Flow : 100 g/min Back Pressure : 100 bar Temperature : 30 °C Solubility : ACN UV : 308 nm [0292] Compound 62: 1H NMR (400 MHz, DMSO-d6): δ 13.12 (br s, 1H), 10.05 (br s, 1H), 8.22 (s, 1H), 7.86-7.82 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.22 – 7.30 (m, 3H), 6.80 (s, 1H), 3.28-3.26 (m, 2H), 2.52-2.51 (m, 1H), 2.17-2.13 (m, 1H), 1.45 (s, 3H). MS (LCMS): m/z 402.73 [M+H]+. [0293] Compound 63: 1H NMR (400 MHz, DMSO-d6): δ 13.15 (br s, 1H), 10.13 (br s, 1H) 8.20 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.62-760 (m, 2H), 7.29-7.20 (m, 2H), 6.83 (s, 1H), 3.28-3.26 (m, 2H), 2.54-2.51 (m, 1H), 2.17-2.05 (m, 1H), 1.46 (s, 3H). MS (LCMS): m/z 402.73 [M+H]+. [0294] Examples 64-70 were prepared using similar procedures as shown for Examples 1, 2, 5 and 15 by changing the starting materials that are readily commercially available or prepared by known and published procedures.
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Examples 71 and 72 (R)-3-(fluoromethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one (71) and (S)-3-(fluoromethyl)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (72)
Figure imgf000158_0001
[0295] To a stirred solution of tert-butyl (2-(5-(1-(4-methoxybenzyl)-2-oxopyrrolidin- 3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (2.00 g, 3.28 mmol) in THF (20 mL) was added 1.4M LiHMDS in THF (3.51 mL, 4.92 mmol) dropwise at -78 ℃. The mixture was stirred at -78 ℃ for 30 min, followed by the addition of a solution of paraformaldehyde (1.477 g, 49.26 mmol) in THF (5 mL). The mixture was warmed up to 0 ℃ and then stirred at 0 ℃ for 2 h. The reaction was quenched with sat. NH4Cl (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography (Hex:EtOAc 1:3) to afford tert-butyl (2-(5-(3-(hydroxymethyl)-1-(4-methoxybenzyl)-2- oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)carbamate (1.7 g, 81%). MS (LCMS) m/z 584.62 [M-56]-. [0296] To a stirred solution of tert-butyl (2-(5-(3-(hydroxymethyl)-1-(4- methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4- (trifluoromethyl)phenyl)carbamate (1.00 g, 1.56 mmol) in DCM (10 mL) was added DAST (1.27 g, 7.82 mmol) portion wise at 0 ℃. The mixture was warmed up to rt and then stirred at rt for 16 h. The reaction was quenched with ice-cold water (50 mL) and then extracted with DCM (3 x 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography to afford tert-butyl (2- (5-(3-(fluoromethyl)-1-(4-methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3- yl)(4-(trifluoromethyl)phenyl)carbamate (0.53 g, 53%). MS (LCMS) m/z 642.76[M+H]+. [0297] To a stirred solution of tert-butyl (2-(5-(3-(fluoromethyl)-1-(4- methoxybenzyl)-2-oxopyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)(4- (trifluoromethyl)phenyl)carbamate (0.530 g, 0.826 mmol) in DCM (5.3 mL) was added TFA (15.9 mL) and triflic acid (0.36 mL, 4.13 mmol) at 0 ℃. The mixture was warmed up to rt and then stirred at rt for 24 h. The mixture was concentrated and neutralized with sat. NaHCO3 and then extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography (MeOH:DCM, 1:20), followed by chiral SFC to afford (R)-3-(fluoromethyl)-3-(5-(3-((4- (trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (71) (40 mg; 28%), and (S)-3-(fluoromethyl)-3-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyridin-2-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (72) (40 mg; 28%). The stereochemistry of 71 and 72 are assigned arbitrarily. Preparative SFC Conditions: Column/dimensions : CHIRALPACK- IJ (30 × 250 mm), 5μ % CO2 : 60% %Co solvent : 40 % (MeOH) Total Flow : 100 g/min Back Pressure : 100 bar Temperature : 30 °C UV : 220 nm Solubility : ACN [0298] Compound 71: 1H NMR (400 MHz, DMSO-d6) δ 9.24 (br s, 1H), 8.47 (br s, 1H), 8.36 (dd, J = 5.6, 1.2 Hz, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d, J = 8.4, 2H), 7.55 (dd, J = 8.8, 4.4 Hz, 1H), 7.41 (d, J = 8.4, 2H), 5.08-4.90 (m, 2H), 3.49-3.38 (m, 2H), 2.80-2.74 (m, 1H), 2.62-2.57 (m, 1H). MS (LCMS) m/z 422.21 [M+H]+. HPLC: 98.87%. Chiral HPLC: 99.94% (RT: 5.88 min). [0299] Compound 72: 1H NMR (400 MHz, DMSO-d6) δ 9.24 (br s, 1H), 8.47 (br s, 1H), 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.68 (d, J = 8.4, 2H), 7.55 (dd, J = 8.8, 4.4 Hz, 1H), 7.41 (d, J = 8.4, 2H), 5.09-4.91 (m, 2H), 3.47-3.38 (m, 2H), 2.80-2.74 (m, 1H), 2.67-2.54 (m, 1H). MS (LCMS) m/z 422.39 [M+H]+. HPLC: 98.18%. Chiral HPLC: 99.86% (RT: 8.19 min). Example 73 (R)-3-(5-(1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4- oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (73)
Figure imgf000160_0001
[0300] To a stirred mixture of ethyl 3-iodo-1H-pyrazole-4-carboxylate (2.00 g, 7.52 mol) in DMF (20 mL) were added NaH (1.00 g, 45.1 mmol) and CF2Br3 (4.0 mL, 45 mmol) at - 10 °C. The mixture was warmed up to rt and then stirred at rt for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with a brine solution (2 x 100 mL). After separation, the organic layer was dried over MgSO4, filtered and concentrated. The residue purified by flash column silica gel chromatography using 10% EtOAc in petroleum ether to afford a mixture of two regioisomers [ethyl 1-(bromodifluoromethyl)-3-iodo-1H-pyrazole-4-carboxylate and ethyl 1- (bromodifluoromethyl)-5-iodo-1H-pyrazole-4-carboxylate] (2.1 g, 71%). 1H NMR (400 MHz, CDCl3) 8.22 (s, 0.62H), 8.11 (s, 0.38H), 4.38-4.33 (m, 2H), 1.41-1.36 (m, 3H). MS (LCMS): m/z 394.85 [M+H]+. [0301] To a stirred solution of [ethyl 1-(bromodifluoromethyl)-5-iodo-1H-pyrazole-4- carboxylate and ethyl 1-(bromodifluoromethyl)-3-iodo-1H-pyrazole-4-carboxylate] (2.00 g, 5.08 mmol) in DCM (20 mL) was added AgBF4 (5.90 g, 30.5 mmol) at -0 °C. The mixture was warmed up to rt and then stirred at rt for 16 h. The mixture was diluted with DCM (100mL) and washed with brine (2 x 50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue purified by silica gel flash column chromatography using 5-10% EtOAc in petroleum ether to afford a mixture of [ethyl 3-iodo-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate and ethyl 5- iodo-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate] (1.2 g, 71%). 1H NMR (400 MHz, CDCl3) 8.21-8.09 (s & s, 1H), 4.39-4.33 (m, 2H), 1.41-1.36 (m, 3H). MS (LCMS): m/z 334.05 [M+H]+. [0302] To a stirred mixture of [ethyl 3-iodo-1-(trifluoromethyl)-1H-pyrazole-4- carboxylate and ethyl 5-iodo-1-(trifluoromethyl)-1H-pyrazole-4-carboxylate] (1.20 g, 3.60 mmol) in dioxane (10 mL) were added 4-(trifluoromethyl)aniline (1.16 g, 7.21 mmol) and Cs2CO3 (3.50 g, 10.8 mmol). The mixture degassed with N2 for 5 min, followed by Xantphos (416 mg, 0.720 mmol) and Pd(OAc)2 (81 mg, 0.36 mmol). After the mixture was stirred at 130 °C for 16 h, it was cooled down to rt, diluted with EtOAc (100 mL) and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated. The residue purified by silica gel flash column chromatography using 5-10% EtOAc in petroleum ether to afford ethyl 1-(trifluoromethyl)-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carboxylate (650 mg, 49%). 1H NMR (400 MHz, CDCl3) 8.44 (s, 1H), 8.31 (s, 1H), 7.66 (d, J = 8.4, 2H), 7.57 (d, J = 8.4, 2H), 4.40-4.33 (m, 2H), 1.41-1.34 (m, 3H). MS (LCMS): m/z 368.27 [M+H]+. [0303] To a stirred mixture of ethyl 1-(trifluoromethyl)-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carboxylate (650 mg, 1.77 mmol) in MeOH (6.5 mL) was added hydrazine hydrate (3.3 mL). After the mixture was stirred at 60 °C for 2 h, it was concentrated, and azeotropically dried with toluene (3x). The resulting crude was washed with pentane (3x) and dried under reduced pressure to afford 1-(trifluoromethyl)-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbohydrazide (580 mg, 92%). MS (LCMS): m/z 354.41 [M+H]+ [0304] To a stirred solution of 1-(trifluoromethyl)-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbohydrazide (500 mg, 1.42 mmol) in THF (10 mL) were added (S)-1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carboxylic acid (584 mg, 2.12 mmol), 50% T3P in EtOAc (0.70 mL, 2.1 mmol) and DIPEA (0.80 mL, 4.2 mmol). After the mixture was stirred at rt for 16 h, it was diluted with EtOAc (50mL) and washed with brine. After separation, the organic layer was dried over MgSO4, filtered and concentrated. The residue purified by flash silica gel column chromatography using 30-74% EtOAc in petroleum ether to afford (S)-N'-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carbonyl)-1-(trifluoromethyl)-3- ((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbohydrazide (750 mg, 87%). MS (LCMS): m/z 611.62 [M+H]+. [0305] To a stirred mixture of (S)-N'-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine- 3-carbonyl)-1-(trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4- carbohydrazide (500 mg, 0.819 mmol) in DCM (5.0 mL) were added DIEA (0.50 mL, 2.4 mmol) and Burgess reagent (780 mg, 3.28 mmol). After the mixture was stirred at rt for 16 h, it was diluted with brine (20 mL) and extracted with DCM (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue purified by silica gel flash column chromatography using 20-30% EtOAc in petroleum ether to afford (R)-1-(4-methoxybenzyl)-3-(5-(1- (trifluoromethyl)-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)- 3-vinylpyrrolidin-2-one (320 mg, 66%). MS (LCMS): m/z 593.78 [M+H]+. [0306] To a stirred mixture of (R)-1-(4-methoxybenzyl)-3-(5-(1-(trifluoromethyl)-3- ((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2- one (400 mg, 0.675 mmol) in DCM (8.0 mL ) was added TFA (2.0 mL) and triflic acid (2.0 mL) at 0 °C. The mixture was warmed up to rt and then stirred at rt for 16 h. The mixture was diluted with DCM and ice water, and then neutralized with sat. NaHCO3. After extraction and separation, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue purified by prep-HPLC to afford (R)-3-(5-(1-(trifluoromethyl)-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (73) (120 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.90 (s, 1H), 8.31 (s, 1H), 7.76-7.69 (m, 4H), 6.30-6.23 (m, 1H), 5.45-5.41 (m, 2H), 3.43-3.31 (m, 1H), 3.29-3.28 (m, 1H), 2.84-2.77 (m, 1H), 2.56-2.53 (m, 1H). MS (LCMS): m/z 473.26 [M+H]+. Example 74 (R)-3-(5-(1-(Methyl-d3)-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol- 4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (74)
Figure imgf000163_0001
[0307] To a stirred mixture of ethyl (S)-1-(4-methoxybenzyl)-2-oxo-3- vinylpyrrolidine-3-carboxylate (500 mg, 2.73 mmol) in THF (2.5 mL), EtOH (2.5 mL) and water (2.5 mL) was added NaOH (109 mg, 2.73 mmol) at 0 °C. After the mixture was stirred at 0 °C for 2 h, it was concentrated and lyophilized for 12 h to afford sodium (S)-1-(4-methoxybenzyl)-2-oxo- 3-vinylpyrrolidine-3-carboxylate (450 mg, 85% yield). 1H NMR (400 MHz, CD3OD-d4) δ 7.19 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 6.34 (dd, J = 17.6, 10.8 Hz, 1 H), 5.06-5.20 (m, 2 H), 4.43-4.55 (m, 1 H), 4.22-4.39 (m, 1 H), 3.77 (s, 3 H), 3.31-3.36 (m, 1 H), 3.12-3.15 (m, 1 H), 2.54-2.57 (m, 1 H), 1.99-2.21 (m, 1 H). [0308] To a stirred mixture of methyl 1H-pyrazole-4-carboxylate (35.0 g, 277 mmol) and aq. NaOAc (1.42 M, 1.33 L) in MeOH (1.05 L) was added Br2 (57.2 mL, 1.11 mol) dropwise at 0 °C. The mixture was warmed up to 25 °C and then stirred at 25 °C for 5 h. The reaction was quenched with sat. Na2S2O3 (1.50 L) and extracted with EtOAc (3 x 2.0 L). The combined organic layers were washed with sat. Na2S2O3, brine, dried over Na2SO4, filtered and concentrated to give methyl 3,5-dibromo-1H-pyrazole-4-carboxylate (69.0 g, 87% yield). 1H NMR (400 MHz, DMSO- d6) δ 14.62 (br s, 1 H), 3.84 (s, 3 H). LCMS (ESI+) m/z: [MH]+ 284.9. [0309] To a stirred mixture of methyl 3,5-dibromo-1H-pyrazole-4-carboxylate (59.0 g, 207 mmol) in THF (900 mL) was added NaH (9.14 g, 228 mmol, 60 wt%) portionwise at 0 °C. The mixture stirred at 0 °C for 30 min, followed by the addition of iodomethane-d3 (37.5 mL, 589 mmol). The mixture was warmed up to 25 °C and then stirred at 25 °C for 16 h. The reaction was quenched with water (300 mL) and extracted with CH2Cl2 (4 x 300 mL). The combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated to give methyl 3,5- dibromo-1-(methyl-d3)-1H-pyrazole-4-carboxylate (62.0 g, 99% yield), which was used in the next step directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ 3.79 (s, 3 H). LCMS (ESI+) m/z 301.9 [M+H]+. [0310] To a stirred mixture of methyl 3,5-dibromo-1-(methyl-d3)-1H-pyrazole-4- carboxylate (10.0 g, 33.2 mmol) in THF (100 mL) was added iPrMgCl (2 M, 33.2 mL) dropwise at -10 °C. After the mixture was stirred at -10 °C for 1 h, the reaction was quenched with H2O and then extracted with CH2Cl2 (3x). The combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography eluting with 25% ethyl acetate in petroleum ether to afford methyl 3-bromo-1-(methyl-d3)-1H- pyrazole-4-carboxylate (3.50 g, 45% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1 H), 3.74 (s, 3 H). LCMS (ESI+) m/z 222.1 [M+H]+. [0311] To a vial were added sequentially, methyl 3-bromo-1-(methyl-d3)-1H-pyrazole- 4-carboxylate (1.00 g, 4.50 mmol), 4-(trifluoromethyl)aniline (562 mg, 3.49 mmol), sodium tert- butoxide (503 mg, 5.24 mmol), di-tert-butyl(2',4',6'-triisopropyl- [1,1'-biphenyl]-2-yl)phosphane (296 mg, 0.698 mmol) tris(dibenzylideneacetonyl) bis-palladium (319 mg, 0.349 mmol) and PhMe (10 mL). After the mixture was degassed and purged with N2 (3x), it was stirred at 110 °C for 4 h and then cooled down to rt. The reaction was quenched with water (30 mL) and extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to afford methyl 1-(methyl-d3)-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carboxylate (800 mg, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1 H), 8.22 (d, J = 1.6 Hz, 1 H), 7.78 (br d, J = 8.0 Hz, 2 H), 7.60 (br d, J = 8.0 Hz, 2 H), 3.79 (s, 3 H). LCMS (ESI+) m/z 302.9 [M+H]+. 19F NMR (376 MHz, DMSO- d6) δ -59.61. [0312] To a mixture of methyl 1-(methyl-d3)-3-((4-(trifluoromethyl)phenyl)amino)- 1H-pyrazole-4- carboxylate (400 mg, 1.32 mmol) in MeOH (4 mL) and THF (0.4 mL) was added hydrazine hydrate (662 mg, 13.2 mmol) dropwise at 20 °C. After the mixture was degassed and purged with nitrogen (3x), it was stirred at 80 °C for 16 h and then cooled down to rt. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography eluting with 50% ethyl acetate in petroleum ether to afford 1-(methyl-d3)-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbohydrazide (300 mg, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.37-9.46 (m, 2 H), 8.06 (s, 1 H), 7.64-7.72 (m, 2 H), 7.54-7.62 (m, 2 H), 4.37 (br s, 2 H). LCMS (ESI+) m/z 302.8 [M+H]+. 19F NMR (376 MHz, DMSO-d6) δ -59.52. [0313] To a mixture of 1-(methyl-d3)-3-((4-(trifluoromethyl)phenyl)amino)-1H- pyrazole-4- carbohydrazide (140 mg, 0.463 mmol), sodium (S)-1-(4-methoxybenzyl)-2-oxo- 3- vinylpyrrolidine-3-carboxylate (206 mg, 0.694 mmol) in DMF (2.0 mL) were added O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (211 mg, 0.555 mmol) and Et3N (0.193 mL, 1.39 mmol) at 15 °C. The mixture was stirred at rt for 16 h. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography eluting with 50% ethyl acetate in petroleum ether to afford (S)-N'-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3-carbonyl)-1-(methyl-d3)-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbohydrazide (230 mg, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.00-10.44 (m, 1 H), 9.58 (br s, 1 H), 9.22 (br s, 1 H), 8.19 (s, 1 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.11-7.24 (m, 2 H), 6.91 (br d, J = 8.4 Hz, 2 H), 6.15 (dd, J = 17.2, 10.57 Hz, 1 H), 5.27-5.43 (m, 2 H), 4.29-4.45 (m, 2 H), 3.73 (s, 3 H), 3.24 (br dd, J = 8.4, 4.4 Hz, 1 H), 3.11-3.18 (m, 1 H), 2.53-2.60 (m, 1 H), 2.19-2.24 (m, 1 H). LCMS (ESI+) m/z 560.1 [M+H]+. 19F NMR (376 MHz, DMSO-d6) δ -59.56. [0314] To a mixture of (S)-N'-(1-(4-methoxybenzyl)-2-oxo-3-vinylpyrrolidine-3- carbonyl)-1- (methyl-d3)-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazole-4-carbohydrazide (230 mg, 0.411 mmol) in CH2Cl2 were added DIEA (0.143 mL, 0.822 mmol) and Burgess reagent (195 mg, 0.822 mmol) at 0 °C. The mixture was warmed up to 25 °C and then stirred at 25 °C for 12 h. The reaction was quenched with H2O (5 mL) and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography eluting with 50% ethyl acetate in petroleum ether to afford (R)-1-(4-methoxybenzyl)-3-(5-(1-(methyl-d3)-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (170 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 8.36 (s, 1 H), 7.50-7.79 (m, 4 H), 7.17 (d, J = 8.4 Hz, 2 H), 6.90 (d, J = 8.4 Hz, 2 H), 6.24 (dd, J = 17.6, 10.4 Hz, 1 H), 5.30- 5.44 (m, 2 H), 4.28-4.49 (m, 2 H), 3.73 (s, 3 H), 2.83 (br d, J = 5.6 Hz, 2 H), 2.62-2.69 (m, 1 H), 2.41-2.48 (m, 1 H). LCMS (ESI+) m/z 542.2 [M+H]+. 19F NMR (376 MHz, DMSO-d6) δ -59.61. [0315] To a stirred mixture of (R)-1-(4-methoxybenzyl)-3-(5-(1-(methyl-d3)-3-((4- (trifluoromethyl)phenyl) amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (160 mg, 0.295 mmol) in CH2Cl2 (1.6 mL) were added trifluoromethanesulfonic acid (1.6 mL, 18 mmol) and TFA (1.6 mL, 21.6 mmol) at 20 °C. After the mixture was stirred at 20 °C for 12 h, it was cooled to 0 °C, neutralized with sat NaHCO3, and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography eluting with 70% ethyl acetate in petroleum ether to afford (R)-3-(5-(1-(methyl-d3)-3-((4- (trifluoromethyl)phenyl)amino)-1H- pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (74) (21.8 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1 H), 8.41 (s, 1 H), 8.25 (s, 1 H), 7.63-7.69 (m, 2 H), 7.56-7.62 (m, 2 H), 6.22 (dd, J = 17.6, 10.8 Hz, 1 H), 5.34-5.45 (m, 2 H), 3.33-3.41 (m, 2 H), 2.72-2.75 (m, 1 H), 2.50-2.70 (m, 1 H). LCMS (ESI+) m/z 422.3 [M+H]+. 19F NMR (376 MHz, DMSO-d6) δ - 59.61. Example 75 (R)-3-(5-(3-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-1-methyl-1H-pyrazol-4-yl)-1,3,4- oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (75)
Figure imgf000167_0001
[0316] To a stirred mixture of (R)-3-(5-(1-methyl-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (26) (67 mg, 0.16 mmol) in CH2Cl2:DMF (1:1) was added Selectfluor (407 mg, 1.15 mmol). After the mixture was stirred at rt for 16 h, it was diluted with brine (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue purified by silica gel column chromatography eluting with 0-100% EtOAc/hexanes, and further purified by prep-HPLC to afford (R)-3-(5-(3-((3-fluoro-4- (trifluoromethyl)phenyl)amino)-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3- vinylpyrrolidin-2-one (75) (6.1 mg, 8.7%). 1H NMR (400 MHz, CD3OD-d4) δ 8.60-8.46 (m, 1H), 8.16 (s, 1H), 7.45 (d, J = 9.8 Hz, 2H), 6.36-6.21 (m, 1H), 5.54-5.37 (m, 2H), 3.93 (s, 3H), 3.57- 3.41 (m, 2H), 3.03-2.84 (m, 1H), 2.67-2.50 (m, 1H). LC-MS (APCI) m/z 437.1 [M+1]+.
Example 76 (S)-3-ethyl-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (76)
Figure imgf000168_0001
[0317] To a mixture of (R)-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H- pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (26) (21.1 mg, 0.050 mmol) in anhydrous MeOH (2.0 mL) at rt under N2 was added Pd/C (5.4 mg, 0.05 mmol, 10% wt). After the mixture was purged with a balloon of H2, it was stirred at rt for 16 h, and then the H2 atmosphere replaced with N2. The mixture was filtered through a pad of Celite and washed with MeOH. The combined filtrates were concentrated to afford (S)-3-ethyl-3-(5-(1-methyl-3-((4- (trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (76) (11.1 mg, 49.7%). 1H NMR (DMSO-d6) δ: 8.55 (s, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.57-7.68 (m, 4H), 4.03-4.19 (m, 1H), 3.88 (s, 3H), 3.28-3.42 (m, 1H), 2.60-2.68 (m, 1H), 2.22-2.31 (m, 1H), 2.09 (dd, J = 13.9, 7.5 Hz, 1H), 1.88 (dd, J = 13.9, 7.3 Hz, 1H), 0.89 (t, J = 7.4 Hz, 3H). MS (APCI) m/z 421.20 [M+H]+. [0318] Examples 77-81 were prepared using similar procedures as shown for Examples 1-28 and 78 by changing the starting materials that are readily commercially available or prepared by known and published procedures, or prepared in this application.
Figure imgf000169_0001
Figure imgf000170_0001
Example A TEAD Reporter Assay [0319] TEAD luciferase Reporter Assay MCF-7 (BPS Bioscience, Cat#60618) cells were plated, and the following day were treated with inhibitors and 0.1% v/v DMSO. After 24 h incubation with the inhibitor, luciferase activity was evaluated using Firefly luciferase reagent (Promega, E1501). Plates were read on a M5e plate reader (Molecular Devices) using luciferase assay protocol. The potency of compounds was determined by IC50 value generated with GraphPad Prism software. The results are provided in Table 1, and demonstrate that Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are inhibitors of TEAD. Table 1
Figure imgf000171_0001
Figure imgf000171_0002
Figure imgf000171_0003
Figure imgf000172_0003
Figure imgf000172_0002
Figure imgf000172_0001
A: <15 nM; B: >15 and < 25 nM; C: >25 nM and <100 nM; D: >100 nM and <1000 nM; E: >1000 nM and <3000 nM; F >3000 nM Example B Solubility [0320] Solubility was determined at pH 7.4. Several compounds showed superior solubility compared to (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one, which is a desirable drug property as shown in Table 2. Table 2
Figure imgf000172_0004
[0321] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the disclosure provided herein.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically salt thereof, wherein the compound has the structure:
Figure imgf000173_0001
wherein: Ring A is an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted bicyclic heteroaryl or an unsubstituted or a substituted bicyclic heterocyclyl, wherein when the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl is substituted, the phenyl, the monocyclic heteroaryl, the monocyclic heterocyclyl, the bicyclic heteroaryl or the bicyclic heterocyclyl is substituted with one or more substituents selected from the group consisting of –F, –Cl, –CN, an unsubstituted C1- 6 alkyl, a deuterium-substituted C1-6 alkyl, hydroxy, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkyl; X1 is absent, –(CH2)n–NR3a–, –O–, –S–, –S(O)–, –S(=O)2– or –C(R4R5)–; X2, X3, and X4 are independently N, NR3b, O, S, or CR3c; R1 is an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl, wherein when the cycloalkyl, the aryl, the heteroaryl and the heterocyclyl is substituted, the aryl, the heteroaryl and the heterocyclyl is substituted with one or more substituents selected from the group consisting of –F, –Cl, –CF3, –CH2CF3, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkoxy; R2 is an unsubstituted or a substituted C3-C10 cycloalkyl, an unsubstituted or a substituted C2-C10 heterocyclyl,
Figure imgf000173_0002
R3a, R3b and R3c are independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; R4 and R5 are independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; or R4 and R5 are taken together to form an unsubstituted or a substituted C3-8 cycloalkyl, wherein the substituted cycloalkyl is substituted 1 to 6 times with a substituent independently selected from the group consisting of halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl; R6 is hydrogen, –F, –Cl, –CN, an unsubstituted or a substituted C3-6 cycloalkyl, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C2-C6 alkenyl, an unsubstituted or a substituted C2-6 alkynyl, an unsubstituted or a substituted C1-C6 haloalkyl, an unsubstituted or a substituted C1-6 alkoxy, an unsubstituted or a substituted hydroxyalkyl or an unsubstituted or a substituted aminoalkyl; R7 is hydrogen, cyano, an unsubstituted or a substituted C1-C6 alkyl, an unsubstituted or a substituted C1-C6 haloalkyl or an unsubstituted or a substituted hydroxyalkyl; Y1 is –CH2–, –CH2CH2–, –O–, –OCH2–, –CF2–, –CHF– or –C(CH3)2–; R8 is hydrogen, –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl; and R9 is hydrogen, –F, –CN, an unsubstituted or a substituted C1-C6 alkyl or an unsubstituted C1-C6 haloalkyl; or R8 and R9 are taken together to form an unsubstituted or a substituted monocyclic cycloalkyl or an unsubstituted monocyclic heterocyclyl, wherein the substituted monocyclic cycloalkyl is substituted 1 to 6 times with a substituent independently selected from the group consisting of halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl; and R10 and R11 are independently hydrogen or an unsubstituted or a substituted C1-C6 alkyl; or R10 and R11 are taken together to form an unsubstituted or a substituted 3- to 8-membered heterocyclyl; n is 0 or 1; and provided that
Figure imgf000174_0001
is aromatic; provided that R1 cannot be selected from the group consisting of an unsubstituted or a substituted cyclopropyl, an unsubstituted or a substituted cyclobutyl, an unsubstituted or a substituted cyclopentyl, an unsubstituted or a substituted oxirane, an unsubstituted or a substituted oxetane, an unsubstituted or a substituted tetrahydrofuran, an unsubstituted or a substituted 1,3- dioxolane, an unsubstituted or a substituted tetrahydropyran, an unsubstituted or a substituted 1,3- dioxane, an unsubstituted or a substituted piperidine and an unsubstituted or a substituted pyrrolidine; when Ring A is an unsubstituted or a substituted phenyl; and R1 is an unsubstituted or a substituted aryl; provided that Ring A cannot be an unsubstituted or a substituted; when X1 is NH; and R1 is an unsubstituted or a substituted tetrahydropyran; provided that R2 cannot be an unsubstituted or a substituted piperidine or an unsubstituted or a substituted pyrrolidine; and provided that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be selected from the group consisting of: (R)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one, (S)-3-methyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one, 3-methyl-3-{5-[3-(4-trifluoromethyl-phenylamino)-pyrazin-2-yl]-[1,3,4]oxadiazol-2-yl}- pyrrolidin-2-one, (3R)-3-ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-1,3,4-oxadiazol-2- yl]pyrrolidin-2-one, (3S)-3-Ethyl-3-[5-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-1,3,4-oxadiazol-2- yl]pyrrolidin-2-one, 3-ethyl-3-(5-(2-((4-(trifluoromethyl)phenyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2- yl)pyrrolidin-2-one; and
Figure imgf000175_0001
or a pharmaceutically acceptable salt of any of the foregoing.
2. The compound of Claim 1, wherein R2 is
Figure imgf000176_0001
3. The compound of Claim 2, wherein Y1 is –CH2–.
4. The compound of Claim 2, wherein Y1 is –CH2CH2–.
5. The compound of Claim 2, wherein Y1 is –O–.
6. The compound of Claim 2, wherein Y1 is –OCH2–.
7. The compound of Claim 2, wherein Y1 is –CF2–.
8. The compound of Claim 2, wherein Y1 is –CHF–.
9. The compound of Claim 2, wherein Y1 is –C(CH3)2–.
10. The compound of any one of Claims 2-9, wherein R6 is hydrogen.
11. The compound of any one of Claims 2-9, wherein R6 is –F or –Cl.
12. The compound of any one of Claims 2-9, wherein R6 is –CN.
13. The compound of any one of Claims 2-9, wherein R6 is an unsubstituted or a substituted C3-6 cycloalkyl.
14. The compound of any one of Claims 2-9, wherein R6 is an unsubstituted or a substituted C1-C6 alkyl.
15. The compound of any one of Claims 2-9, wherein R6 is an unsubstituted or a substituted C2-C6 alkenyl or an unsubstituted or a substituted C2-6 alkynyl.
16. The compound of any one of Claims 2-9, wherein R6 is an unsubstituted or a substituted C1-C6 haloalkyl.
17. The compound of any one of Claims 2-9, wherein R6 is an unsubstituted or a substituted C1-6 alkoxy.
18. The compound of any one of Claims 2-9, wherein R6 is an unsubstituted or a substituted hydroxyalkyl.
19. The compound of any one of Claims 2-9, wherein R6 is an unsubstituted or a substituted aminoalkyl.
20. The compound of any one of Claims 2-19, wherein R7 is hydrogen.
21. The compound of any one of Claims 2-19, wherein R7 is cyano.
22. The compound of any one of Claims 2-19, wherein R7 is an unsubstituted or a substituted C1-C6 alkyl.
23. The compound of any one of Claims 2-19, wherein R7 is an unsubstituted or a substituted C1-C6 haloalkyl.
24. The compound of any one of Claims 2-19, wherein R7 is an unsubstituted or a substituted hydroxyalkyl.
25. The compound of Claim 1, wherein R2 is
Figure imgf000177_0001
26. The compound of Claim 25, wherein R8 is hydrogen.
27. The compound of Claim 25, wherein R8 is –F.
28. The compound of Claim 25, wherein R8 is –CN.
29. The compound of Claim 25, wherein R8 is an unsubstituted or a substituted C1-C6 alkyl.
30. The compound of Claim 25, wherein R8 is an unsubstituted C1-C6 haloalkyl.
31. The compound of any one of Claims 25-30, wherein R9 is hydrogen.
32. The compound of any one of Claims 25-30, wherein R9 is –F.
33. The compound of any one of Claims 25-30, wherein R9 is –CN.
34. The compound of any one of Claims 25-30, wherein R9 is an unsubstituted or a substituted C1-C6 alkyl.
35. The compound of any one of Claims 25-30, wherein R9 is an unsubstituted C1-C6 haloalkyl.
36. The compound of Claim 25, wherein R8 and R9 are taken together to form an unsubstituted or a substituted monocyclic cycloalkyl, wherein the substituted monocyclic cycloalkyl is substituted 1 to 6 times with a substituent independently selected from the group consisting of halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl.
37. The compound of Claim 25, wherein R8 and R9 are taken together to form an unsubstituted monocyclic heterocyclyl,
38. The compound of any one of Claims 25-37, wherein R10 is hydrogen.
39. The compound of any one of Claims 25-37, wherein R10 is an unsubstituted or a substituted C1-C6 alkyl.
40. The compound of any one of Claims 25-39, wherein R11 is hydrogen.
41. The compound of any one of Claims 25-39, wherein R11 is an unsubstituted or a substituted C1-C6 alkyl.
42. The compound of any one of Claims 25-37, wherein R10 and R11 are taken together to form an unsubstituted or a substituted C3-8 cycloalkyl.
43. The compound of any one of Claims 1-42, wherein
Figure imgf000178_0001
is selected from the group consisting of imidazole, pyrazole, oxazole, 1,3,4-oxadiazole, triazole and 1,3,4- thiadiazole.
44. The compound of any one of Claims 1-42, wherein X2 is CR3c; X3 is N; and X4 is NH.
45. The compound of any one of Claims 1-42, wherein X2 is CR3c; X3 is N; and X4 is O.
46. The compound of any one of Claims 1-42, wherein X2 is N; X3 is CR3c; and X4 is O.
47. The compound of any one of Claims 1-42, wherein X2 is N; X3 is N; and X4 is O.
48. The compound of any one of Claims 1-42, wherein X2 is CR3c; X3 is N; and X4 is S.
49. The compound of any one of Claims 1-42, wherein X2 is N; X3 is N; and X4 is S.
50. The compound of any one of Claims 1-42, wherein X2 is NR3b; X3 is N; and X4 is CR3c.
51. The compound of any one of Claims 1-50, wherein Ring A is an unsubstituted or a substituted phenyl.
52. The compound of any one of Claims 1-50, wherein Ring A is an unsubstituted or a substituted monocyclic heteroaryl.
53. The compound of any one of Claims 1-50, wherein Ring A is an unsubstituted or a substituted monocyclic heterocyclyl.
54. The compound of any one of Claims 1-50, wherein Ring A is an unsubstituted or a substituted bicyclic heteroaryl.
55. The compound of any one of Claims 1-50, wherein Ring A is an unsubstituted or a substituted bicyclic heterocyclyl.
56. The compound of any one of Claims 1-50, wherein Ring A is selected from the group consisting of pyridine, pyrazole, triazole and imidazole.
57. The compound of any one of Claims 1-50, wherein Ring A is selected from the group consisting of 1H-indazole and pyrazolo[1,5-a]pyridine.
58. The compound of any one of Claims 1-50, wherein Ring A is selected from the group consisting of pyridin-2-one and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole.
59. The compound of any one of Claims 51-58, wherein Ring A is unsubstituted.
60. The compound of any one of Claims 51-58, wherein Ring A is substituted, Ring A is substituted with one or more substituents selected from the group consisting of –F, –Cl, –CN, an unsubstituted C1-6 alkyl, a-deuterium substituted C1-6 alkyl, hydroxy, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkyl.
61. The compound of any one of Claims 1-50, wherein Ring A is selected from the group consisting of:
Figure imgf000179_0001
indicates the point of attachment to X1.
62. The compound of any one of Claims 1-50, wherein Ring A is selected from the group consisting of:
Figure imgf000179_0002
, wherein the asterisk indicates the point of attachment to X1.
63. The compound of any one of Claims 1-50, wherein Ring A is selected from the group consisting of:
Figure imgf000180_0001
, wherein the asterisk indicates the point of attachment to X1.
64. The compound of any one of Claims 1-63, wherein X1 is absent.
65. The compound of any one of Claims 1-63, wherein X1 is –NR3a–.
66. The compound of any one of Claims 1-63, wherein X1 is –O– or –S–.
67. The compound of any one of Claims 1-63, wherein X1 is –S(O)– or –S(=O)2–.
68. The compound of any one of Claims 1-63, wherein X1 is –CH2–.
69. The compound of any one of Claims 1-63, wherein X1 is –CH(an unsubstituted C1- C6 alkyl)–.
70. The compound of any one of Claims 1-63, wherein X1 is –CH(a substituted C1-C6 alkyl)–.
71. The compound of any one of Claims 1-63, wherein X1 is –C(an unsubstituted C1- C6 alkyl)2–.
72. The compound of any one of Claims 1-63, wherein X1 is –C(a substituted C1-C6 alkyl)2–.
73. The compound of any one of Claims 1-63, wherein X1 is –C(R4R5)–, wherein R4 and R5 are taken together to form an unsubstituted C3-8 cycloalkyl.
74. The compound of any one of Claims 1-63, wherein X1 is –C(R4R5)–, wherein R4 and R5 are taken together to form a substituted C3-8 cycloalkyl, wherein the substituted cycloalkyl is substituted 1 to 6 times with a substituent independently selected from the group consisting of halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl.
75. The compound of any one of Claims 1-74, wherein R1 is an unsubstituted or a substituted cycloalkyl.
76. The compound of any one of Claims 1-74, wherein R1 is an unsubstituted or a substituted aryl.
77. The compound of Claim 76, wherein R1 is an unsubstituted or a substituted phenyl.
78. The compound of any one of Claims 1-74, wherein R1 is an unsubstituted or a substituted heteroaryl.
79. The compound of any one of Claims 1-74, wherein R1 is an unsubstituted or a substituted heterocyclyl.
80. The compound of any one of Claims 75-79, wherein R1 is unsubstituted.
81. The compound of any one of Claims 75-79, wherein R1 is a substituted with one or more substituents selected from the group consisting of –F, –Cl, –CF3, –CH2CF3, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkoxy.
82. The compound of any one of Claims 1-74, wherein R1 is
Figure imgf000181_0001
; Z1, Z2, Z3, Z4 and Z5 are independently CR12 or N; and each R12 is hydrogen, –F, –Cl, –CF3, –CH2CF3, an unsubstituted C1-C6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkoxy .
83. The compound of Claim 82, wherein Z1, Z2, Z3, Z4 and Z5 are each CR12.
84. The compound of Claim 82, wherein at least one of Z1, Z2, Z3, Z4 and Z5 is N.
85. The compound of Claim 82, wherein one of Z1, Z2, Z3, Z4 and Z5 is N; and the remaining four of Z1, Z2, Z3, Z4 and Z5 are each CR12.
86. The compound of Claim 82, wherein two of Z1, Z2, Z3, Z4 and Z5 is N; and the remaining three of Z1, Z2, Z3, Z4 and Z5 are each CR12.
87. The compound of any one of Claims 1-74, wherein R1 is
Figure imgf000181_0002
; Z6, Z7, Z8, Z9 and Z10 are independently CHR13; and each R13 is hydrogen, –F, –Cl, –CF3, –CH2CF3, an unsubstituted C1-C6 alkyl, an unsubstituted C1-6 alkoxy and an unsubstituted C1-6 haloalkoxy .
88. The compound of Claim 1, wherein the compound is selected from the group consisting of:
Figure imgf000182_0001
, , , , , ,
Figure imgf000183_0001
, , , , , , , , ,
Figure imgf000184_0001
, , , , , , , ,
Figure imgf000185_0001
, , , , , , , ,
Figure imgf000186_0001
,
Figure imgf000187_0001
Figure imgf000187_0002
, or a pharmaceutically acceptable salt of any of the foregoing. 89. The compound of Claim 1, wherein the compound is selected from the group consisting of: , , ,
Figure imgf000187_0003
, , , , , , , , ,
Figure imgf000188_0001
, , , , , , , , ,
Figure imgf000189_0001
,
Figure imgf000190_0001
189
Figure imgf000191_0001
190 , , , , , ,
Figure imgf000192_0001
, , , , , ,
Figure imgf000193_0001
,
Figure imgf000194_0001
, , , , ,
Figure imgf000195_0001
, , , , , , ,
Figure imgf000196_0001
, , , , , , , , ,
Figure imgf000197_0001
, , ,
Figure imgf000198_0001
a pharmaceutically acceptable salt of any of the foregoing. 90. A pharmaceutical composition comprising an effective amount of the compound of any one of any one of Claims 1-89, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
91. Use of a compound of any one of Claims 1-89, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for ameliorating a disease, wherein the disease is selected from the group consisting of an autoimmune disorder, an inflammatory condition or a cancer.
92. The use of Claim 91, wherein the disease is selected from the group consisting of mesothelioma, renal cell carcinoma, cervical squamous cell cancer, endocervical adenocarcinoma, hepatocellular carcinoma, medulloblastoma, oral squamous cell cancer, lung squamous cell cancer, lung adenocarcinoma, schwannoma, meningioma, ependymoma, epithelioid hemangioendothelioma, luminal A breast cancer, luminal B breast cancer, colorectal cancer, uveal melanoma, pancreatic adenocarcinoma, kidney renal papillary cell carcinoma, rectum adenocarcinoma, bladder urothelial carcinoma, esophageal carcinoma, head and neck squamous cell cancer, squamous cell cancers, a cancers that is resistant to an EGFR inhibitor and a cancers that is resistant to a MEK inhibitors.
93. Use of a compound of any one of Claims 1-89, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD.
94. A method for ameliorating a disease comprising administering an effective amount of a compound of any one of Claims 1-89, or a pharmaceutically acceptable salt thereof, to a subject suffering from the disease, wherein the disease is selected from the group consisting of an autoimmune disorder, an inflammatory condition or a cancer.
95. The method of Claim 94, wherein the disease is selected from the group consisting of mesothelioma, renal cell carcinoma, cervical squamous cell cancer, endocervical adenocarcinoma, hepatocellular carcinoma, medulloblastoma, oral squamous cell cancer, lung squamous cell cancer, lung adenocarcinoma, schwannoma, meningioma, ependymoma, epithelioid hemangioendothelioma, luminal A breast cancer, luminal B breast cancer, colorectal cancer, uveal melanoma, pancreatic adenocarcinoma, kidney renal papillary cell carcinoma, rectum adenocarcinoma, bladder urothelial carcinoma, esophageal carcinoma, head and neck squamous cell cancer, squamous cell cancers, a cancers that is resistant to an EGFR inhibitor and a cancers that is resistant to a MEK inhibitors.
96. A method for inhibiting a YAP/TAZ-TEAD protein-protein interaction and/or inhibition of lipid binding to TEAD comprising contacting a cell with an effective amount of a compound of any one of Claims 1-89, or a pharmaceutically acceptable salt thereof, wherein the cell is a cancer cell.
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