WO2022263829A1 - COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY - Google Patents

COMPOUNDS AND THEIR USE FOR THE TREATMENT OF α1-ANTITRYPSIN DEFICIENCY Download PDF

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Publication number
WO2022263829A1
WO2022263829A1 PCT/GB2022/051520 GB2022051520W WO2022263829A1 WO 2022263829 A1 WO2022263829 A1 WO 2022263829A1 GB 2022051520 W GB2022051520 W GB 2022051520W WO 2022263829 A1 WO2022263829 A1 WO 2022263829A1
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Prior art keywords
halogen
optionally substituted
alkyl
independently selected
compound
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PCT/GB2022/051520
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French (fr)
Inventor
Nigel Ramsden
David John Fox
James Andrew HUNTINGTON
James Michael TOMLINSON
Jonathan Richard Heal
Joseph Michael Sheridan
Matthew William Mark EARL
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Z Factor Limited
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Publication of WO2022263829A1 publication Critical patent/WO2022263829A1/en

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/68—One oxygen atom attached in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/04—1,2,3-Triazines
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    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D413/10—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 linked by a carbon chain containing aromatic rings

Definitions

  • ⁇ 1-Antitrypsin is a member of the serpin superfamily produced by the liver and secreted into the blood. It inhibits a variety of serine proteases, especially neutrophil elastase. When blood levels of A1AT are low, excessive neutrophil elastase activity degrades lung tissue resulting in respiratory complications, such as chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • A1-antitrypsin deficiency A1AD or AATD
  • A1AT ⁇ 1-antitrypsin deficiency
  • the Z mutation the most common cause of AATD, is the substitution of glutamate to lysine at position 366 of A1AT (UniProtKB - P01009 (A1AT_HUMAN)), corresponding to position 342 in the mature protein (Z A1AT).
  • the Z mutation affects the folding of A1AT resulting in only a small fraction acquiring the native/active state. The remainder is either cleared as misfolded protein or accumulates in the liver as stable polymers.
  • homozygous carriers of the Z mutation have plasma levels of A1AT that are 10-15% of normal, predisposing carriers to COPD.
  • Accumulation of Z A1AT polymers in liver cells predisposes carriers to cirrhosis, liver cancer and other liver pathologies.
  • the current treatment for the lung manifestation of AATD involves augmentation therapy using A1AT concentrates prepared from the plasma of blood donors.
  • the US FDA has approved the use of four A1AT products: Prolastin, Zemaira, Glassia, and Aralast. Dosing is via once weekly intravenous infusion. Augmentation therapy has been demonstrated to slow progression of COPD.
  • the liver manifestations of AATD e.g.
  • cirrhosis and cancer are treated with steroids and liver transplantation.
  • Investigational approaches to improved treatment of the liver manifestations include inhibition of Z A1AT polymerization and increased clearance of polymers through the activation of autophagy.
  • Investigational approaches to improved treatment of both the lung and the liver manifestations are directed towards improvement of Z A1AT folding and secretion.
  • the present disclosure provides a compound represented by the structure of Formula (I-d): or a pharmaceutically acceptable salt thereof, wherein: each of R 1 and R 2 are independently selected from hydrogen and C 1-6 alkyl; and is a represented by: , and .
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound or salt of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d).
  • the present disclosure provides a method of inducing ⁇ 1 -antitrypsin (A1AT) comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d) or a pharmaceutically composition thereof.
  • A1AT ⁇ 1 -antitrypsin
  • the present disclosure provides a method of treating a ⁇ 1-antitrypsin deficiency comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d) or a pharmaceutically composition thereof.
  • the present disclosure provides a method of treating a ⁇ 1 -antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (II) or a pharmaceutical composition of Formula (II), wherein, R 1 is selected from C3-6 carbocycle and 6- to 12-membered bicyclic heteroaryl, any of which are optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; and Ring is selected from a 5- to 6-membered saturated heterocycle.
  • the administering induces ⁇ 1 -antitrypsin (A1AT) in the subject in need thereof.
  • A1AT ⁇ 1 -antitrypsin
  • Cx-y when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C 1-6 alkyl refers to saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • –Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • –C 1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • Cx-yalkenyl and “Cx-yalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the term –Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain.
  • – C 2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted.
  • An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain.
  • the term –C x-y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain.
  • alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted.
  • An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
  • Alkylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like.
  • alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • "Alkenylene” refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • Alkenylene chain refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • the term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro- ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl.
  • the carbocycle is a cycloalkenyl.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.
  • Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.
  • cycloalkyl refers to a saturated carbocycle. Exemplary cycloalkyl rings include cyclopropyl, cyclohexyl, and norbornane. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.
  • heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings.
  • the heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle.
  • Bicyclic heterocycles may be fused, bridged or spiro-ring systems.
  • the heterocycle is a heteroaryl.
  • the heterocycle is a heterocycloalkyl.
  • a heterocycle e.g., pyridyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl.
  • Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.
  • the term “heteroaryl” includes aromatic single ring structures, preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • the term “heteroaryl” also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.
  • the term “heterocycloalkyl” as used herein refers to a saturated heterocycle. Exemplary heterocycloalkyl rings include morpholinyl, piperidinyl, and piperazinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the terms "subject,” “individual,” and “patient” may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like).
  • the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context.
  • the subject may not be under the care or prescription of a physician or other health worker.
  • a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.
  • the terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration.
  • oral routes of administering a composition can be used.
  • the terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.
  • the term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein.
  • the specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • treatment refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and/or a prophylactic benefit.
  • treatment or treating involves administering a compound or composition disclosed herein to a subject.
  • a therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.
  • the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • a “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • . embodiments is .
  • . is .
  • . is . in some embodiments, .
  • A is 5-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -OC(O)N(R 11 ) 2, -C(O)N(R 11 ) 2 , - N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , -N(R 11 )S(O)2(R 11 ), -S(O)2N(R 11 )2, -NO 2 , -CN; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)OR 11 ,
  • A is 5-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -OC(O)N(R 11 ) 2, -C(O)N(R 11 ) 2 , - N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , -N(R 11 )S(O)2(R 11 ), -S(O)2N(R 11 )2, -NO 2 , -CN.
  • A is 5-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , N(R 11 )2, -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN.
  • A is 5-membered heteroaryl optionally substituted with C 1-6 alkyl.
  • A is 5-membered heteroaryl optionally substituted with C 1-3 alkyl.
  • A is 5-membered heteroaryl optionally substituted with methyl, ethyl, propyl, and isopropyl, any of which is optionally substituted.
  • A is optionally substituted 5-membered heteroaryl comprising one or more heteroatoms selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • A is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted.
  • A is selected from oxazole, isoxazole, thiazole, isothiazole, and imidazole, any one of which is optionally substituted.
  • A is selected from optionally substituted oxazole.
  • Formula (I-a) is represented by: , [0046]
  • Formula (I-a) is represented by: , and . [0051]
  • R 2 and R 3 are each independently C 1-3 alkyl optionally substituted with C6 carbocycle optionally substituted with one or more substituents selected from fluoro, chloro, and bromo.
  • the C 6 carbocycle of R 2 or R 3 is phenyl optionally substituted with one or more substituents selected from fluoro, chloro, and bromo.
  • Formula (I-a) is represented by: .
  • R ⁇ is selected from hydrogen, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl , - NO 2 , -CN, C3-6 carbocycle and 3- to 6-membered heterocycle.
  • R ⁇ is selected from hydrogen, halogen, -OH, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R ⁇ is selected from hydrogen, halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl, -NO 2 , and -CN. In some embodiments, R ⁇ is selected from C3-6 carbocycle and 3- to 6-membered heterocycle. In some embodiments, R ⁇ is selected from hydrogen, halogen, -OH, C 1-3 alkyl, and C 1-3 haloalkyl In some embodiments, R’ is selected from hydrogen and halogen; and is represented by: and . In some embodiments, is represented by: . In some embodiments, is represented by: .
  • B is a 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, - C(O)N(R 21 ) 2 , -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )S(O) 2 (R 21 ), -S(O) 2 N(R 21 ) 2 , - NO 2 , -CN; and C
  • B is a 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR 21 , -N(R 21 ) 2 , -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , - OC(O)N(R 21 ) 2, -C(O)N(R 21 ) 2 , -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )S(O) 2 (R 21 ), - S(O)2N(R 21 )2, -NO 2 , and -CN.
  • B is a 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -NO 2 , and -CN.
  • B is a 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , - OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )S(O)2(R 21 ), - S(O)2N(
  • B is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, and imidazole, any of which is optionally substituted.
  • Formula (I-b) is represented by: .
  • Formula (I-b) is represented by: and [0061]
  • R 5 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 23 , -N(R 23 )2, -C(O)R 23 , -C(O)OR 23 , -OC(O)R 23 , - OC(O)N(R 23 ) 2, -C(O)N(R 23 ) 2 , -N(R 23 )C(O)R 23 , -N(R 23 )C(O)OR 23 , - N(R 23 )S(O) 2 (R 23 ), -S(O) 2 N(R 23 ) 2 , -NO
  • R 5 is C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 23 , -N(R 23 )2, -C(O)R 23 , -C(O)OR 23 , -OC(O)R 23 , - OC(O)N(R 23 )2, -C(O)N(R 23 )2, -N(R 23 )C(O)R 23 , -N(R 23 )C(O)OR 23 , - N(R 23 )S(O)2(R 23 ), -S(O)2N(R 23 )2, -NO 2 , and -CN; and R 6 is C 1 alkyl substituted with one more substituents one or more substituents independently selected from halogen, -OR 24 , -
  • Formula (I-b) is represented by: and [0067]
  • each R ⁇ is independently selected from hydrogen, halogen, C 1-3 alkyl. In some embodiments, each R ⁇ is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, fluoro, chloro, and bromo. In some embodiments, each R ⁇ is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, fluoro, chloro, and bromo; and is represented by: and . In some embodiments, is represented by: and . In some embodiments, is represented by: . In some embodiments, is represented by: .
  • X is a 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3- triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -OC(O)N(R 31 )2, - C(O)N(R 31 )2, -N(R 31 )C(O)R 31 , -N(R 31 )C(O)OR 31 , -N(R 31 )S(O)2(R 31 ), -S(O)2N(R 31 )2, -NO
  • X is a 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3- triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , - OC(O)R 31 , -OC(O)N(R 31 ) 2, -C(O)N(R 31 ) 2 , -N(R 31 )C(O)R 31 , -N(R 31 )C(O)OR 31 , -N(R 31 )S(O) 2 (R 31 ), -S(O) 2 N(R 31 ) 2
  • X is a 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 31 , -N(R 31 )2, -C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -OC(O)N(R 31 )2, - C(O)N(R 31 )2, -N(R 31 )C(O)R 31 , -N(R 31 )C(O)OR 31 , -N(R 31 )S(O)2(R 31 ), -S(O)2N(R 31 )
  • X is 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3- triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted.
  • Formula (I-c) is represented by: and [0072]
  • C 3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 34 , -N(R 34 )2, -C(O)R 34 , -C(O)OR 34 , -OC(O)R 34 , -OC(O)N(R 34 )2, -C(O)N(R 34 )2, - N(R 34 )C(O)R 34 , -N(R 34 )C(O)OR 34 , -N(R 34 )S(O) 2 (R 34 ), -S(O) 2 N(R 34 ) 2 , -NO 2 , and -CN.
  • substituents independently selected from: halogen, -OR 34 , -N(R 34 )2, -C(O)R 34 , -C(O)OR 34 , -OC(O)R 34 , -OC(O)N(R 34
  • Formula (I-c) is represented by: , , and [0083]
  • R A is selected from methyl, ethyl, propyl, chloro, fluoro, and bromo.
  • Formula (I-c) is represented by: , , , , , and .
  • the optionally substituted 5- to 6-membered saturated heterocycle is selected from pyrrolidine, morpholine, and piperazine.
  • the 5- to 6-membered saturated heterocycle is selected from pyrrolidine, morpholine, and piperazine, any of which is optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, fluoro, and chloro.
  • Formula (I-c) is represented by: , , and .
  • n is selected from 0, 1, 2, and 3.
  • n is selected from 1, 2, 3, and 4.
  • n is 0.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • X is 5- to 6-membered heterocycle with one or two oxo groups and optionally substituted with one or more C 1-3 alkyl.
  • X is 5- to 6-membered heterocycle with one or two oxo groups and optionally substituted with methyl, ethyl, and propyl. . In some embodiments, for the compound or salt of Formula (I-c), X is 5- to 6-membered heterocycle with one oxo groups and optionally substituted with methyl, ethyl, and propyl.
  • Formula (I-c) is represented by: , , , and [0087]
  • Formula (I-c) is represented by: , , and .
  • the present disclosure provides a compound of Formula (I-d): (I-d), or a pharmaceutically acceptable salt thereof, wherein: each of R 1 and R 2 are independently selected from hydrogen and C 1-6 alkyl; and is a represented by: and [0089] In some embodiments, the compound or salt of Formula (I-d) is represented by: and . [0090] In some embodiments, the present disclosure provides a compound or salt of Formula (I- a), (I-b), (I-c), or (I-d) is selected from: , ,
  • compounds or salts of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) are intended to include all Z-, E- and tautomeric forms as well.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • the compounds or salts for Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation.
  • Stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
  • compounds or salts for Formula (I-a), Formula (I-b), Formula (I- c), Formula (I-d) or Formula (II) may comprise two or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers.
  • Methods of producing substantially pure enantiomers are well known to those of skill in the art.
  • a single stereoisomer e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302).
  • Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds or salts for Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) exist as tautomers.
  • a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 I are all contemplated.
  • salts particularly pharmaceutically acceptable salts, of the compounds of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II).
  • the compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • an appropriate counterion e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • the methods and compositions of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I- d) or Formula (II) include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • Compounds of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • salts particularly pharmaceutically acceptable salts, of compounds represented by Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II).
  • the compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged, such as those with a quaternary nitrogen can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • compounds or salts of Formula (I-a), Formula (I-b), Formula (I- c), Formula (I-d) or Formula (II), may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
  • the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell.
  • the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell.
  • the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell.
  • the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent.
  • the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J.
  • the present disclosure provides methods of producing the above-defined compounds.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • compositions comprising a compound or salt of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen.
  • Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate.
  • the pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.
  • Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate).
  • the active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated.
  • the active compounds can have complementary activities that do not adversely affect each other.
  • the composition can also comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant.
  • a chemotherapeutic agent cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant.
  • Such molecules can be present in combination in amounts that are effective for the purpose intended.
  • a compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I- d) or Formula (II) may be formulated in any suitable pharmaceutical formulation.
  • a pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II)), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.
  • an active ingredient e.g., compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II)
  • pharmaceutically acceptable excipients or carriers including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and
  • compositions may also be prepared from a compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art.
  • the present disclosure provides a method of inducing ⁇ 1 -antitrypsin (A1AT), the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof.
  • A1AT ⁇ 1 -antitrypsin
  • the present disclosure provides a method of inducing Z A1AT secretion, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof.
  • the present disclosure provides a method of treating a ⁇ 1 -antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof.
  • the present disclosure provides a method of treating low plasma levels of A1AT, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof.
  • the present disclosure provides a method of treating a ⁇ 1 -antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (II) or a pharmaceutical composition of Formula (II), wherein, R 1 is selected from C3-6 carbocycle and 6- to 12-membered bicyclic heteroaryl, any of which are optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; and Ring is selected from a 5- to 6-membered saturated heterocycle.
  • Formula (II) is represented by: , , , , , and [0125]
  • the administration of a compound or salt of Formula (II) induces ⁇ 1-antitrypsin (A1AT) in the subject in need thereof.
  • A1AT ⁇ 1-antitrypsin
  • the present disclosure provides a method of inducing Z A1AT secretion, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof.
  • the present disclosure provides a method of treating a ⁇ 1 -antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof.
  • the present disclosure provides a method of treating low plasma levels of A1AT, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof.
  • N-Ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared using the following sequential synthesis procedures: [0133] Step a: Synthesis of tert-butyl 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoate
  • Step b Synthesis of 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid
  • Tert-butyl 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoate (10g, 35 mmol) was dissolved in dichloromethane (50ml) and trifluoroacetic acid (70ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (300ml) for 20 minutes at room temperature.
  • Step c Synthesis of N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide
  • 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0 o C under nitrogen.
  • Example 2 3-(4-(Pyrrolidine-1-carbonyl)benzyl)pyrimidin-4(3H)-one [0139] 3-(4-(Pyrrolidine-1-carbonyl)benzyl)pyrimidin-4(3H)-one was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using pyrrolidine instead of ethylmethylamine in step c of Example 1.
  • Example 3 3-(4-(Morpholine-4-carbonyl)benzyl)pyrimidin-4(3H)-one [0140] 3-(4-(Morpholine-4-carbonyl)benzyl)pyrimidin-4(3H)-one was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using morpholine instead of ethylmethylamine in step c of Example 1.
  • N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide [0142] N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using quinazolin-4(3H)-one instead of pyrimidin-4(3H)-one in step a and methylamine instead of ethylmethylamine in step c.
  • Example 6 4-((6-chloro-4-oxoquinazolin-3(4H)-yl)methyl)-N-methylbenzamide [0143] 4-((6-chloro-4-oxoquinazolin-3(4H)-yl)methyl)-N-methylbenzamide was prepared similarly to N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using 6- chloroquinazolin-4(3H)-one instead of quinazolin-4(3H)-one in step a of Example 1.
  • Example 7 N-isopropyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide
  • N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using N,N-dimethylpropan-2- amine instead of ethylmethylamine in step c of Example 1.
  • Example 8 N-benzyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide
  • N-benzyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using N-methyl benzylamine instead of ethylmethylamine in step c of Example 1.
  • N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using 2,2,2-trifluoro-N-methylethan-1-amine instead of ethylmethylamine in step c of Example 1.
  • N,N-diethyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using diethylamine instead of ethylmethylamine in step c of Example 1.
  • N-isopropyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using isopropylamine instead of ethylmethylamine in step c of Example 1.
  • N-(4-fluorobenzyl)-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using 4- fluorobenzylamine instead of ethylmethylamine in step c of Example 1.
  • Example 15 N-isopropyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide [0152] N-isopropyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using isopropyl methylamine in step c of Example 1.
  • Example 16 N-benzyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide
  • N-benzyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using N-methyl benzylamine in step c of Example 1.
  • N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using 2,2,2- trifluoro-N-methylethan-1-amine in step c of Example 1.
  • Step a Synthesis of tert-butyl 4-((2-oxopyridin-1(2H)-yl)methyl)benzoate
  • Pyridin-2(1H)-one (5g, 53 mmol) and caesium carbonate (50.85g, 156 mmol) were stirred in dimethylformamide (50ml) for 10 minutes at room temperature.
  • Tert-butyl 4-(bromomethyl) benzoate 14.11g, 52 mmol
  • the reaction was diluted with water and the resulting yellow precipitate collected by filtration.
  • Step b Synthesis of 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid
  • Step b Synthesis of 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid
  • Tert-butyl 4-((2-oxopyridin-1(2H)-yl)methyl)benzoate (10g, 35 mmol) was dissolved in dichloromethane (50ml) and trifluoroacetic acid (70ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (300ml) for 20 minutes at room temperature.
  • Step c Synthesis of N,N-dimethyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide
  • 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0 o C under nitrogen.
  • Example 20 N-ethyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide [0163] N-ethyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamidewas prepared similarly using ethylmethylaminee instead of dimethylamine in step c of Example 19.
  • Example 21 N-isopropyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide [0164] N-isopropyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide was prepared similarly using isopropyl methylamine instead of dimethylamine in step c of Example 19.
  • Example 22 N-benzyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide
  • N-benzyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide was prepared similarly using N-methylbenzylamine instead of dimethylamine in step c of Example 19.
  • 1 H NMR (400 MHz, d6 DMSO) ⁇ 7.80 (1H, br), 7.42 - 7.29 (9H, br), 7.16 (1H, br), 6.41 (1H, br), 6.24 (1H, br), 5.12 (2H, br s), 2.85-2.79 (3H, br).
  • Example 23 N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)-N-(2,2,2- trifluoroethyl)benzamide [0166] N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide was prepared similarly using 2,2,2-trifluoro-N-methylethan-1-amine instead of dimethylamine in step c of Example 19.
  • Example 24 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide [0167] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide was prepared using the following sequential synthesis procedures.
  • Step a Synthesis of tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)benzoate:
  • Uracil (5g) and caesium carbonate (50.85g) were stirred in dimethylformamide (50ml) for 10 minutes at room temperature.
  • Tert-butyl 4- (bromomethyl)benzoate (14.11g) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration.
  • tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoate (3.5g, most polar product)
  • tert-butyl 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoate (420mg. least polar product).
  • Step b Synthesis of 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid: Tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoate (3g) was dissolved in dichloromethane (20ml) and trifluoroacetic acid (30ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (100ml) for 20 minutes at room temperature.
  • Step c Synthesis of 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0 o C under nitrogen. The reaction was then allowed to warm to room temperature.
  • Triethylamine (0.11ml, 81 mmol) and dimethylamine (2M solution in tetrahydrofuran, 69 mmol) were added and the reaction was stirred for 2 hours.
  • the reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide.
  • Example 25 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-methylbenzamide
  • 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-methylbenzamide was prepared similarly using methylamine instead of dimethylamine in step c of Example 24.m/z (M+Na): 282.08 (calc 282.08) 1H NMR (400 MHz, d6 DMSO) ⁇ 11.34 (1H, s), 8.44-8.39 (1H, m), 7.84- 7.74 (3H, m), 7.39-7.32 (2H, m), 5.61 (1H, dd), 4.91 (2H, s), 2.77 (3H, d).
  • Example 26 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-isopropylbenzamide [0172] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-isopropylbenzamide was prepared similarly using isopropylamine instead of dimethylamine in step c of Example 24.
  • Example 27 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(4- fluorobenzyl)benzamide [0173] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(4-fluorobenzyl)benzamide was prepared similarly using 4-fluorobenzylamine instead of dimethylamine in step c of Example 24.
  • Example 28 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide [0174] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide was prepared using the following sequential synthesis procedures.
  • Step a Synthesis of 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid: Tert-butyl 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoate (2g) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (15ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (50ml) for 20 minutes at room temperature.
  • Step b Synthesis of 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid (32mg) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (43mg) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0 o C under nitrogen. The reaction was then allowed to warm to room temperature.
  • Triethylamine (0.06ml) and dimethylamine (2M solution in tetrahydrofuran) were added and the reaction was stirred for 2 hours.
  • the reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give 4-((2,6-dioxo-3,6- dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide.
  • Example 29 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl-N- methylbenzamide [0177] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl-N-methylbenzamide was prepared similarly using methylethylamine instead of dimethylamine in step b of Example 28.
  • Example 30 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-isopropyl-N- methylbenzamide [0178] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-isopropyl-N-methylbenzamide was prepared similarly using methylisopropylamine instead of dimethylamine in step b of Example 28.
  • Example 31 N-benzyl-4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N- methylbenzamide [0179] N-benzyl-4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-methylbenzamide was prepared similarly using N-methylbenzylamine instead of dimethylamine in step b of Example 28.
  • Example 32 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-methyl-N-(2,2,2- trifluoroethyl)benzamide
  • 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-methyl-N-(2,2,2- trifluoroethyl)benzamide was prepared similarly using 2,2,2-trifluoro-N-methylethan-1-amine instead of dimethylamine in step b of Example 28.
  • Example 34 3-(4-(oxazol-2-yl)benzyl)quinazolin-4(3H)-one [0183] 3-(4-(oxazol-2-yl)benzyl)quinazolin-4(3H)-one was prepared similarly to Example 33 using quinazolin-4(3H)-one instead of pyrimidin-4(3H)-one.
  • Example 35 3-(4-(oxazol-2-yl)benzyl)pyrimidine-2,4(1H,3H)-dione
  • 3-(4-(oxazol-2-yl)benzyl)pyrimidine-2,4(1H,3H)-dione was prepared similarly to Example 33 using uracil instead of pyrimidin-4(3H)-one.
  • Example 36 1-(Quinolin-8-ylsulfonyl)piperidine-4-carboxylic acid [0187] 1-(Quinolin-8-ylsulfonyl)piperidine-4-carboxylic acid was prepared using the general method of Scheme 1 and 1-quinolin-8-ylsulfonylchloride and piperidine-4-carboxylic acid.
  • Example 37 1-((2-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0188] Example 37 was prepared using the general method and 1-(2- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 38 1-((3-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0189] Example 38 was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 39 1-((2,3-Dichlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0190]
  • Example 39 was prepared using the general method and 1-(2,3- dichlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 40 (S)-1-((3-Fluorophenyl)sulfonyl)piperidine-3-carboxylic acid [0191] Example 40 was prepared using the general method and 1-(3- fluorophenyl)sulfonylchloride and (S)-piperidine-3-carboxylic acid.
  • Example 41 (S)-1-((3-Chlorophenyl)sulfonyl)piperidine-3-carboxylic acid [0192]
  • Example 41 was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and (S)-piperidine-3-carboxylic acid.
  • Example 42 (R)-1-((3-Fluorophenyl)sulfonyl)piperidine-3-carboxylic acid [0193] Example 42 was prepared using the general method and 1-(3- fluorophenyl)sulfonylchloride and (R)-piperidine-3-carboxylic acid.
  • Example 43 (R)-1-((3-Chlorophenyl)sulfonyl)piperidine-3-carboxylic acid [0194] Example 43was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and (R)-piperidine-3-carboxylic acid.
  • Example 44 1-((4-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0195] Example 44 was prepared using the general method and 1-(4- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 45 1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid [0196] Example 45 was prepared using the general method and 1-(2-(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 46 1-((3-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid [0197] Example 46 was prepared using the general method and 1-(3- (trifluoromethyl)phenyl)sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 47 1-((4-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid [0198] Example 47 was prepared using the general method and 1-(4-(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 48 1-((2,5-Bis(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid [0199] Example 48 was prepared using the general method and 1-(2,5-bis(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 49 1-((2-(Trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxylic acid [0200]
  • Example 49 was prepared using the general method and 1-(2- (trifluoromethoxy)phenyl)sulfonylchloride and piperidine-4-carboxylic acid.
  • Example 50 (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)pyrrolidine-3-carboxylic acid [0201] Example 50 was prepared using the general method and 1-(2-(trifluoromethyl)phenyl) sulfonylchloride and (S)-pyrrolidine-3-carboxylic acid.
  • Example 51 (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)pyrrolidine-3-carboxylic acid [0202]
  • Example 51 was prepared using the general method and 1-(2- (trifluoromethyl)phenyl)sulfonylchloride and (R)-pyrrolidine-3-carboxylic acid 1 H NMR (400 MHz, d6 DMSO) ⁇ 12.62 (1H, br s), 8.05 (2H, m), 7.90 (2H, m), 3.48 (2H, m), 3.38 (2H, m), 3.15 (1H, m), 2.11 (2H, m).
  • Example 52 (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid [0203] (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid was prepared using the following synthesis procedure. [0204] (S)-Piperidine-3-carboxylic acid (1g, 7.7 mmol), potassium hydroxide (434mg, 7.7 mmol) and potassium carbonate (2.14g, 15.4 mmol) were added to water (20ml) and stirred.
  • Example 53 (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid [0205] (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid was prepared in the same manner as (S)-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid, but using (R)-piperidine-3-carboxylic acid. Tlc Rf 0.370% ethyl acetate in hexane.
  • Suitable R 8 groups include CH 3 , CH 2 CH 3 , C(CH 3 )3.
  • Suitable R 1 and R 2 groups include H, CH 3 , CH 2 CH 3 , CH(CH 3 )2, C(CH 3 )3, CH 2 Ph.
  • DMF means dimethylformamide
  • CDI means carbonyldiimidazole.
  • step 1 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound Table 2.
  • Structure of step 4 electrophiles references for the synthesis of the electrophiles and the structure of the final compound
  • General Scheme 2 for the Synthesis of Examples 60-81
  • Active compounds made in two steps involving for instance an alkylation to give an aryl halide intermediate followed by a palladium catalyzed C-C or C-N bond formation (General Scheme 2, Steps 1 and 2), or directly using an electrophile containing the final X-group (Scheme 1, Step 3).
  • Suitable R 1 and R 2 groups include H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 Ph.
  • DMF means dimethylformamide
  • CDI means carbonyldiimidazole Table 5.
  • Example 107 Activity of compounds of the invention in an A1AT cell secretion assay using HEK-Z cells
  • HEK-Z cells a human embryonic kidney cell line stably transfected with the human Z A1AT gene, were plated into 96 well plates (3.0 x 10 5 cells/ml with 200 ⁇ l of media/well) overnight at 37 ⁇ C in a humidified atmosphere containing 5% CO 2 .
  • the supernatants were removed from the wells, centrifuged at 1000 x g at 4 ⁇ C for 10 min and were assayed for human A1AT levels by ELISA (Human Serpin A1/ ⁇ 1-antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions.
  • ELISA Human Serpin A1/ ⁇ 1-antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions.
  • the capture antibody was then removed and wells washed three times with 300 ⁇ l wash buffer (0.05% Tween 20 in PBS) and then 200 ⁇ l reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h.
  • samples were removed and all wells washed as previously and 100 ⁇ l detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed and wells were washed as previously and 100 ⁇ l streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 ⁇ l stop solution (2M H 2 SO 4 ) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader.
  • detection antibody 1:180 dilution from stock
  • Examples 36-53 the amount of human A1AT secreted from transfected HEK-EBNA cells into the media was measured by ELISA. SAHA at 10 ⁇ M was used a positive control for all in vitro A1AT secretion experiments. [0215] The data in Table 8 show that the compounds of Examples 36-53 increase the secretion of human Z A1AT from HEK-Z cells in a dose dependent manner as measured by ELISA.
  • Example 108 Activity of the compounds of Examples 1-18 in an A1AT cell secretion assay using HEK-M cells
  • HEK-M cells a human embryonic kidney cell line stably transfected with M A1AT, were plated into 96 well plates (3.0 x 10 5 cells/ml with 200 ⁇ l of media/well) overnight at 37 ⁇ C in a humidified atmosphere containing 5% CO 2 .
  • a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 ⁇ l final volume/well). The capture antibody was then removed and wells washed three times with 300 ⁇ l wash buffer (0.05% Tween 20 in PBS) and then 200 ⁇ l reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h.
  • samples were removed and all wells washed as previously and 100 ⁇ l detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed and wells were washed as previously and 100 ⁇ l streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 ⁇ l stop solution (2M H2SO4) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader.
  • detection antibody 1:180 dilution from stock
  • a 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. Results [0218] The amount of human M A1AT secreted from transfected HEK-EBNA cells into the media was measured by ELISA. SAHA at 10 ⁇ M was used a positive control for all in vitro A1AT secretion experiments. The compounds of Examples 36, 38, 39, 45, 52 and 53 did not lead to an increase in secretion of human M A1AT from HEK-M cells at 10 ⁇ M.
  • Example 109 Activity of the compounds of Examples 36 and 52 in an A1AT cell secretion assay using HEK-Siiyama cells
  • the rare Siiyama mutation (Ser 53 to Phe, mature A1AT numbering) was identified in a Japanese male with AATD (Seyama et al J Biol Chem (1991) 266:12627-32).
  • Ser53 is one the conserved serpin residues and is thought to be important for the organization of the internal core of the A1AT molecule.
  • the change from an uncharged polar to a large nonpolar amino acid on the conserved backbone of the protein affects the folding and intracellular processing of Siiyama A1AT.
  • HEK-Siiyama cells a human embryonic kidney cell line stably transfected with the human Siiyama A1AT gene, were plated into 96 well plates (3.0 x 10 5 cells/ml with 200 ⁇ l of media/well) overnight at 37 ⁇ C in a humidified atmosphere containing 5% CO 2 . Following incubation cells were washed with 200 ⁇ l serum-free media three times and media was replaced with serum-free media containing vehicle, 10 ⁇ M suberanilohydroxamic acid (SAHA) or a compound of Example 1 (at 1 and 10 ⁇ M) in replicates of eight for 48 h in a 37 ⁇ C incubator in a final volume of 200 ⁇ l.
  • SAHA suberanilohydroxamic acid
  • Example 1 at 1 and 10 ⁇ M
  • the supernatants were removed from the wells, centrifuged at 1000 x g at 4 ⁇ C for 10 min and were assayed for human A1AT levels by ELISA (Human Serpin A1/ ⁇ 1 - antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions.
  • ELISA Human Serpin A1/ ⁇ 1 - antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions.
  • the capture antibody was then removed, and wells washed three times with 300 ⁇ l wash buffer (0.05% Tween 20 in PBS) and then 200 ⁇ l reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h.
  • samples were removed, and all wells washed as previously and 100 ⁇ l detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed, and wells were washed as previously and 100 ⁇ l streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 ⁇ l stop solution (2M H2SO4) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader.
  • detection antibody 1:180 dilution from stock
  • Example 110 Activity of the compounds of Examples 36 and 52 in a mouse expressing human Z (huZ mouse) [0223]
  • the huZ mouse (also referred to as the PiZZ mouse) is a transgenic mouse strain that contains multiple copies of the Z variant of the human A1AT gene, developed by two separate groups (Dycaico et al Science (1988) 242:1409-12) and Carlson et al J. Clin Invest (1989) 83:1183-90).
  • HuZ mice are on a C57Bl/6 background and express the human Z A1AT protein in liver tissue. The mice used in this study are from the progeny of Carlson and colleagues (transgenic line Z11.03).
  • HuZ mice have been used as a tool to assess the effects of an exemplar compound of the invention on either increasing the circulating levels of Z A1AT in plasma or the effects of compound on the accumulation of Z A1AT polymers in the liver and associated liver pathology.
  • Human Z A1AT levels in mouse plasma samples were measured by ELISA (Human Serpin A1/ ⁇ 1 antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions.
  • ELISA Human Serpin A1/ ⁇ 1 antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions.
  • a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 ⁇ l final volume/well). The capture antibody was then removed and wells washed three times with 300 ⁇ l wash buffer (0.05% Tween 20 in PBS) and then 200 ⁇ l reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature.

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Abstract

The invention relates to compounds or salts of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (II) and pharmaceutical compositions containing these compounds. The compounds may be inducers of α1-antitrypsin (A1AT), and may be used in the treatment of a disease or disorder such as α1-antitrypsin deficiency (A1AD or AATD).

Description

Compounds and their Use for the Treatment of α1-Antitrypsin Deficiency BACKGROUND OF THE INVENTION [0001] α1-Antitrypsin (A1AT) is a member of the serpin superfamily produced by the liver and secreted into the blood. It inhibits a variety of serine proteases, especially neutrophil elastase. When blood levels of A1AT are low, excessive neutrophil elastase activity degrades lung tissue resulting in respiratory complications, such as chronic obstructive pulmonary disease (COPD). [0002] The reference range of A1AT in blood is 0.9–2.3 g/L. Levels lower than this are typical of α1-antitrypsin deficiency (A1AD or AATD), a genetic disorder caused by mutations in the SERPINA1 gene, coding for A1AT. The Z mutation, the most common cause of AATD, is the substitution of glutamate to lysine at position 366 of A1AT (UniProtKB - P01009 (A1AT_HUMAN)), corresponding to position 342 in the mature protein (Z A1AT). The Z mutation affects the folding of A1AT resulting in only a small fraction acquiring the native/active state. The remainder is either cleared as misfolded protein or accumulates in the liver as stable polymers. As a consequence of the misfolding, homozygous carriers of the Z mutation (ZZ) have plasma levels of A1AT that are 10-15% of normal, predisposing carriers to COPD. Accumulation of Z A1AT polymers in liver cells predisposes carriers to cirrhosis, liver cancer and other liver pathologies. [0003] The current treatment for the lung manifestation of AATD involves augmentation therapy using A1AT concentrates prepared from the plasma of blood donors. The US FDA has approved the use of four A1AT products: Prolastin, Zemaira, Glassia, and Aralast. Dosing is via once weekly intravenous infusion. Augmentation therapy has been demonstrated to slow progression of COPD. The liver manifestations of AATD (e.g. cirrhosis and cancer) are treated with steroids and liver transplantation. Investigational approaches to improved treatment of the liver manifestations include inhibition of Z A1AT polymerization and increased clearance of polymers through the activation of autophagy. Investigational approaches to improved treatment of both the lung and the liver manifestations are directed towards improvement of Z A1AT folding and secretion. SUMMARY OF THE INVENTION [0004] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I-a):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein: is a 6-membered heterocycle selected from:
Figure imgf000004_0002
, and ;
Figure imgf000004_0003
A is selected from: -C(=O)N(H)(R1), -C(=O)N(R2)(R3); and 5-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, -OR11, N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, - OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)OR11, - OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2,=O and -CN; R1 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - N(R12)S(O)2(R12), -S(O)N(R12)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - S(O)2N(R12)2, -NO2, and -CN; R2 and R3 are each C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - OC(O)N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -S(O)2R13, - N(R13)S(O)2(R13), -S(O)2N(R13)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, - C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)C(O)N(R13)2, -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and R11, R12 and R13 are each independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. [0005] In certain aspects the present disclosure provides a compound represented by the structure of Formula (I-b):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000005_0002
is a bicyclic heterocycle selected from
Figure imgf000005_0003
; B selected from -C(=O)N(H)(R4), -C(=O)N(R5)(R6), and 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, - N(R21)S(O)2(R21), -S(O)2N(R21)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, - OC(O)R21, -OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, - N(R21)S(O)2(R21), -S(O)2N(R21)2, -NO2, =O, and -CN; R4 is selected from: C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, - OC(O)R22, -OC(O)N(R22)2, -C(O)N(R22)2, -N(R22)C(O)R22, -NO2, =O, and -CN; and C2-6 alkyl substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, - C(O)N(R22)2, -N(R22)C(O)R22, -N(R22)C(O)OR22, -N(R22)S(O)2(R22), - S(O)2N(R22)2, -NO2,=O, and -CN; R5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, -OC(O)N(R23)2, - C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, -N(R23)S(O)2(R23), - S(O)2N(R23)2, -NO2, and -CN; R6 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, - OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, - N(R24)C(O)OR24, -N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1- 6 alkyl, -O-C1-6 haloalkyl, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; R21, R23, and R24 are each independently selected at each occurrence from hydrogen, - OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and R22 is independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. [0006] In certain aspects the present disclosure provides a compound represented by the structure of Formula (I-c):
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein: is a 6-membered heterocycle represented by:
Figure imgf000008_0002
X is selected from (a), (b), and (c): (a) -C(=O)N(H)(R7), -C(=O)N(R8)(R9), -CH2C(=O)N(H)(C1-6 alkyl), - CH2C(=O)N(C1-6 alkyl)2 , -CHC(=O)N(H)(C1-6 alkyl), -CHC(=O)N(C1-6 alkyl)2, - S(=O)2N(H)(C1-6 alkyl), -S(=O)2N(C1-6 alkyl)2; (b) 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR31, -N(R31)2, -C(O)R31, -C(O)OR31, -OC(O)R31, - OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)C(O)OR31, - N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -N(R31)2, -C(O)R31, - C(O)OR31, -OC(O)R31, -OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, - N(R31)C(O)OR31, -N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, =O, and -CN; and (c) 5- to 6-membered heterocycle with one or two oxo group and optionally substituted with one or more C1-3 alkyl; R7 is selected from: C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, - N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, - N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, - N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, - N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, and -CN; R8 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), - S(O)2N(R33)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), - S(O)2N(R33)2, -NO2, -CN; R9 is selected from: C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, - OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, - OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN; or R8 and R9 can come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from: halogen, C1-6 alkyl, - OR35, -N(R35)2, -C(O)R35, -C(O)OR35, -OC(O)R35, -OC(O)N(R35)2, -C(O)N(R35)2, -N(R35)C(O)R35, -N(R35)C(O)OR35, -N(R35)S(O)2(R35), -S(O)2N(R35)2, -NO2, - CN; RA is independently selected at each occurrence from halogen and C1-6 alkyl; R`` is each independently selected from hydrogen, halogen, C1-3 alkyl, -NO2, and -CN; R31, R32, R33, R34 and R35 are each independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and n is selected from 0, 1, 2, 3, and 4. [0007] In some aspects the present disclosure provides a compound represented by the structure of Formula (I-d):
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein: each of R1 and R2 are independently selected from hydrogen and C1-6 alkyl; and is a represented by:
Figure imgf000011_0003
Figure imgf000011_0002
Figure imgf000011_0004
Figure imgf000011_0005
, and
Figure imgf000011_0006
. [0008] In some aspects the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound or salt of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d). [0009] In some aspects the present disclosure provides a method of inducing α1-antitrypsin (A1AT) comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d) or a pharmaceutically composition thereof. [0010] In some aspects the present disclosure provides a method of treating a α1-antitrypsin deficiency comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d) or a pharmaceutically composition thereof. [0011] In some aspects the present disclosure provides a method of treating a α1-antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (II) or a pharmaceutical composition of Formula (II),
Figure imgf000012_0001
wherein, R1 is selected from C3-6 carbocycle and 6- to 12-membered bicyclic heteroaryl, any of which are optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and Ring
Figure imgf000012_0002
is selected from a 5- to 6-membered saturated heterocycle. In some embodiments, the administering induces α1-antitrypsin (A1AT) in the subject in need thereof. INCORPORATION BY REFERENCE [0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION [0013] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. Definitions [0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference. [0015] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. [0016] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6 alkyl” refers to saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term –Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example –C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. [0017] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term –Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, – C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term –Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, –C2-6alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain. [0018] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. [0019] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. [0020] "Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. [0021] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro- ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein. [0022] The term “cycloalkyl” as used herein refers to a saturated carbocycle. Exemplary cycloalkyl rings include cyclopropyl, cyclohexyl, and norbornane. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein. [0023] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. [0024] The term “heteroaryl” includes aromatic single ring structures, preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term “heteroaryl” also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. [0025] The term “heterocycloalkyl” as used herein refers to a saturated heterocycle. Exemplary heterocycloalkyl rings include morpholinyl, piperidinyl, and piperazinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein. [0026] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. [0027] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N- H), oximo(=N-OH), hydrazine(=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine(=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -R b-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rc is a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. [0028] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0029] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker. [0030] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein. [0031] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need. [0032] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. [0033] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and/or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely. [0034] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. [0035] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. Compounds [0036] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I-a):
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000019_0003
is a 6-membered heterocycle selected from:
Figure imgf000019_0002
, and
Figure imgf000019_0004
; A is selected from: -C(=O)N(H)(R1), -C(=O)N(R2)(R3); and 5-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, -OR11, N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, - OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)OR11, - OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2,=O and -CN; R1 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - N(R12)S(O)2(R12), -S(O)N(R12)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - S(O)2N(R12)2, -NO2, and -CN; R2 and R3 are each C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - OC(O)N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -S(O)2R13, - N(R13)S(O)2(R13), -S(O)2N(R13)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, - C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)C(O)N(R13)2, -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and R11, R12 and R13 are each independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. [0037] In some embodiments, for the compound or salt of Formula (I-a),
Figure imgf000020_0001
is a 6-membered heterocycle selected from:
Figure imgf000020_0003
, , , and
Figure imgf000020_0004
. In some embodiments,
Figure imgf000020_0002
is a 6-membered heterocycle selected from:
Figure imgf000020_0005
. In some embodiments,
Figure imgf000021_0003
is a 6-membered heterocycle selected from:
Figure imgf000021_0004
and
Figure imgf000021_0005
. In some embodiments,
Figure imgf000021_0008
is
Figure imgf000021_0009
. In some embodiments,
Figure imgf000021_0001
. embodiments,
Figure imgf000021_0006
is
Figure imgf000021_0007
. In some embodiments,
Figure imgf000021_0002
. [0038] In some embodiments, for the compound or salt of Formula (I-a), A is 5-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, -OR11, N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, - N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, - N(R11)C(O)OR11, -N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2,=O and -CN. [0039] In some embodiments, for the compound or salt of Formula (I-a), A is 5-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, -OR11, N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, - N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2, -CN. In some embodiments, A is 5-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, -OR11, N(R11)2, -C(O)R11, -C(O)OR11, -NO2, -CN. [0040] In some embodiments, for the compound or salt of Formula (I-a), A is 5-membered heteroaryl optionally substituted with C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)OR11, - OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2,=O and -CN. In some embodiments, A is 5-membered heteroaryl optionally substituted with C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)OR11, -NO2,=O and -CN. In some embodiments, A is 5-membered heteroaryl optionally substituted with C1-6 alkyl. In some embodiments, A is 5-membered heteroaryl optionally substituted with C1-3 alkyl. In some embodiments, A is 5-membered heteroaryl optionally substituted with methyl, ethyl, propyl, and isopropyl, any of which is optionally substituted. [0041] In some embodiments, for the compound or salt of Formula (I-a), A is optionally substituted 5-membered heteroaryl comprising one or more heteroatoms selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, A is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted. In some embodiments, A is selected from oxazole, isoxazole, thiazole, isothiazole, and imidazole, any one of which is optionally substituted. In some embodiments, A is selected from optionally substituted oxazole. In some embodiments, Formula (I-a) is represented by:
Figure imgf000022_0001
. [0042] In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(H)(R1). In some embodiments, R1 of -C(=O)N(H)(R1) is selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, - C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, - N(R12)C(O)OR12, -S(O)2R12, -N(R12)S(O)2(R12), -S(O)N(R12)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - S(O)2N(R12)2, -NO2, and -CN. [0043] In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(H)(R1) and R1 is selected from C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, - N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, -S(O)2N(R12)2, -NO2, and -CN. In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(H)(R1) and R1 is selected from C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, - C(O)OR12, -NO2, and -CN. In some embodiments, A is -C(=O)N(H)(R1) and R1 is selected from C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted. [0044] In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(H)(R1) and R1 is selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, -N(R12)S(O)2(R12), -S(O)N(R12)2, -NO2, =O, and -CN. In some embodiments, A is -C(=O)N(H)(R1) and R1 is selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, and -CN. In some embodiments, A is -C(=O)N(H)(R1) and R1 is selected from optionally substituted C1-3 alkyl. In some embodiments, A is -C(=O)N(H)(R1) and R1 is selected from methyl, ethyl, propyl, and isopropyl, any of which is optionally substituted. [0045] In some embodiments, for the compound of salt of Formula (I-a), A is -C(=O)N(H)(R1) and R1 is C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -NO2, and -CN. In some embodiments, Formula (I-a) is represented by:
Figure imgf000023_0001
,
Figure imgf000023_0002
[0046] In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -S(O)2R13, - N(R13)S(O)2(R13), -S(O)2N(R13)2, -NO2, =O, -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, - C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)C(O)N(R13)2, -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN. [0047] In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -S(O)2R13, - N(R13)S(O)2(R13), -S(O)2N(R13)2, -NO2, =O, and -CN. In some embodiments, A is - C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)OR13, -NO2, =O, and -CN. [0048] In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -C(O)N(R13)2, - N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)C(O)N(R13)2, -S(O)2R13, -S(O)2N(R13)2, -NO2, and - CN. In some embodiments, A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -NO2, and -CN. In some embodiments, [0049] In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -NO2, -CN; and C3- 6 carbocycle optionally substituted with one or more substituents selected from: halogen, -OR13, - N(R13)2, -C(O)R13, -NO2, and -CN. A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-6 alkyl optionally substituted with one or more substituents independently selected from C3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted. [0050] In some embodiments, for the compound or salt of Formula (I-a), A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -S(O)2R13, - N(R13)S(O)2(R13), -S(O)2N(R13)2, -NO2, =O, and -CN. In some embodiments, A is - C(=O)N(R2)(R3) and R2 and R3 are each independently C1-3 alkyl optionally substituted with one or more substituents independently selected from fluoro, chloro, and bromo. In some embodiments, Formula (I-a) is represented by:
Figure imgf000025_0003
Figure imgf000025_0004
Figure imgf000025_0005
, and
Figure imgf000025_0006
. [0051] In some embodiments, for the compound or salt of Formula (I-a), R2 and R3 are each independently C1-3 alkyl optionally substituted with C6 carbocycle optionally substituted with one or more substituents selected from fluoro, chloro, and bromo. In some embodiments, the C6 carbocycle of R2 or R3 is phenyl optionally substituted with one or more substituents selected from fluoro, chloro, and bromo. In some embodiments, Formula (I-a) is represented by:
Figure imgf000025_0001
. [0052] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I-b)
Figure imgf000025_0002
or a pharmaceutically acceptable salt thereof, wherein: is a bicyclic heterocycle selected from
Figure imgf000026_0001
B selected from -C(=O)N(H)(R4), -C(=O)N(R5)(R6), and 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, - N(R21)S(O)2(R21), -S(O)2N(R21)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, - OC(O)R21, -OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, - N(R21)S(O)2(R21), -S(O)2N(R21)2, -NO2, =O, and -CN; R4 is selected from: C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, - OC(O)R22, -OC(O)N(R22)2, -C(O)N(R22)2, -N(R22)C(O)R22, -NO2, =O, and -CN; and C2-6 alkyl substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, - C(O)N(R22)2, -N(R22)C(O)R22, -N(R22)C(O)OR22, -N(R22)S(O)2(R22), - S(O)2N(R22)2, -NO2,=O, and -CN; R5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, -OC(O)N(R23)2, - C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, -N(R23)S(O)2(R23), - S(O)2N(R23)2, -NO2, and -CN; R6 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, - OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, - N(R24)C(O)OR24, -N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1- 6 alkyl, -O-C1-6 haloalkyl, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; R21, R23, and R24 are each independently selected at each occurrence from hydrogen, - OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and R22 is independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. [0053] In some embodiments, for the compound or salt of Formula (I-c), R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, - NO2, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle. R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, and -CN. In some embodiments, R` is selected from C3-6 carbocycle and 3- to 6-membered heterocycle. In some embodiments, R` is selected from hydrogen, halogen, -OH, C1-3 alkyl, and C1-3 haloalkyl In some embodiments, R’ is selected from hydrogen and halogen; and
Figure imgf000028_0001
is represented by:
Figure imgf000028_0002
and
Figure imgf000028_0003
. In some embodiments,
Figure imgf000028_0004
is represented by:
Figure imgf000028_0005
. In some embodiments,
Figure imgf000028_0006
is represented by:
Figure imgf000028_0007
. [0054] In some embodiments, for the compound or salt or Formula (I-b), B is a 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -OC(O)R21, -OC(O)N(R21)2, - C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, -N(R21)S(O)2(R21), -S(O)2N(R21)2, - NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, -N(R21)S(O)2(R21), - S(O)2N(R21)2, -NO2, =O, and -CN. [0055] In some embodiments, for the compound or salt or Formula (I-b), B is a 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, -N(R21)S(O)2(R21), - S(O)2N(R21)2, -NO2, and -CN. In some embodiments, B is a 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -NO2, and -CN. [0056] In some embodiments, for the compound or salt or Formula (I-b), B is a 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, -N(R21)S(O)2(R21), - S(O)2N(R21)2, -NO2, =O, and -CN. In some embodiments, B is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -NO2, =O, and -CN. [0057] In some embodiments, for the compound or salt of Formula (I-b), B is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, and imidazole, any of which is optionally substituted. In some embodiments, Formula (I-b) is represented by:
Figure imgf000029_0001
. [0058] In some embodiments, for the compound or salt of Formula (I-b), B is -C(=O)N(H)(R4). In some embodiments, R4 of -C(=O)N(H)(R4) is selected from: C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, - C(O)N(R22)2, -N(R22)C(O)R22, -NO2, =O, and -CN; and C2-6 alkyl substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, -C(O)N(R22)2, - N(R22)C(O)R22, -N(R22)C(O)OR22, -N(R22)S(O)2(R22), -S(O)2N(R22)2, -NO2,=O, and -CN. [0059] In some embodiments, for the compound or salt of Formula (I-b) R4 of -C(=O)N(H)(R4) is selected from: C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, -C(O)N(R22)2, - N(R22)C(O)R22, -NO2, =O, and -CN. In some embodiments, R4 of -C(=O)N(H)(R4) is selected from: C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -NO2, =O, and -CN. In some embodiments, R4 of -C(=O)N(H)(R4) is selected from: C2-6 alkyl substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, -C(O)N(R22)2, - N(R22)C(O)R22, -N(R22)C(O)OR22,-N(R22)S(O)2(R22), -S(O)2N(R22)2, -NO2,=O, and -CN. In some embodiments, R4 of -C(=O)N(H)(R4) is selected from: C2-6 alkyl substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -NO2,=O, and -CN. [0060] In some embodiments, for the compound or salt of Formula (I-b), B is –C(=O)N(H)(R4) and R4 is C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, -C(O)N(R22)2, - N(R22)C(O)R22, -NO2, and -CN. In some embodiments, Formula (I-b) is represented by:
Figure imgf000030_0001
and
Figure imgf000030_0002
[0061] In some embodiments, for the compound or salt of Formula (I-b), B is -C(=O)N(R5)(R6). In some embodiments, B is -C(=O)N(R5)(R6) and; R5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, =O, and -CN; and R6 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, - OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, - N(R24)C(O)OR24, -N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN. [0062] In some embodiments, for the compound or salt of Formula (I-b), B is -C(=O)N(R5)(R6) and; R5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, -OC(O)N(R23)2, - C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, -N(R23)S(O)2(R23), - S(O)2N(R23)2, -NO2, and -CN; and R6 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, - OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, - N(R24)C(O)OR24, -N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN. [0063] In some embodiments, for the compound or salt of Formula (I-b), B is -C(=O)N(R5)(R6) and; R5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, -OC(O)N(R23)2, - C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, -N(R23)S(O)2(R23), - S(O)2N(R23)2, -NO2, and -CN; and R6 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, - OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, - N(R24)C(O)OR24, -N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN. [0064] In some embodiments, for the compound or salt of Formula (I-b), B is -C(=O)N(R5)(R6) and; R5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, -OC(O)N(R23)2, - C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, -N(R23)S(O)2(R23), - S(O)2N(R23)2, -NO2, and -CN; and R6 is selected from: C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN. [0065] In some embodiments, for the compound or salt of Formula (I-b) B is -C(=O)N(R5)(R6) and; R5 is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, and -CN; and R6 is C1 alkyl substituted with one more substituents one or more substituents independently selected from halogen, -OR24, -N(R24)2, -C(O)R24, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -NO2, and -CN. [0066] In some embodiments, for the compound or salt of Formula (I-b), Formula (I-b) is represented by:
Figure imgf000034_0003
and
Figure imgf000034_0004
[0067] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I-c):
Figure imgf000034_0001
, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000034_0005
is a 6-membered heterocycle represented by:
Figure imgf000034_0002
X is selected from: (a) -C(=O)N(H)(R7), -C(=O)N(R8)(R9), -CH2C(=O)N(H)(C1-6 alkyl), - CH2C(=O)N(C1-6 alkyl)2, -CHC(=O)N(H)(C1-6 alkyl), -CHC(=O)N(C1-6 alkyl)2, - S(=O)2N(H)(C1-6 alkyl), -S(=O)2N(C1-6 alkyl)2; (b) 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR31, -N(R31)2, -C(O)R31, -C(O)OR31, -OC(O)R31, - OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)C(O)OR31, - N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -N(R31)2, -C(O)R31, - C(O)OR31, -OC(O)R31, -OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, - N(R31)C(O)OR31, -N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, =O, and -CN; and (c) 5- to 6-membered heterocycle with one or two oxo groups and optionally substituted with one or more C1-3 alkyl; R7 is selected from: C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, - N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, - N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, - N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, - N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, and -CN; R8 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, - OC(O)N(R33)2, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, - N(R33)S(O)2(R33), -S(O)2N(R33)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), - S(O)2N(R33)2, -NO2, and -CN; R9 is selected from: C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, - OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, - OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN; or R8 and R9 can come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from: halogen, C1-6 alkyl, - OR35, -N(R35)2, -C(O)R35, -C(O)OR35, -OC(O)R35, -OC(O)N(R35)2, -C(O)N(R35)2, -N(R35)C(O)R35, -N(R35)C(O)OR35, -N(R35)S(O)2(R35), -S(O)2N(R35)2, -NO2, and -CN; RA is independently selected at each occurrence from halogen and C1-6 alkyl; R`` is each independently selected from hydrogen, halogen, C1-3 alkyl, -NO2, and -CN; R31, R32, R33, R34 and R35 are each independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and n is selected from 0, 1, 2, 3, and 4. [0068] In some embodiments, for the compound or salt of Formula (I-c), is each R`` is independently selected from hydrogen, halogen, C1-3 alkyl. In some embodiments, each R`` is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, fluoro, chloro, and bromo. In some embodiments, In some embodiments, each R`` is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, fluoro, chloro, and bromo; and
Figure imgf000037_0001
is represented by:
Figure imgf000038_0001
and
Figure imgf000038_0002
. In some embodiments, is represented by:
Figure imgf000038_0003
and
Figure imgf000038_0004
. In some embodiments,
Figure imgf000038_0005
is represented by:
Figure imgf000038_0006
. [0069] In some embodiments, for the compound or salt of Formula (I-c), X is a 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3- triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR31, -N(R31)2, -C(O)R31, -C(O)OR31, -OC(O)R31, -OC(O)N(R31)2, - C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)C(O)OR31, -N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -N(R31)2, -C(O)R31, -C(O)OR31, -OC(O)R31, -OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)C(O)OR31, -N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, =O, and -CN. [0070] In some embodiments, for the compound or salt of Formula (I-c), X is a 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3- triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR31, -N(R31)2, -C(O)R31, -C(O)OR31, - OC(O)R31, -OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)C(O)OR31, -N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, -CN. In some embodiments, X is a 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -N(R31)2, -C(O)R31, -C(O)OR31, -OC(O)R31, -OC(O)N(R31)2, - C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)C(O)OR31, -N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, =O, and -CN. [0071] In some embodiments, for the compound or salt of Formula (I-c), X is 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3- triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted. In some embodiments, Formula (I-c) is represented by:
Figure imgf000039_0001
Figure imgf000039_0002
and
Figure imgf000039_0003
[0072] In some embodiments, for the compound or salt of Formula (I-c), X is -C(=O)N(H)(R7). In some embodiments, R7 of -C(=O)N(H)(R7) is C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, - C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, - NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, - N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, - N(R32)C(O)R32, -N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, and -CN. [0073] In some embodiments, for the compound or salt of Formula (I-c), X is -C(=O)N(H)(R7). In some embodiments, R7 of -C(=O)N(H)(R7) is C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, -N(R32)S(O)2(R32), - S(O)2N(R32)2, -NO2, =O, and -CN. In some embodiments, R7 of -C(=O)N(H)(R7) is C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -NO2, =O, and -CN. In some embodiments, for the compound or salt of Formula (I-c), X is -C(=O)N(H)(R7). In some embodiments, R7 of -C(=O)N(H)(R7) is C1 alkyl substituted with one or more substituents independently selected from: C3-6carbocycle and 3- to 6- membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, -N(R32)S(O)2(R32), - S(O)2N(R32)2, -NO2, and -CN. In some embodiments, R7 of -C(=O)N(H)(R7) is C1 alkyl substituted with one or more substituents independently selected from: C3-6carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -NO2, and -CN. [0074] In some embodiments, for the compound or salt of Formula (I-c), R7 of -C(=O)N(H)(R7) is C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, - C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, - NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, - N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, - N(R32)C(O)R32, -N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, and -CN. [0075] In some embodiments, for the compound or salt of Formula (I-c), R7 of -C(=O)N(H)(R7) is C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, - N(R32)C(O)R32, -N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, and -CN. In some embodiments, R7 of -C(=O)N(H)(R7) is C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -NO2, =O, and -CN. In some embodiments, R7 of -C(=O)N(H)(R7) is C2-6 alkyl optionally substituted with one or more substituents independently selected from: C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, - C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, and - CN. In some embodiments, R7 of -C(=O)N(H)(R7) is C2-6 alkyl optionally substituted with one or more substituents independently selected from: C3-6 carbocycle and 3- to 6-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -NO2, and -CN. [0076] In some embodiments, for the compound or salt of Formula (I-c), R7 of -C(=O)N(H)(R7) is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, - C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN; and C2-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN. [0077] In some embodiments, for the compound of salt Formula (I-c), Formula (I-c) is represented by:
Figure imgf000041_0001
, , and
Figure imgf000041_0002
[0078] In some embodiments, for the compound or salt of Formula (I-c), X is -C(=O)N(R8)(R9). In some embodiments, X is -C(=O)N(R8)(R9); and R8 is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -NO2, -CN; and C3-6carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, -C(O)N(R33)2, -N(R33)C(O)R33, - N(R33)C(O)OR33, -NO2, and -CN; and R9 is selected from: C1 alkyl substituted with one or more substituents independently selected halogen, -OR34, -N(R34)2, -C(O)R34, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, - OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -NO2, and -CN; and C2-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - NO2, and -CN. [0079] In some embodiments, for the compound or salt of Formula (I-c), R8 of -C(=O)N(R8)(R9) is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, -C(O)N(R33)2, - N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), -S(O)2N(R33)2, -NO2, =O, and -CN. In some embodiments, R8 of -C(=O)N(R8)(R9) is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -NO2, =O, and -CN. In some embodiments, R8 of -C(=O)N(R8)(R9) is C1-6 alkyl optionally substituted with one or more substituents independently selected from: C3-10 carbocycle and 3- to 10- membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, - OC(O)N(R33)2, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), - S(O)2N(R33)2, -NO2, and -CN. In some embodiments, R8 of -C(=O)N(R8)(R9) is C1-6 alkyl optionally substituted with one or more substituents independently selected from: C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -NO2, and -CN. [0080] In some embodiments, for the compound or salt of Formula (I-c), R9 of -C(=O)N(R8)(R9) is C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN. In some embodiments, R9 of -C(=O)N(R8)(R9) is C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -NO2, and -CN. In some embodiments, R9 of -C(=O)N(R8)(R9) is C1 alkyl substituted with one or more substituents independently selected from: C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, - C(O)OR34, -OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN. In some embodiments, R9 of -C(=O)N(R8)(R9) is C1 alkyl substituted with one or more substituents independently selected from: C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -NO2, and -CN. [0081] In some embodiments, for the compound or salt of Formula (I-c), R9 of -C(=O)N(R8)(R9) is C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, - N(R34)C(O)R34, -N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, =O, and -CN. In some embodiments, R9 of -C(=O)N(R8)(R9) is C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -NO2, =O, and -CN. In some embodiments, C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, - N(R34)C(O)R34, -N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN. In some embodiments, R9 of -C(=O)N(R8)(R9) is C2-6 alkyl optionally substituted with one or more substituents independently selected from: C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -NO2, and -CN. [0082] In some embodiments, for the compound or salt of Formula (I-c), Formula (I-c) is represented by:
Figure imgf000043_0002
, ,
Figure imgf000043_0003
and
Figure imgf000043_0004
[0083] In some embodiments, for the compound or salt of Formula (I-c), RA is selected from methyl, ethyl, propyl, chloro, fluoro, and bromo. In some embodiments, In some embodiments, X is -C(=O)N(H)(R7); and RA is selected from methyl, ethyl, propyl, chloro, fluoro, and bromo. In some embodiments, In some embodiments, X is -C(=O)N(R8)(R9); and RA is selected from methyl, ethyl, propyl, chloro, fluoro, and bromo. Formula (I-c) is represented by:
Figure imgf000043_0001
,
Figure imgf000044_0001
, , ,
Figure imgf000044_0002
, and
Figure imgf000044_0003
. [0084] In some embodiments, for the compound or salt of Formula (I-c), X is -C(=O)N(R8)(R9) and both of R8 and R9 come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, -OR35, -N(R35)2, - C(O)R35, -C(O)OR35, -OC(O)R35, -OC(O)N(R35)2, -C(O)N(R35)2, -N(R35)C(O)R35, - N(R35)C(O)OR35, -N(R35)S(O)2(R35), -S(O)2N(R35)2, -NO2, and -CN. In some embodiments, X is -C(=O)N(R8)(R9) and both of R8 and R9 come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from halogen, C1-6 alkyl, -OR35, -N(R35)2, -C(O)R35, -C(O)OR35, -NO2, and -CN. In some embodiments, X is - C(=O)N(R8)(R9) and both of R8 and R9 come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from halogen, C1-3 alkyl and C1-3 haloalkyl. In some embodiments, the optionally substituted 5- to 6-membered saturated heterocycle is selected from pyrrolidine, morpholine, and piperazine. In some embodiments, the 5- to 6-membered saturated heterocycle is selected from pyrrolidine, morpholine, and piperazine, any of which is optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, fluoro, and chloro. In some embodiments, Formula (I-c) is represented by:
Figure imgf000044_0004
, , and
Figure imgf000044_0005
. [0085] In some embodiments, for the compound or salt of Formula (I-c), n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 1, 2, 3, and 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [0086] In some embodiments, for the compound or salt of Formula (I-c), X is 5- to 6-membered heterocycle with one or two oxo groups and optionally substituted with one or more C1-3 alkyl. In some embodiments, for the compound or salt of Formula (I-c), X is 5- to 6-membered heterocycle with one or two oxo groups and optionally substituted with methyl, ethyl, and propyl. . In some embodiments, for the compound or salt of Formula (I-c), X is 5- to 6-membered heterocycle with one oxo groups and optionally substituted with methyl, ethyl, and propyl. In some embodiments, Formula (I-c) is represented by:
Figure imgf000045_0001
, ,
Figure imgf000045_0002
Figure imgf000045_0003
, and
Figure imgf000045_0004
[0087] In some embodiments, for the compound or salt of Formula (I-c), X is selected from - CH2C(=O)N(H)(C1-6 alkyl), -CH2C(=O)N(C1-6 alkyl)2, -CHC(=O)N(H)(C1-6 alkyl), - CHC(=O)N(C1-6 alkyl)2, and -S(=O)2N(H)(C1-6 alkyl), -S(=O)2N(C1-6 alkyl)2. In some embodiments, X is selected from -CH2C(=O)N(H)(C1-3 alkyl), -CH2C(=O)N(C1-3 alkyl)2, - CHC(=O)N(H)(C1-3 alkyl), -CHC(=O)N(C1-3 alkyl)2, and -S(=O)2N(H)(C1-3 alkyl), -S(=O)2N(C1- 3 alkyl)2. In some embodiments, X is selected from -CH2C(=O)N(H)(C1-3 alkyl), and - CH2C(=O)N(C1-3 alkyl)2. In some embodiments, X is selected from -CHC(=O)N(H)(C1-3 alkyl) and -CHC(=O)N(C1-3 alkyl)2. In some embodiments, X is selected from -S(=O)2N(H)(C1-3 alkyl) and -S(=O)2N(C1-3 alkyl)2. In some embodiments, Formula (I-c) is represented by:
Figure imgf000046_0001
, , and
Figure imgf000046_0002
. [0088] In certain aspects, the present disclosure provides a compound of Formula (I-d):
Figure imgf000046_0003
(I-d), or a pharmaceutically acceptable salt thereof, wherein: each of R1 and R2 are independently selected from hydrogen and C1-6 alkyl; and
Figure imgf000046_0004
is a represented by:
Figure imgf000046_0008
Figure imgf000046_0005
Figure imgf000046_0006
and
Figure imgf000046_0007
[0089] In some embodiments, the compound or salt of Formula (I-d) is represented by:
Figure imgf000047_0001
and
Figure imgf000048_0001
. [0090] In some embodiments, the present disclosure provides a compound or salt of Formula (I- a), (I-b), (I-c), or (I-d) is selected from:
Figure imgf000048_0002
, ,
Figure imgf000048_0003
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
, , ,
Figure imgf000051_0002
, , and
Figure imgf000051_0003
[0091] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. [0092] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) , are intended to include all Z-, E- and tautomeric forms as well. [0093] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined. [0094] The compounds or salts for Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration. [0095] In certain embodiments, compounds or salts for Formula (I-a), Formula (I-b), Formula (I- c), Formula (I-d) or Formula (II) , may comprise two or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis. [0096] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) , exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non–limiting examples of tautomeric equilibrium include:
Figure imgf000053_0001
Figure imgf000054_0001
[0097] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. [0098] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. [0099] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [0100] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [0101] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. [0102] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0103] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [0104] The methods and compositions of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I- d) or Formula (II), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [0105] Compounds of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. [0106] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of compounds represented by Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II). The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [0107] In certain embodiments, compounds or salts of Formula (I-a), Formula (I-b), Formula (I- c), Formula (I-d) or Formula (II), may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure. [0108] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell. [0109] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity. [0110] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. [0111] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations [0112] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) and at least one pharmaceutically acceptable excipient. [0113] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form. [0114] Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0115] Pharmaceutical compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate). The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. [0116] Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated. The active compounds can have complementary activities that do not adversely affect each other. For example, the composition can also comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant. Such molecules can be present in combination in amounts that are effective for the purpose intended. [0117] A compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I- d) or Formula (II) may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II)), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants. [0118] Pharmaceutical compositions may also be prepared from a compound or salt of any one of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d) or Formula (II) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999). Methods of Treatment [0119] In some aspects, the present disclosure provides a method of inducing α1-antitrypsin (A1AT), the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof. [0120] In some aspects, the present disclosure provides a method of inducing Z A1AT secretion, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof. [0121] In some aspects, the present disclosure provides a method of treating a α1-antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof. [0122] In some aspects, the present disclosure provides a method of treating low plasma levels of A1AT, the method comprising administering to a subject in need thereof a compound or salt of Formula (I-a), (I-b), (I-c), (I-d) or a pharmaceutical composition thereof. [0123] In some aspects, the present disclosure provides a method of treating a α1-antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (II) or a pharmaceutical composition of Formula (II),
Figure imgf000059_0001
wherein, R1 is selected from C3-6 carbocycle and 6- to 12-membered bicyclic heteroaryl, any of which are optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and Ring
Figure imgf000060_0001
is selected from a 5- to 6-membered saturated heterocycle. [0124] In some embodiments, Formula (II) is represented by:
Figure imgf000060_0002
,
Figure imgf000060_0003
Figure imgf000061_0003
, , ,
Figure imgf000061_0001
, and
Figure imgf000061_0002
[0125] In some embodiments, the administration of a compound or salt of Formula (II) induces α1-antitrypsin (A1AT) in the subject in need thereof. [0126] In some aspects, the present disclosure provides a method of inducing Z A1AT secretion, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof. [0127] In some aspects, the present disclosure provides a method of treating a α1-antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof. [0128] In some aspects, the present disclosure provides a method of treating low plasma levels of A1AT, the method comprising administering to a subject in need thereof a compound or salt of Formula (II) or a pharmaceutical composition thereof. EXAMPLES [0129] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way. [0130] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. [0131] Examples 1-106 show general and exemplary procedures for the preparation of the claimed compounds and Examples 107-110 provide A1AT cell secretion bioassays or mouse model data. Example 1. Synthesis of N-Ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide [0132] N-Ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared using the following sequential synthesis procedures:
Figure imgf000062_0001
[0133] Step a: Synthesis of tert-butyl 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoate
Figure imgf000063_0001
[0134] Pyrimidin-4(3H)-one (5g, 32 mmol) and caesium carbonate (50.85g, 156 mmol) were stirred in dimethylformamide (50ml) for 10 minutes at room temperature. Tert-butyl 4- (bromomethyl)benzoate (14.11g, 52 mmol) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration. The crude product was purified by column chromatography on silica, eluting with ethyl acetate/hexane (30 % to 33%) to give tert-butyl 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoate. Tlc Rf 0.21:1 Ethyl acetate/hexane. [0135] Step b: Synthesis of 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid
Figure imgf000063_0002
[0136] Tert-butyl 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoate (10g, 35 mmol) was dissolved in dichloromethane (50ml) and trifluoroacetic acid (70ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (300ml) for 20 minutes at room temperature. The resultant solid was collected by filtration, washed with diethyl ether (2 x 30ml) and dried in vacuo to give 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid. [0137] Step c: Synthesis of N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide
Figure imgf000064_0001
[0138] 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0oC under nitrogen. The reaction was then allowed to warm to room temperature. Triethylamine (0.11ml, 81 mmol) and ethylmethylamine (2M solution in tetrahydrofuran, 69 mmol) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give N-ethyl-N- methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide. m/z: 270.96 (calc 271.13) 1H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 7.94 (1H, d), 7.36 (4H, s), 6.44 (1H, d), 5.13 (2H, s), 3.43 (1H, br s), 3.17 (1H, br s), 2.88 (3H, br s), 1.05 (3H, br s). Example 2: 3-(4-(Pyrrolidine-1-carbonyl)benzyl)pyrimidin-4(3H)-one
Figure imgf000064_0002
[0139] 3-(4-(Pyrrolidine-1-carbonyl)benzyl)pyrimidin-4(3H)-one was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using pyrrolidine instead of ethylmethylamine in step c of Example 1. m/z: 282.91 (calc 283.13) 1H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 7.94 (1H, d), 7.49 (2H, d), 7.35 (2H, d), 6.44 (1H, d), 5.13 (2H, s), 3.44 (2H, t), 3.34 (2H, t), 1.83 (4H, m). Example 3: 3-(4-(Morpholine-4-carbonyl)benzyl)pyrimidin-4(3H)-one
Figure imgf000065_0001
[0140] 3-(4-(Morpholine-4-carbonyl)benzyl)pyrimidin-4(3H)-one was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using morpholine instead of ethylmethylamine in step c of Example 1. m/z: 298.97 (calc 299.13) 1H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 7.94 (1H, d), 7.38 (4H, m), 6.43 (1H, d), 5.13 (2H, s), 3.59-3.34 (8H, br m). Example 4: 3-(4-(4-Methylpiperazine-1-carbonyl)benzyl)pyrimidin-4(3H)-one
Figure imgf000065_0002
[0141] 3-(4-(4-Methylpiperazine-1-carbonyl)benzyl)pyrimidin-4(3H)-one was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using N-methylpiperazine instead of ethylmethylamine in step c. m/z: 312.18 (calc 312.16) 1H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 7.94 (1H, d), 7.36 (4H, s), 6.43 (1H, d), 5.13 (2H, s), 3.58 (2H, br), 3.33 (2H), 2.29 (4H, br m), 2.17 (3H, br s).
Example 5: N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide
Figure imgf000066_0001
[0142] N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using quinazolin-4(3H)-one instead of pyrimidin-4(3H)-one in step a and methylamine instead of ethylmethylamine in step c. m/z: 292.92 (calc 293.12) 1H NMR (400 MHz, d6 DMSO) δ 8.60 (1H, s), 8.41 (1H, br m), 8.15 (1H, dd), 7.85 (1H, m), 7.79 (2H, d), 7.71 (1H, d), 7.56 (1H, m), 7.42 (2H, d), 5.24 (2H, s), 2.75 (3H, d). Example 6: 4-((6-chloro-4-oxoquinazolin-3(4H)-yl)methyl)-N-methylbenzamide
Figure imgf000066_0002
[0143] 4-((6-chloro-4-oxoquinazolin-3(4H)-yl)methyl)-N-methylbenzamide was prepared similarly to N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using 6- chloroquinazolin-4(3H)-one instead of quinazolin-4(3H)-one in step a of Example 1. m/z: 326.92, 329.10 (calc 327.08, 329.07) 1H NMR (400 MHz, d6 DMSO) δ 8.63 (1H, s), 8.42 (1H, br m), 8.09 (1H, d), 7.88 (1H, m), 7.79 (2H, d), 7.74 (1H, d), 7.42 (2H, d), 5.24 (2H, s), 2.75 (3H, d). Example 7: N-isopropyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide
Figure imgf000067_0002
[0144] N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using N,N-dimethylpropan-2- amine instead of ethylmethylamine in step c of Example 1. m/z: 285.10 (calc 285.15) 1H NMR (400 MHz, d6 DMSO) δ 8.68 (1H, s), 7.93 (1H, br m), 7.34 (4H, s), 6.43 (1H, br m), 5.12 (2H, s), 3.75 (1H br m), 2.67-2.74 (3H), 1.10 (6H). Example 8: N-benzyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide
Figure imgf000067_0001
[0145] N-benzyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamidewas prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using N-methyl benzylamine instead of ethylmethylamine in step c of Example 1. m/z: 333.13 (calc 333.15) 1H NMR (400 MHz, d6 DMSO) δ 8.60 (1H, s), 7.93 (1H, d), 7.41 (7H, m), 7.29 (3H, m), 6.42 (1H, d), 5.16 (2H, s). Example 9: N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2- trifluoroethyl)benzamide.
Figure imgf000068_0001
[0146] N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using 2,2,2-trifluoro-N-methylethan-1-amine instead of ethylmethylamine in step c of Example 1. m/z: 325.12 (calc 325.10) 1H NMR (400 MHz, d6 DMSO) δ 8.68 (1H, s), 7.94 (1H, d), 7.39 (4H, br s), 6.44 (1H, d), 5.13 (2H, s), 4.33 (2H, br), 3.00 (3H, br s). Example 10 : 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide.
Figure imgf000068_0002
[0147] 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N-ethyl-N- methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using ammonium chloride instead of ethylmethylamine in step c of Example 1. m/z (M+Na): 252.07 (calc 252.07) 1H NMR (400 MHz, d6 DMSO) δ 8.68 (1H, s), 7.95 (1H, s,), 7.94 (1H, d), 7.86-7.81 (2H, m), 7.37 (1H, s), 7.40-7.34 (2H, m), 6.43 (1H, d), 5.14 (2H, s). Example 11: N,N-diethyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide.
Figure imgf000068_0003
[0148] N,N-diethyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using diethylamine instead of ethylmethylamine in step c of Example 1. m/z (M+Na): 308.14 (calc 308.14) 1H NMR (400 MHz, d6 DMSO) δ 8.68 (1H, s), 7.94 (1H, d), 7.37-7.30 (4H, m), 6.44 (1H, d), 5.13 (2H, s), 3.48-3.37 (2H, m), 3.22-3.08 (2H, m), 1.17-1.08 (3H, m), 1.08-0.96 (3H, m). Example 12: N-isopropyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide.
Figure imgf000069_0001
[0149] N-isopropyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N- ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using isopropylamine instead of ethylmethylamine in step c of Example 1. m/z (M+Na): 294.12 (calc 294.12) 1H NMR (400 MHz, d6 DMSO) δ 8.63 (1H, s), 7.93 (1H, s), 7.79-7.73 (2H, m), 7.38-7.32 (2H, m), 6.43 (1H, d), 5.12 (2H, s), 4.04 (1H, sept.), 1.12 (6H, d). Example 13: N-(4-fluorobenzyl)-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide.
Figure imgf000069_0002
[0150] N-(4-fluorobenzyl)-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using 4- fluorobenzylamine instead of ethylmethylamine in step c of Example 1. m/z (M+Na): 360.11 (calc 360.11) 1H NMR (400 MHz, d6 DMSO) δ 9.03 (1H, t), 8.68 (1H, s), 7.94 (1H, d), 7.88-7.83 (2H, m), 7.42-7.38 (2H, m), 7.34 (2H, dd), 7.17-7.11 (2H, m), 6.43 (1H, d), 5.15 (2H, s), 4.44 (2H, d). Example 14: 4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide.
Figure imgf000070_0001
[0151] 4-((6-oxopyrimidin-1(6H)-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using 2,2,2- trifluoroethan-1-amine instead of ethylmethylamine in step c of Example 1.m/z (M+Na): 334.08 (calc 334.08) 1H NMR (400 MHz, d6 DMSO) δ 9.07 (1H, t), 8.69 (1H, s), 7.95 (1H, d), 7.89-7.81 (2H, m), 7.47-7.36 (2H, m), 6.44 (1H, d), 5.16 (2H, s), 4.08 (2H, qd). Example 15: N-isopropyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide
Figure imgf000070_0002
[0152] N-isopropyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using isopropyl methylamine in step c of Example 1. m/z: 335.28 (calc 335.16) 1H NMR (400 MHz, d6 DMSO) δ 8.59 (1H, s), 8.15 (1H, d), 7.84 (1H, t), 7.70 (1H, d), 7.56 (1H, t), 7.39 (2H, m), 7.32 (2H, br), 5.22 (2H, s), 4.66 and 3.75 (1H, br), 2.86-2.66 (3H, br), 1.06 (6H, br). Example 16: N-benzyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide
Figure imgf000070_0003
[0153] N-benzyl-N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using N-methyl benzylamine in step c of Example 1. m/z: 383.19 (calc 383.16) 1H NMR (400 MHz, d6 DMSO) δ 8.58 (1H, d), 8.14 (1H, d), 7.83 (1H, t), 7.70 (1H, d), 7.75 (1H, t), 7.40-7.00 (9H, br), 5.23 (2H, s), 4.64 and 4.43 (2H, br), 2.84-2.78 (3H, br). Example 17: N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)-N-(2,2,2-trifluoroethyl) benzamide.
Figure imgf000071_0001
[0154] N-methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide was prepared similarly to N-Methyl-4-((4-oxoquinazolin-3(4H)-yl)methyl)benzamide using 2,2,2- trifluoro-N-methylethan-1-amine in step c of Example 1. m/z: 375.19 (calc 375.12) 1H NMR (400 MHz, d6 DMSO) δ 8.56 (1H, d), 8.12 (1H, d), 7.81 (1H, t), 7.67 (1H, d), 7.52 (1H, t), 7.39 (4H, br), 5.21 (2H, s), 4.29 and 4.10 (2H, br), 3.00 (3H, br). Example 18: 4-((4,5-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-N,N-dimethylbenzamide. [0155] 4-((4,5-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-N,N-dimethylbenzamide was prepared similarly to N-ethyl-N-methyl-4-((6-oxopyrimidin-1(6H)-yl)methyl)benzamide using 5,6-dimethylpyrimidin-4(3H)-one instead of pyrimidin-4(3H)-one in step a and dimethylamine instead of ethylmethylamine in step c of Example 1. m/z: 285.01 (calc 285.15) 1H NMR (400 MHz, d6 DMSO) δ 8.45 (1H, s), 7.34 (4H, ABq), 5.09 (2H, s), 3.95-2.86 (3H, br), 2.20 (3H, s), 1.93 (3H, s). Example 19: N,N-dimethyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide [0156] N,N-dimethyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide was prepared using the following sequential synthesis procedures.
Figure imgf000072_0001
[0157] Step a - Synthesis of tert-butyl 4-((2-oxopyridin-1(2H)-yl)methyl)benzoate
Figure imgf000072_0002
[0158] Pyridin-2(1H)-one (5g, 53 mmol) and caesium carbonate (50.85g, 156 mmol) were stirred in dimethylformamide (50ml) for 10 minutes at room temperature. Tert-butyl 4-(bromomethyl) benzoate (14.11g, 52 mmol) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration. The crude product was purified by column chromatography on silica, eluting with ethyl acetate/hexane (30 % to 50%) to give tert-butyl 4-((2-oxopyridin-1(2H)-yl)methyl)benzoate. m/z: 285.16 (calc 285.14) [0159] Step b - Synthesis of 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid
Figure imgf000072_0003
[0160] Tert-butyl 4-((2-oxopyridin-1(2H)-yl)methyl)benzoate (10g, 35 mmol) was dissolved in dichloromethane (50ml) and trifluoroacetic acid (70ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (300ml) for 20 minutes at room temperature. The resultant solid was collected by filtration, washed with diethyl ether (2 x 30ml) and dried in vacuo to give 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid. m/z: 229.09 (calc 229.07) [0161] Step c - Synthesis of N,N-dimethyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide
Figure imgf000073_0001
[0162] 4-((2-oxopyridin-1(2H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0oC under nitrogen. The reaction was then allowed to warm to room temperature. Triethylamine (0.11ml, 81 mmol) and dimethylamine (2M solution in tetrahydrofuran, 69 mmol) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give N,N-dimethyl-4-((2- oxopyridin-1(2H)-yl)methyl)benzamide. m/z: 255.96 (calc 256.12) 1H NMR (400 MHz, d6 DMSO) δ 7.81 (1H, dd), 7.43 (1H, m), 7.36 (2H, d), 7.29 (2H, d), 6.41 (1H, d), 6.25 (1H, t), 5.11 (2H, s), 2.95-2.87 (6H, br). Example 20: N-ethyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide
Figure imgf000073_0002
[0163] N-ethyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamidewas prepared similarly using ethylmethylaminee instead of dimethylamine in step c of Example 19. m/z: 270.01 (calc 270.14) 1H NMR (400 MHz, d6 DMSO) δ 7.81 (1H, dd), 7.44 (1H, m), 7.41 (2H, d), 7.29 (2H, d), 6.41 (1H, d), 6.25 (1H, t), 5.11 (2H, s), 3.42-3.16 (2H, br), 2.91-2.83 (3H, br), 1.10-1.03 (3H, br). Example 21: N-isopropyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide
Figure imgf000074_0001
[0164] N-isopropyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide was prepared similarly using isopropyl methylamine instead of dimethylamine in step c of Example 19. m/z: 284.0 (calc 284.15) 1H NMR (400 MHz, d6 DMSO) δ 7.81 (1H, dd), 7.43 (1H, m), 7.30 (2H, d), 6.42 (1H, d), 6.25 (1H, t), 4.67 and 3.76 (1H, br), 2.78-2.68 (3H, br), 1.07 (6H, br). Example 22: N-benzyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide
Figure imgf000074_0002
[0165] N-benzyl-N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)benzamide was prepared similarly using N-methylbenzylamine instead of dimethylamine in step c of Example 19. m/z: 332.18 (calc 332.15) 1H NMR (400 MHz, d6 DMSO) δ 7.80 (1H, br), 7.42 - 7.29 (9H, br), 7.16 (1H, br), 6.41 (1H, br), 6.24 (1H, br), 5.12 (2H, br s), 2.85-2.79 (3H, br). Example 23: N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)-N-(2,2,2- trifluoroethyl)benzamide
Figure imgf000075_0002
[0166] N-methyl-4-((2-oxopyridin-1(2H)-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide was prepared similarly using 2,2,2-trifluoro-N-methylethan-1-amine instead of dimethylamine in step c of Example 19. m/z: 324.07 (calc 324.11) 1H NMR (400 MHz, d6 DMSO) δ 7.81 (1H, dd), 7.46 - 7.32 (5H, m), 6.42 (1H, d), 6.25 (1H, t), 5.13 (2H, s), 4.40.4.00 (2H, br), 3.00 (3H, br s). Example 24: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide [0167] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide was prepared using the following sequential synthesis procedures.
Figure imgf000075_0001
[0168] Step a - Synthesis of tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)benzoate: Uracil (5g) and caesium carbonate (50.85g) were stirred in dimethylformamide (50ml) for 10 minutes at room temperature. Tert-butyl 4- (bromomethyl)benzoate (14.11g) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration. The crude product was purified by column chromatography on silica, eluting with ethyl acetate/hexane (30 % to 50%) to give tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoate (3.5g, most polar product) and tert-butyl 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoate (420mg. least polar product). [0169] Step b - Synthesis of 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid: Tert-butyl 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoate (3g) was dissolved in dichloromethane (20ml) and trifluoroacetic acid (30ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (100ml) for 20 minutes at room temperature. The resultant solid was collected by filtration, washed with diethyl ether (2 x 30ml) and dried in vacuo to give 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid. [0170] Step c - Synthesis of 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid (64mg, 0.27 mmol) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (86mg, 0.54 mmol) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0oC under nitrogen. The reaction was then allowed to warm to room temperature. Triethylamine (0.11ml, 81 mmol) and dimethylamine (2M solution in tetrahydrofuran, 69 mmol) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide. m/z: 273.101H NMR (400 MHz, d6 DMSO) δ 11.35, (1H, s), 7.78 (1H, d), 7.38 (2H, d), 7.32 (2H, d), 5.60 (1H, d), 4.90 (2H, s), 2.96-2.86 (6H, br). Example 25: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-methylbenzamide
Figure imgf000076_0001
[0171] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-methylbenzamide was prepared similarly using methylamine instead of dimethylamine in step c of Example 24.m/z (M+Na): 282.08 (calc 282.08) 1H NMR (400 MHz, d6 DMSO) δ 11.34 (1H, s), 8.44-8.39 (1H, m), 7.84- 7.74 (3H, m), 7.39-7.32 (2H, m), 5.61 (1H, dd), 4.91 (2H, s), 2.77 (3H, d). Example 26: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-isopropylbenzamide
Figure imgf000077_0001
[0172] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-isopropylbenzamide was prepared similarly using isopropylamine instead of dimethylamine in step c of Example 24. m/z (M+Na): 310.12 (calc 310.12)1H NMR (400 MHz, d6 DMSO) δ 11.34 (1H, s), 8.18 (1H, d), 7.84- 7.79 (2H, m), 7.77 (1H, d), 7.39-7.30 (2H, m), 5.61 (1H, dd), 4.91 (2H, s), 4.08 (1H, sept.), 1.15 (6H, d). Example 27: 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(4- fluorobenzyl)benzamide
Figure imgf000077_0002
[0173] 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(4-fluorobenzyl)benzamide was prepared similarly using 4-fluorobenzylamine instead of dimethylamine in step c of Example 24. m/z (M+Na): 376.11 (calc 376.11) 1H NMR (400 MHz, d6 DMSO) δ 11.27 (1H, s), 9.04 (1H, t), 7.91-7.82 (2H, m), 7.77 (1H, d), 7.42-7.30 (4H, m), 7.18-7.10 (2H, m), 5.61 (1H, s), 4.92 (2H, s), 4.45 (2H, d). Example 28: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide [0174] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide was prepared using the following sequential synthesis procedures.
Figure imgf000078_0001
[0175] Step a - Synthesis of 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid: Tert-butyl 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoate (2g) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (15ml) was added slowly. The reaction was stirred for 3 hours at room temperature. The reaction was concentrated under reduced pressure and the resulting oil stirred with diethyl ether (50ml) for 20 minutes at room temperature. The resultant solid was collected by filtration, washed with diethyl ether (2 x 15ml) and dried in vacuo to give 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid. [0176] Step b - Synthesis of 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N,N- dimethylbenzamide: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)benzoic acid (32mg) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (43mg) were stirred in tetrahydrofuran (1ml) for 10 minutes at 0oC under nitrogen. The reaction was then allowed to warm to room temperature. Triethylamine (0.06ml) and dimethylamine (2M solution in tetrahydrofuran) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue columned on silica eluting with 4% methanol in dichloromethane. Product containing fractions were concentrated to give 4-((2,6-dioxo-3,6- dihydropyrimidin-1(2H)-yl)methyl)-N,N-dimethylbenzamide. m/z: 273.51 (calc 273.11) 1H NMR (400 MHz, d6 DMSO) δ 7.48 (1H, d), 7.32 (2H, d), 7.27 (2H, d), 5.61 (1H, d), 4.95 (2H, s), 2.95- 2.85 (6H, br). Example 29: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl-N- methylbenzamide
Figure imgf000078_0002
[0177] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl-N-methylbenzamide was prepared similarly using methylethylamine instead of dimethylamine in step b of Example 28. m/z: 287.18 (calc 287.13) 1H NMR (400 MHz, d6 DMSO) δ 7.49 (1H, d), 7.28 (4H, br s), 5.64 (1H, d), 4.95 (2H, d), 3.4-3.2 (2H, m), 2.95-2.85 (3H, br), 1.1-1.0 (3H, br). Example 30: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-isopropyl-N- methylbenzamide
Figure imgf000079_0001
[0178] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-isopropyl-N-methylbenzamide was prepared similarly using methylisopropylamine instead of dimethylamine in step b of Example 28. m/z: 301.18 (calc 301.14) 1H NMR (400 MHz, d6 DMSO) δ 11.20 (1H, s), 7.49 (1H, d), 7.28 (4H, br s), 5.65 (1H, d), 4.95 (2H, d), 3.78 (2H, br m), 2.78-2.60 (3H, br), 1.2-1.0 (6H, br). Example 31: N-benzyl-4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N- methylbenzamide
Figure imgf000079_0002
[0179] N-benzyl-4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-methylbenzamide was prepared similarly using N-methylbenzylamine instead of dimethylamine in step b of Example 28. m/z: 349.36 (calc 349.14) 1H NMR (400 MHz, d6 DMSO) δ 11.20 (1H, s), 7.48 (1H, d), 7.35-7.29 (8H, br m), 7.15 (1H, br m), 5.62 (1H, br), 4.95 (2H, br), 4.64 and 4.44 (2H, br), 2.84-2.79 (3H, br). Example 32: 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-methyl-N-(2,2,2- trifluoroethyl)benzamide
Figure imgf000080_0001
[0180] 4-((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-methyl-N-(2,2,2- trifluoroethyl)benzamide was prepared similarly using 2,2,2-trifluoro-N-methylethan-1-amine instead of dimethylamine in step b of Example 28. m/z: 341.10 (calc 341.10) 1H NMR (400 MHz, d6 DMSO) δ 11.25 (1H, s), 7.49 (1H, d), 7.36-7.31 (4H, br m), 5.65 (1H, br), 4.96 (2H, s), 4.34 and 4.11 (2H, br), 3.00 (3H, br). Example 33: 3-(4-(oxazol-2-yl)benzyl)pyrimidin-4(3H)-one [0181] 3-(4-(oxazol-2-yl)benzyl)pyrimidin-4(3H)-one was prepared using the following synthesis procedure.
Figure imgf000080_0002
[0182] Pyrimidin-4(3H)-one (500mg, 5.2 mmol) and caesium carbonate (5g, 15.6 mmol) were stirred in dimethylformamide (25ml) for 10 minutes at room temperature. 2-(4- (bromomethyl)phenyl)oxazole (1.26g, 5.3 mmol) was added and the reaction was stirred for 3 hours. The reaction was diluted with water and the resulting yellow precipitate collected by filtration. The crude product was purified by column chromatography on silica, eluting with ethyl acetate/hexane (5 % to 95%) to give 3-(4-(oxazol-2-yl)benzyl)pyrimidin-4(3H)-one. m/z: 253.01 (calc 253.09) 1H NMR (400 MHz, d6 DMSO) δ 8.69 (1H, s), 8.21 (1H, s), 7.94 (3H, m), 7.45 (2H, d), 7.37 (1H, d), 6.44 (1H, d), 5.11 (2H, s). Example 34: 3-(4-(oxazol-2-yl)benzyl)quinazolin-4(3H)-one
Figure imgf000081_0001
[0183] 3-(4-(oxazol-2-yl)benzyl)quinazolin-4(3H)-one was prepared similarly to Example 33 using quinazolin-4(3H)-one instead of pyrimidin-4(3H)-one. m/z: 303.07 (calc 303.10) 1H NMR (400 MHz, d6 DMSO) δ 8.61 (1H, s), 8.20 (1H, s), 8.15 (1H, d), 7.94 (2H, d), 7.82 (1H, m), 7.70 (1H, d), 7.56 (1H, m), 7.50 (2H, d), 7.36 (1H, s), 5.26 (2H, s). Example 35: 3-(4-(oxazol-2-yl)benzyl)pyrimidine-2,4(1H,3H)-dione
Figure imgf000081_0002
[0184] 3-(4-(oxazol-2-yl)benzyl)pyrimidine-2,4(1H,3H)-dione was prepared similarly to Example 33 using uracil instead of pyrimidin-4(3H)-one. m/z: 269.13 (calc 269.08) 1H NMR (400 MHz, d6 DMSO) δ 8.20 (1H, s), 7.91 (2H, d), 7.50 (1H, m), 7.39 (2H, d), 7.36 (1H, s), 5.60 (1H, d), 4.98 (2H, s). Scheme 1 - General Method For The Synthesis of Sulfonyl Derivatives [0185] Examples 36-53 were prepared using the following synthetic procedure.
Figure imgf000082_0001
[0186] The carboxylic acid (1 equivalent), potassium hydroxide (1 equivalent) and potassium carbonate (2 equivalents) were added to water and stirred. The sulfonyl chloride (1 equivalent) was added and the reaction was stirred at room temperature for 3 hours. The reaction was cooled to 0oC and acidified with 2M hydrochloric acid to give a white precipitate. This precipitate was dried and triturated with n-pentane to give the compound of formula (1). Example 36: 1-(Quinolin-8-ylsulfonyl)piperidine-4-carboxylic acid [0187] 1-(Quinolin-8-ylsulfonyl)piperidine-4-carboxylic acid was prepared using the general method of Scheme 1 and 1-quinolin-8-ylsulfonylchloride and piperidine-4-carboxylic acid.1H NMR (400 MHz, d6 DMSO) δ 12.26 (1H, s), 9.07 (1H, s), 8.54 (1H, d), 8.36 (1H, d), 8.30 (1H, d), 7.74 (1H, m), 7.70 (1H, m), 3.81 (2H, m), 2.82 (2H, m), 2.31 (1H, m), 1.82 (2H, m), 1.44 (1H, m). Example 37: 1-((2-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0188] Example 37 was prepared using the general method and 1-(2- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid.1H NMR (400 MHz, d6 DMSO) δ 12.38 (1H, br s), 7.97 (1H, d), 7.88 (2H, m), 7.56 (1H, m), 3.60 (2H, m), 2.83 (2H, t), 2.40 (1H, m), 1.86 (2H, m),1.48 (2H, m). Example 38: 1-((3-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0189] Example 38 was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid. 1H NMR (400 MHz, CDCl3) δ 7.77 (1H, s), 7.76 (1H, d), 7.63 (1H, m), 7.60 (1H, m), 3.68 (2H, m), 2.55 (2H, t), 2.37 (1H, m), 2.02 (2H, m),1.86 (2H, m). Example 39: 1-((2,3-Dichlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0190] Example 39 was prepared using the general method and 1-(2,3- dichlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid.1H NMR (400 MHz, d6 DMSO) δ 12.36 (1H, br s), 7.97 (2H, d), 7.59 (1H, m), 3.64 (2H, m), 2.90 (2H, t), 2.43 (1H, m), 1.80 (2H, m),1.54 (2H, m). Example 40: (S)-1-((3-Fluorophenyl)sulfonyl)piperidine-3-carboxylic acid [0191] Example 40 was prepared using the general method and 1-(3- fluorophenyl)sulfonylchloride and (S)-piperidine-3-carboxylic acid.1H NMR (400 MHz, CD3OD) δ 7.52 (2H, m), 7.48 (1H, m), 7.44 (1H, m), 3.73 (1H, d), 3.53 (1H, d), 2.60 (3H, m), 1.97 (1H, m),1.81 (1H, m), 1.59 (1H, m), 1.50 (1H, m). Example 41: (S)-1-((3-Chlorophenyl)sulfonyl)piperidine-3-carboxylic acid [0192] Example 41 was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and (S)-piperidine-3-carboxylic acid.1H NMR (400 MHz, CD3OD) δ 7.79 (1H, s), 7.68 (2H, m), 7.62 (1H, m), 3.72 (1H, d), 3.51 (1H, d), 2.60 (3H, m), 1.97 (1H, m),1.81 (1H, m), 1.58 (1H, m), 1.51 (1H, m). Example 42: (R)-1-((3-Fluorophenyl)sulfonyl)piperidine-3-carboxylic acid [0193] Example 42 was prepared using the general method and 1-(3- fluorophenyl)sulfonylchloride and (R)-piperidine-3-carboxylic acid.1H NMR (400 MHz, CD3OD) δ 7.52 (2H, m), 7.48 (1H, m), 7.44 (1H, m), 3.73 (1H, d), 3.53 (1H, d), 2.60 (3H, m), 1.97 (1H, m),1.81 (1H, m), 1.59 (1H, m), 1.50 (1H, m). Example 43: (R)-1-((3-Chlorophenyl)sulfonyl)piperidine-3-carboxylic acid [0194] Example 43was prepared using the general method and 1-(3- chlorophenyl)sulfonylchloride and (R)-piperidine-3-carboxylic acid.1H NMR (400 MHz, CD3OD) δ 7.79 (1H, s), 7.68 (2H, m), 7.62 (1H, m), 3.73 (1H, d), 3.53 (1H, d), 2.60 (3H, m), 1.97 (1H, m),1.81 (1H, m), 1.59 (1H, m), 1.50 (1H, m). Example 44: 1-((4-Chlorophenyl)sulfonyl)piperidine-4-carboxylic acid [0195] Example 44 was prepared using the general method and 1-(4- chlorophenyl)sulfonylchloride and piperidine-4-carboxylic acid.1H NMR (400 MHz, d6 DMSO) δ 12.32 (1H, s), 7.73 (4H, m), 3.47 (2H, m), 2.44 (2H, m), 2.28 (1H, m), 1.86 (2H, m), 1.57 (2H, m). Example 45: 1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid [0196] Example 45 was prepared using the general method and 1-(2-(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid. 1H NMR (400 MHz, d6 DMSO) δ 12.36 (1H, s), 8.03 (2H, m), 7.90 (2H, m), 3.61 (2H, m), 2.85 (2H, m), 2.41 (1H, m), 1.90 (2H, m), 1.55 (2H, m). Example 46: 1-((3-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid [0197] Example 46 was prepared using the general method and 1-(3- (trifluoromethyl)phenyl)sulfonylchloride and piperidine-4-carboxylic acid. 1H NMR (400 MHz, d6 DMSO) δ 12.33 (1H, s), 8.13 (1H, m), 8.07 (1H, m), 7.95 (1H, m), 7.90 (1H, m), 3.53 (2H, m), 2.45 (2H, m), 2.32 (1H, m), 1.89 (2H, m), 1.57 (2H, m). Example 47: 1-((4-(Trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid [0198] Example 47 was prepared using the general method and 1-(4-(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid.1H NMR (400 MHz, d6 DMSO) δ 8.00 (2H, m), 7.92 (2H, m), 3.20 (2H, m), 2.54 (2H, m), 1.70 (3H, m), 1.57 (2H, m). Example 48: 1-((2,5-Bis(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxylic acid [0199] Example 48 was prepared using the general method and 1-(2,5-bis(trifluoromethyl)phenyl) sulfonylchloride and piperidine-4-carboxylic acid.1H NMR (400 MHz, d6 DMSO) δ 12.36 (1H, s), 8.30 (2H, m), 8.24 (1H, s), 3.65 (2H, m), 2.87 (2H, m), 2.43 (1H, m), 1.89 (2H, m), 1.54 (2H, m). Example 49: 1-((2-(Trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxylic acid [0200] Example 49 was prepared using the general method and 1-(2- (trifluoromethoxy)phenyl)sulfonylchloride and piperidine-4-carboxylic acid.1H NMR (400 MHz, d6 DMSO) δ 12.33 (1H, s), 7.93 (1H, m), 7.83 (1H, m), 7.62 (2H, m), 3.56 (2H, m), 2.71 (2H, m), 2.36 (1H, m), 1.87 (2H, m), 1.52 (2H, m). Example 50: (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)pyrrolidine-3-carboxylic acid [0201] Example 50 was prepared using the general method and 1-(2-(trifluoromethyl)phenyl) sulfonylchloride and (S)-pyrrolidine-3-carboxylic acid. 1H NMR (400 MHz, d6 DMSO) δ 12.62 (1H, br s), 8.05 (2H, m), 7.90 (2H, m), 3.48 (2H, m), 3.38 (2H, m), 3.15 (1H, m), 2.11 (2H, m). Example 51: (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)pyrrolidine-3-carboxylic acid [0202] Example 51 was prepared using the general method and 1-(2- (trifluoromethyl)phenyl)sulfonylchloride and (R)-pyrrolidine-3-carboxylic acid 1H NMR (400 MHz, d6 DMSO) δ 12.62 (1H, br s), 8.05 (2H, m), 7.90 (2H, m), 3.48 (2H, m), 3.38 (2H, m), 3.15 (1H, m), 2.11 (2H, m). Example 52: (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid [0203] (S)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid was prepared using the following synthesis procedure.
Figure imgf000085_0001
[0204] (S)-Piperidine-3-carboxylic acid (1g, 7.7 mmol), potassium hydroxide (434mg, 7.7 mmol) and potassium carbonate (2.14g, 15.4 mmol) were added to water (20ml) and stirred. 2- (Trifluoromethyl)benzenesulfonyl chloride (1.89g, 7.7 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was cooled to 0oC and acidified with 2M hydrochloric acid to give a white precipitate. This precipitate was dried and triturated with n- pentane to give (S)-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid. Tlc Rf 0.370% ethyl acetate in hexane. m/z: 337.98 (calc 338.03) 1H NMR (400 MHz, d6 DMSO) δ 12.33 (1H, s), 8.04 (2H, m), 7.90 (2H, m), 3.69 (1H, dd), 3.50 (1H, dd), 2.93 (1H, m), 2.81 (1H, m), 1.91 (1H, m), 1.72 (1H, m), 1.50 (2H, m). Example 53: (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid [0205] (R)-1-((2-(Trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid was prepared in the same manner as (S)-1-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-3-carboxylic acid, but using (R)-piperidine-3-carboxylic acid. Tlc Rf 0.370% ethyl acetate in hexane. m/z: 338.03 (calc 338.03) 1H NMR (400 MHz, d6 DMSO) δ 12.53 (1H, s), 8.04 (2H, m), 7.90 (2H, m), 3.69 (1H, dd), 3.49 (1H, dd), 2.93 (1H, m), 2.81 (1H, m), 1.90 (1H, m), 1.72 (1H, m), 1.49 (2H, m). General Scheme 1 for the Synthesis of Examples 54–59 [0206] Active compounds can be made directly using an amide electrophile (Step 4) or indirectly via ester hydrolysis and then amidation (Steps 1, 2 and 3) (General Scheme 1). Those skilled in the art may select amines with a range of suitable R1 and R2 groups. Suitable R8 groups include CH3, CH2CH3, C(CH3)3. Suitable R1 and R2 groups include H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2Ph. Herein DMF means dimethylformamide and CDI means carbonyldiimidazole. [0207] Electrophiles to be used in Step 1 of the General Scheme 1 below and their resulting amides formed after Steps 2 and 3 are shown in Table 1. Electrophiles to be used in Step 4 of Scheme 1 and their resulting amides formed directly are shown in Table 2.
Figure imgf000087_0001
Table 1. Structure of step 1 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound
Figure imgf000087_0002
Figure imgf000088_0002
Table 2. Structure of step 4 electrophiles, references for the synthesis of the electrophiles and the structure of the final compound
Figure imgf000088_0001
General Scheme 2 for the Synthesis of Examples 60-81 [0208] Active compounds made in two steps involving for instance an alkylation to give an aryl halide intermediate followed by a palladium catalyzed C-C or C-N bond formation (General Scheme 2, Steps 1 and 2), or directly using an electrophile containing the final X-group (Scheme 1, Step 3).
Figure imgf000089_0001
Table 3 – Possible electrophiles to be used in Step 3 of General Scheme 2, references for their synthesis, and the final compounds.
Figure imgf000089_0002
Figure imgf000090_0002
Table 4 – Possible coupling reagents to be used in Step 2 of Scheme 1, references for their reactions, and the final compounds.
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
General Scheme 3 for the Synthesis of Examples 82-106 [0209] Active compounds made directly by N-alkylation of a heterocyclic compound to give an amide (Step 4) or indirectly via an ester followed by hydrolysis and then amidation (Steps 1, 2 and 3) (Scheme 3). Those skilled in the art may select amines with a range of suitable R1 and R2 groups. Suitable R8 groups include CH3, CH2CH3, C(CH3)3. Suitable R1 and R2 groups include H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2Ph. Herein DMF means dimethylformamide and CDI means carbonyldiimidazole
Figure imgf000093_0001
Table 5. Structure of Step 1 and Step 4 heterocyclic compounds, references for the synthesis and / or reaction of the heterocycle with related electrophiles, and the structure of the final compound
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Example 107: Activity of compounds of the invention in an A1AT cell secretion assay using HEK-Z cells [0210] HEK-Z cells, a human embryonic kidney cell line stably transfected with the human Z A1AT gene, were plated into 96 well plates (3.0 x 105 cells/ml with 200 µl of media/well) overnight at 37˚C in a humidified atmosphere containing 5% CO2. Following incubation cells were washed with 200 µl serum-free media three times and media was replaced with treatments in quadruplicate using serum free media containing either vehicle, 10 µM suberanilohydroxamic acid (SAHA) or a compound of the invention (at concentrations of 10, 33, 100 and 333 nM) for 48 h in a 37˚C incubator in a final volume of 200 µl. At the end of the incubation step the supernatants were removed from the wells, centrifuged at 1000 x g at 4˚C for 10 min and were assayed for human A1AT levels by ELISA (Human Serpin A1/α1-antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions. [0211] Briefly, a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 µl final volume/well). The capture antibody was then removed and wells washed three times with 300 µl wash buffer (0.05% Tween 20 in PBS) and then 200 µl reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h. At the end of the sample incubation step, samples were removed and all wells washed as previously and 100 µl detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed and wells were washed as previously and 100 µl streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 µl stop solution (2M H2SO4) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader. A 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. [0212] The data in Table 6 show that compounds of Examples 1-18 and 24-32 increase secretion of Z A1AT from HEK-Z cells at 300nM. Table 6
Figure imgf000097_0001
Figure imgf000098_0001
[0213] The data in Table 7 show that compounds of Examples 19-23 and 33-35 increase secretion of Z A1AT from HEK-Z cells at 33nM. Table 7
Figure imgf000098_0002
Figure imgf000099_0001
[0214] For examples 36-53, the amount of human A1AT secreted from transfected HEK-EBNA cells into the media was measured by ELISA. SAHA at 10 µM was used a positive control for all in vitro A1AT secretion experiments. [0215] The data in Table 8 show that the compounds of Examples 36-53 increase the secretion of human Z A1AT from HEK-Z cells in a dose dependent manner as measured by ELISA. Table 8
Figure imgf000099_0002
Figure imgf000100_0001
Example 108: Activity of the compounds of Examples 1-18 in an A1AT cell secretion assay using HEK-M cells [0216] HEK-M cells, a human embryonic kidney cell line stably transfected with M A1AT, were plated into 96 well plates (3.0 x 105 cells/ml with 200 µl of media/well) overnight at 37˚C in a humidified atmosphere containing 5% CO2. Following incubation cells were washed with 200 µl serum-free media three times and media was replaced with serum-free media containing vehicle, 10 µM suberanilohydroxamic acid (SAHA) or a compound of Examples 36-51 in replicates of six for 48 h in a 37˚C incubator in a final volume of 200 µl. At the end of the incubation step the supernatants were removed from the wells, centrifuged at 1000 x g at 4˚C for 10 min and were assayed for human A1AT levels by ELISA (Human Serpin A1/α1 antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions. [0217] Briefly, a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 µl final volume/well). The capture antibody was then removed and wells washed three times with 300 µl wash buffer (0.05% Tween 20 in PBS) and then 200 µl reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h. At the end of the sample incubation step, samples were removed and all wells washed as previously and 100 µl detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed and wells were washed as previously and 100 µl streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 µl stop solution (2M H2SO4) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader. A 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. Results [0218] The amount of human M A1AT secreted from transfected HEK-EBNA cells into the media was measured by ELISA. SAHA at 10 µM was used a positive control for all in vitro A1AT secretion experiments. The compounds of Examples 36, 38, 39, 45, 52 and 53 did not lead to an increase in secretion of human M A1AT from HEK-M cells at 10µM. Example 109: Activity of the compounds of Examples 36 and 52 in an A1AT cell secretion assay using HEK-Siiyama cells [0219] The rare Siiyama mutation (Ser 53 to Phe, mature A1AT numbering) was identified in a Japanese male with AATD (Seyama et al J Biol Chem (1991) 266:12627-32). Ser53 is one the conserved serpin residues and is thought to be important for the organization of the internal core of the A1AT molecule. The change from an uncharged polar to a large nonpolar amino acid on the conserved backbone of the protein affects the folding and intracellular processing of Siiyama A1AT. [0220] HEK-Siiyama cells, a human embryonic kidney cell line stably transfected with the human Siiyama A1AT gene, were plated into 96 well plates (3.0 x 105 cells/ml with 200 µl of media/well) overnight at 37˚C in a humidified atmosphere containing 5% CO2. Following incubation cells were washed with 200 µl serum-free media three times and media was replaced with serum-free media containing vehicle, 10 µM suberanilohydroxamic acid (SAHA) or a compound of Example 1 (at 1 and 10 µM) in replicates of eight for 48 h in a 37˚C incubator in a final volume of 200 µl. At the end of the incubation step the supernatants were removed from the wells, centrifuged at 1000 x g at 4˚C for 10 min and were assayed for human A1AT levels by ELISA (Human Serpin A1/α1- antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions. [0221] Briefly, a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 µl final volume/well). The capture antibody was then removed, and wells washed three times with 300 µl wash buffer (0.05% Tween 20 in PBS) and then 200 µl reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h. At the end of the sample incubation step, samples were removed, and all wells washed as previously and 100 µl detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed, and wells were washed as previously and 100 µl streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 µl stop solution (2M H2SO4) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader. A 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. Results [0222] The amount of human Siiyama A1AT secreted from transfected HEK-EBNA cells into the media was measured by ELISA. SAHA at 10 µM was used a positive control for all in vitro A1AT human secretion experiments. The exemplar compounds of Example 36 and 52 did not stimulate secretion of Siiyama A1AT from HEK-Siiyama cells at 1 or 10 µM, as measured by ELISA. In contrast, the positive control 10 µM SAHA stimulated an increase in Siiyama A1AT secretion. Example 110: Activity of the compounds of Examples 36 and 52 in a mouse expressing human Z (huZ mouse) [0223] The huZ mouse (also referred to as the PiZZ mouse) is a transgenic mouse strain that contains multiple copies of the Z variant of the human A1AT gene, developed by two separate groups (Dycaico et al Science (1988) 242:1409-12) and Carlson et al J. Clin Invest (1989) 83:1183-90). HuZ mice are on a C57Bl/6 background and express the human Z A1AT protein in liver tissue. The mice used in this study are from the progeny of Carlson and colleagues (transgenic line Z11.03). HuZ mice have been used as a tool to assess the effects of an exemplar compound of the invention on either increasing the circulating levels of Z A1AT in plasma or the effects of compound on the accumulation of Z A1AT polymers in the liver and associated liver pathology. [0224] HuZ mice (n=4/group; male or female) with basal human Z A1AT plasma levels of between 200-600 µg/ml were treated with either vehicle or the compounds of Examples 26 or 52 at 5, 15 or 50 mg/kg twice a day by oral gavage for 14 consecutive days. Mice had access to food (standard mouse chow, SAFE diets) and water ad libitum. On study day 14, each mouse was dosed one hour prior to terminal procedures. Blood was taken from each mouse from the tail vein on pre- dosing days -12, -7 and -5, and dosing days 12, 13 and 14. Blood was collected into microvettes containing EDTA and plasma was prepared by centrifugation at 2700 x g at 4˚C for 10 min. Plasma was aliquoted and stored at -80˚C for bioanalysis. Plasma samples from pre-dosing days -12, -7 and -5 were used for to determine mean basal levels of human Z A1AT for each mouse. Plasma samples collected on the last three dosing days of the study (days 12, 13 and 14) were used to determine the effect of the compound of Example 26 or 52 on human Z A1AT secretion by measuring human Z A1AT levels and comparing to basal levels for each mouse. Human Z A1AT levels in mouse plasma samples were measured by ELISA (Human Serpin A1/α1 antitrypsin duo set ELISA, R& D Systems, DY1268) per manufacturer’s instructions. [0225] Briefly, a 96 well plate was coated with human A1AT capture antibody overnight at room temperature (1:180 dilution from stock, 100 µl final volume/well). The capture antibody was then removed and wells washed three times with 300 µl wash buffer (0.05% Tween 20 in PBS) and then 200 µl reagent diluent (25% Tween 20 in PBS) was incubated in each well for 1 h at room temperature. Diluted samples, standards (125, 250, 500, 1000, 2000, 4000 and 8000 pg/ml A1AT) or blanks were then added to each well in duplicate and the plates were covered with a plate sealer and left at room temperature for 2 h. At the end of the sample incubation step, samples were removed, and all wells washed as previously and 100 µl detection antibody (1:180 dilution from stock) was added to each well and incubated for a further 2 h at room temperature. Following incubation with detection antibody, supernatant was removed, and wells were washed as previously and 100 µl streptavidin–HRP solution (1:200 dilution from stock) was added to each well for 20 min in the dark. After which, 50 µl stop solution (2M H2SO4) was added and optical density (OD) of each well was read at 450 nm with 570 nm blank subtracted from each well using a microplate reader. A 4 parameter logistic curve was constructed using GraphPad Prism 7 and A1AT concentrations were determined in each sample by interpolation from a standard curve and multiplying by the appropriate dilution factor. Results [0226] The effect of the compound of Example 26 or 52 on circulating levels of human Z A1AT was assessed in the huZ mouse model. The compounds of Example 26 and 52 stimulated secretion of human Z A1AT compared to baseline levels in huZ mice.

Claims

CLAIMS 1. A compound represented by the structure of Formula (I-a):
Figure imgf000104_0001
or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000104_0004
is a 6-membered heterocycle selected from:
Figure imgf000104_0002
,
Figure imgf000104_0003
A is selected from: -C(=O)N(H)(R1), -C(=O)N(R2)(R3); and 5-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, -OR11, N(R11)2, -C(O)R11, -C(O)OR11, -OC(O)R11, - OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)OR11, - OC(O)R11, -OC(O)N(R11)2, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2(R11), -S(O)2N(R11)2, -NO2,=O and -CN; R1 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - N(R12)S(O)2(R12), -S(O)N(R12)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - OC(O)N(R12)2, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)C(O)OR12, -S(O)2R12, - S(O)2N(R12)2, -NO2, and -CN; R2 and R3 are each C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - OC(O)N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -S(O)2R13, - N(R13)S(O)2(R13), -S(O)2N(R13)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, - C(O)N(R13)2, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)C(O)N(R13)2, -S(O)2R13, -S(O)2N(R13)2, -NO2, and -CN; and R11, R12 and R13 are each independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle.
2. The compound or salt of claim 1, wherein A is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted.
3. The compound or salt of claim 1 or claim 2, wherein A is selected from oxazole, isoxazole, thiazole, isothiazole, and imidazole, any one of which is optionally substituted.
4. The compound or salt of any one of claims 1-3, wherein Formula (I-a) is represented by:
Figure imgf000105_0001
.
5. The compound or salt of claim 1, wherein A is -C(=O)N(H)(R1) and R1 is C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents selected from: halogen, -OR12, -N(R12)2, - C(O)R12, -NO2, and -CN.
6. The compound or salt of claim 5, wherein Formula (I-a) is represented by:
Figure imgf000106_0001
, , and
Figure imgf000106_0002
7. The compound or salt of claim 1, wherein A is -C(=O)N(R2)(R3) and each of R2 and R3 are independently C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents selected from: halogen, - OR13, -N(R13)2, -C(O)R13, -NO2, and -CN.
8. The compound or salt of claim 1 or claim 7, wherein R2 and R3 are each independently C1-3 alkyl optionally substituted with one or more substituents independently selected from fluoro, chloro, and bromo.
9. The compound or salt of any one of clams 1, 7, or 8, wherein Formula (I-a) is represented by:
Figure imgf000106_0003
Figure imgf000106_0004
Figure imgf000107_0003
, , , and
Figure imgf000107_0004
10. The compound or salt of claim 1 or claim 7, wherein R2 and R3 are each independently C1-3 alkyl optionally substituted with C6 carbocycle optionally substituted with one or more substituents selected from fluoro, chloro, and bromo.
11. The compound or salt of claim 10, wherein the C6 carbocycle is phenyl optionally substituted with one or more substituents selected from fluoro, chloro, and bromo.
12. The compound or salt of any one of claims 1, 7, 10, or 11, wherein Formula (I-a) is represented by:
Figure imgf000107_0005
and
Figure imgf000107_0006
13. A compound represented by the structure of Formula (I-b):
Figure imgf000107_0001
or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000107_0007
is a bicyclic heterocycle selected from
Figure imgf000107_0002
B selected from -C(=O)N(H)(R4), -C(=O)N(R5)(R6), and 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, pyrrole, furan, thiophene, imidazole, triazole, and tetrazole, any of which is optionally substituted with one more substituents independently selected from: halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, -OC(O)R21, - OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, - N(R21)S(O)2(R21), -S(O)2N(R21)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR21, -N(R21)2, -C(O)R21, -C(O)OR21, - OC(O)R21, -OC(O)N(R21)2, -C(O)N(R21)2, -N(R21)C(O)R21, -N(R21)C(O)OR21, - N(R21)S(O)2(R21), -S(O)2N(R21)2, -NO2, =O, and -CN; R4 is selected from: C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, - OC(O)R22, -OC(O)N(R22)2, -C(O)N(R22)2, -N(R22)C(O)R22, -NO2, =O, and -CN; and C2-6 alkyl substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, - C(O)N(R22)2, -N(R22)C(O)R22, -N(R22)C(O)OR22, -N(R22)S(O)2(R22), - S(O)2N(R22)2, -NO2,=O, and -CN; R5 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, -OC(O)N(R23)2, - C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, -N(R23)S(O)2(R23), - S(O)2N(R23)2, -NO2, and -CN; R6 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, - OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, - N(R24)C(O)OR24, -N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, - OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR24, N(R24)2, -C(O)R24, -C(O)OR24, -OC(O)R24, -OC(O)N(R24)2, -C(O)N(R24)2, -N(R24)C(O)R24, -N(R24)C(O)OR24, - N(R24)S(O)2(R24), -S(O)2N(R24)2, -NO2, and -CN; R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1- 6 alkyl, -O-C1-6 haloalkyl, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; R21, R23, and R24 are each independently selected at each occurrence from hydrogen, - OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and R22 is independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle.
14. The compound or salt of claim 13, wherein R` is selected from hydrogen, halogen, -OH, C1-6 alkyl, and C1-6 haloalkyl.
15. The compound or salt of claim 13 or claim 14 wherein,
Figure imgf000110_0001
is represented by:
Figure imgf000110_0002
.
16. The compound or salt of any one of claims 13-15, wherein B is 5-membered heteroaryl selected from pyrazole, oxazole, isoxazole, and imidazole, any of which is optionally substituted.
17. The compound or salt of claim of any one of claims 13-16, wherein Formula (I-b) is represented by:
Figure imgf000110_0003
.
18. The compound or salt of claim of any one of claims 13-15, wherein B is C(=O)N(H)(R4) and R4 is C1 alkyl optionally substituted with one or more substituents independently selected from halogen, -N(R22)2, -C(O)R22, -C(O)OR22, -OC(O)R22, -OC(O)N(R22)2, - C(O)N(R22)2, -N(R22)C(O)R22, -NO2, and -CN.
19. The compound or salt claim 18, wherein Formula (I-b) is represented by:
Figure imgf000110_0004
and
Figure imgf000110_0005
O .
20. The compound or salt of any one of claims 13-15, wherein B is C(=O)N(R5)(R6) and; R5 is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR23, -N(R23)2, -C(O)R23, -C(O)OR23, -OC(O)R23, - OC(O)N(R23)2, -C(O)N(R23)2, -N(R23)C(O)R23, -N(R23)C(O)OR23, - N(R23)S(O)2(R23), -S(O)2N(R23)2, -NO2, and -CN; and R6 is C1 alkyl substituted with one more substituents one or more substituents independently selected from halogen, -OR24, -N(R24)2, -C(O)R24, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR24, -N(R24)2, -C(O)R24, -NO2, and -CN.
21. The compound or salt of claim 20, wherein Formula (I-b) is represented by:
Figure imgf000111_0003
, and
Figure imgf000111_0004
22. A compound represented by the structure of Formula (I-c):
Figure imgf000111_0001
, or a pharmaceutically acceptable salt thereof, wherein: is a 6-membered heterocycle represented by:
Figure imgf000111_0002
X is selected from (a), (b), and (c): (a) -C(=O)N(H)(R7), -C(=O)N(R8)(R9), -CH2C(=O)N(H)(C1-6 alkyl), - CH2C(=O)N(C1-6 alkyl)2 , -CHC(=O)N(H)(C1-6 alkyl), -CHC(=O)N(C1-6 alkyl)2, - S(=O)2N(H)(C1-6 alkyl), -S(=O)2N(C1-6 alkyl)2; (b) 5-membered heteroaryl selected from oxazole, isoxazole, pyrrole, furan, imidazole, 1,3,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR31, -N(R31)2, -C(O)R31, -C(O)OR31, -OC(O)R31, - OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, -N(R31)C(O)OR31, - N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR31, -N(R31)2, -C(O)R31, - C(O)OR31, -OC(O)R31, -OC(O)N(R31)2, -C(O)N(R31)2, -N(R31)C(O)R31, - N(R31)C(O)OR31, -N(R31)S(O)2(R31), -S(O)2N(R31)2, -NO2, =O, and -CN; and (c) 5- to 6-membered heterocycle with one or two oxo group and optionally substituted with one or more C1-3 alkyl; R7 is selected from: C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, - N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, - N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -N(R24)C(O)OR32, - N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, - N(R24)C(O)OR32, -N(R32)S(O)2(R32), -S(O)2N(R32)2, -NO2, and -CN; R8 is C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), - S(O)2N(R33)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -N(R33)S(O)2(R33), - S(O)2N(R33)2, -NO2, -CN; R9 is selected from: C1 alkyl substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, - OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN; and C2-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -OC(O)R34, - OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, =O, -CN; C3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, - N(R34)C(O)OR34, -N(R34)S(O)2(R34), -S(O)2N(R34)2, -NO2, and -CN; or R8 and R9 can come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from: halogen, C1-6 alkyl, - OR35, -N(R35)2, -C(O)R35, -C(O)OR35, -OC(O)R35, -OC(O)N(R35)2, -C(O)N(R35)2, -N(R35)C(O)R35, -N(R35)C(O)OR35, -N(R35)S(O)2(R35), -S(O)2N(R35)2, -NO2, - CN; RA is independently selected at each occurrence from halogen and C1-6 alkyl; R`` is each independently selected from hydrogen, halogen, C1-3 alkyl, -NO2, and -CN; R31, R32, R33, R34 and R35 are each independently selected at each occurrence from hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; and n is selected from 0, 1, 2, 3, and 4.
23. The compound or salt of claim 22, wherein each R`` is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, fluoro, chloro, and bromo.
24. The compound or salt of claim 22 or claim 23, wherein
Figure imgf000114_0002
is represented by:
Figure imgf000114_0001
Figure imgf000114_0003
.
25. The compound or salt of any one of claims 22-24, wherein X is 5-membered heteroaryl selected from oxazole, isoxazole, imidazole, 1,3,4-oxaziazole, and triazole, any of which is optionally substituted.
26. The compound or salt of claim 25, wherein Formula (I-c) is represented by:
Figure imgf000115_0001
,
Figure imgf000115_0002
and
Figure imgf000115_0003
27. The compound or salt of any one of claims 22-24, wherein X is -C(=O)N(H)(R7) and R7 is selected from: C1 alkyl substituted with one more substituents one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, - C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN; and C2-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - OC(O)N(R32)2, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, -CN.
28. The compound or salt of claim 27, wherein Formula (I-c) is represented by:
Figure imgf000115_0004
, and
Figure imgf000115_0005
.
29. The compound or salt of any one of claims 22-24, wherein X is -C(=O)N(R8)(R9); and R8 is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, - OC(O)N(R33)2, -C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -NO2, -CN; and C3- 6carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, - C(O)N(R33)2, -N(R33)C(O)R33, -N(R33)C(O)OR33, -NO2, and -CN; and R9 is selected from: C1 alkyl substituted with one or more substituents independently selected halogen, -OR34, -N(R34)2, -C(O)R34, -NO2, -CN; and C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, - OR34, -N(R34)2, -C(O)R34, -C(O)OR34, -NO2, and -CN; and C2-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR34, -N(R34)2, -C(O)R34, -C(O)OR34, - OC(O)R34, -OC(O)N(R34)2, -C(O)N(R34)2, -N(R34)C(O)R34, -N(R34)C(O)OR34, - NO2, and -CN.
30. The compound or salt of claim 29, wherein Formula (I-c) is selected from:
Figure imgf000116_0001
, , ,
Figure imgf000116_0002
, and
Figure imgf000116_0003
31. The compound or salt of any one of claims 22-24, wherein X is -C(=O)N(R8)(R9) and both of R8 and R9 come together to form a 5- to 6-membered saturated heterocycle optionally substituted with one or more substituents selected from halogen, C1-3 alkyl and C1-3 haloalkyl.
32. The compound or salt of claim 31, wherein the optionally substituted 5- to 6-membered saturated heterocycle is selected from pyrrolidine, morpholine, and piperazine.
33. The compound or salt of claim 31 or claim 32, wherein Formula (I-c) is represented by:
Figure imgf000116_0004
, and
Figure imgf000116_0005
34. The compound or salt of any one of claims 22-24, wherein n is selected from 0, 1, and 2.
35. The compound or salt of claim 34, wherein RA is selected from methyl, ethyl, propyl, chloro, fluoro, and bromo.
36. The compound or salt of claim 34 or claim 35, wherein Formula (I-c) is represented by:
Figure imgf000117_0002
Figure imgf000117_0003
and
Figure imgf000117_0004
37. The compound or salt of any one of claims 22-24, wherein X is 5- to 6-membered heterocycle with one or two oxo group and optionally substituted with one or more C1-3 alkyl. 38. The compound or salt of claim 37, wherein Formula (I-c) is represented by:
Figure imgf000117_0001
,
Figure imgf000118_0002
, , , and
Figure imgf000118_0003
. 39. The compound or salt of any one of claims 22-24, wherein X is selected from - CH2C(=O)N(H)(C1-6 alkyl), -CH2C(=O)N(C1-6 alkyl)2, -CHC(=O)N(H)(C1-6 alkyl), - CHC(=O)N(C1-6 alkyl)2, and -S(=O)2N(H)(C1-6 alkyl), -S(=O)2N(C1-6 alkyl)2. 40. The compound or salt of claim 39, wherein Formula (I-c) is represented by:
Figure imgf000118_0001
41. A compound represented by the structure of Formula (I-d):
Figure imgf000118_0004
or a pharmaceutically acceptable salt thereof, wherein: each of R1 and R2 are independently selected from hydrogen and C1-6 alkyl; and
Figure imgf000119_0001
is a represented by:
Figure imgf000119_0002
Figure imgf000119_0003
Figure imgf000119_0004
and
Figure imgf000119_0005
42. The compound or salt of claim 41, wherein Formula (I-d) is represented by:
Figure imgf000119_0006
Figure imgf000120_0001
Figure imgf000120_0002
and
Figure imgf000120_0003
. 43. A compound represented by:
Figure imgf000120_0004
, ,
Figure imgf000120_0005
,
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0002
, , ,
Figure imgf000124_0003
, and
Figure imgf000124_0004
44. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound or salt of any one of claims 1 to 43. 45. A method of inducing α1-antitrypsin (A1AT), the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of any one of claims 1 to 43 or a pharmaceutical composition of claim 44. 46. A method of treating a α1-antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of any one of claims 1 to 43 or a pharmaceutical composition of claim 44. 47. A method of treating a α1-antitrypsin deficiency, the method comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt of Formula (II) or a pharmaceutical composition of Formula (II),
Figure imgf000124_0001
wherein, R1 is selected from C3-6 carbocycle and 6- to 12-membered bicyclic heteroaryl, any of which are optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and Ring
Figure imgf000125_0001
is selected from a 5- to 6-membered saturated heterocycle. 48. The method of claim 47, wherein Formula (II) is represented by:
Figure imgf000125_0002
,
Figure imgf000125_0003
Figure imgf000126_0001
Figure imgf000126_0002
, and
Figure imgf000126_0003
. 49. The method of claim 47 or claim 48, wherein the administering induces α1-antitrypsin (A1AT) in the subject in need thereof.
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