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WO2023215559A1 - Compounds, compositions, and methods - Google Patents

Compounds, compositions, and methods Download PDF

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Publication number
WO2023215559A1
WO2023215559A1 PCT/US2023/021158 US2023021158W WO2023215559A1 WO 2023215559 A1 WO2023215559 A1 WO 2023215559A1 US 2023021158 W US2023021158 W US 2023021158W WO 2023215559 A1 WO2023215559 A1 WO 2023215559A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
compound
heterocyclyl
heteroaryl
Prior art date
Application number
PCT/US2023/021158
Other languages
French (fr)
Inventor
Anjali Pandey
Rajeev Goswami
Athisayamani Jeyaraj DURAISWAMY
Biswajit Kalita
Vikramjit SARKAR
Original Assignee
Aria Pharmaceuticals, Inc.
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Publication date
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Publication of WO2023215559A1 publication Critical patent/WO2023215559A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Caspases are conserved family of aspartic acid-directed cysteinyl proteases that have essential functions in apoptosis, inflammation, cell survival, proliferation and differentiation. Caspases are cysteine proteases so named due to strict specificity for cleaving peptide sequences C-terminal to aspartic acids residues. Currently, 12 caspase isozymes have been identified in humans with numerous reported activities. Caspases are often subcategorized as either pro-apoptotic or pro-inflammatory enzymes. A prominent member of the pro-inflammatory class is caspase 1 (also known as interleukin-converting enzyme or ICE) which is responsible for the proteolytic activation of interleukin (IL)-1 ⁇ and IL-18.
  • caspase 1 also known as interleukin-converting enzyme or ICE
  • IL-1 ⁇ and IL-18 are cytokines that play a major role in the immune response and within numerous autoimmune and inflammatory diseases.
  • Caspase 1 is constitutively and inducibly expressed in immune response elements such as T cells, macrophages and neutrophils.
  • DESCRIPTION [0004] Provided herein are compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, that are useful in treating and/or preventing diseases mediated, at least in part, by caspase 1.
  • n is 0, 1, 2, 3, 4, or 5;
  • R 1 is R 11 is hydrogen, fluoro, chloro, cyano, -CF 3 , or aryl; wherein the aryl is independently optionally substituted with one to five halo;
  • R 12 is hydrogen, fluoro, chloro, cyano, -CF 3 , aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo;
  • R 13 is C 1-6 alkyl, -C(O)OR 8 , or -C(O)N(R 8 ) 2 ;
  • R 2 is hydrogen or C 1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)
  • a compound of Table B-l or Table B-2 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier.
  • a method for treating a disease or condition, at least in part, by a caspase 1 inhibitor comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • a method for treating a disease or condition, at least in part, by inhibiting caspase 1 comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • compositions including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds.
  • the disclosure further provides compounds or compositions thereof for use in a method of treating a disease, disorder, or condition that is mediated, at least in part, by caspase 1.
  • the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder, or condition selected from chronic kidney disease, diabetic nephropathy, IgA nephropathy, uveitis, an excess dietary alcohol intake disease, a necrotic disease, a viral mediated disease, inflammatory peritonitis, osteoarthritis, pancreatitis (e.g., acute pancreatitis or chronic pancreatitis), asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, diabetes (e.g., juvenile diabetes, insulin-dependent diabetes mellitus (Type I)), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn
  • the method comprising administering an effective amount of a compound which inhibits caspase 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • a method for treating chronic kidney disease, diabetic nephropathy, or IgA nephropathy comprising administering an effective amount of a compound of Table A-1 or Table A-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • a method for treating chronic kidney disease, diabetic nephropathy, or IgA nephropathy comprising administering an effective amount of a compound of Table B-1 or Table B-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • a pharmaceutically acceptable carrier comprising administering an effective amount of a compound of Table B-1 or Table B-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -C(O)NH 2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group.
  • Alkyl refers to an unbranched or branched saturated hydrocarbon chain.
  • alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl).
  • alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • butyl includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., - CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 ); and “propyl” includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ), and isopropyl (i.e., -CH(CH 3 ) 2 ).
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl).
  • alkenyl groups include, e.g., ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • Alkoxy refers to the group “alkyl-O-”.
  • alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.
  • Alkoxyalkyl refers to the group “alkyl-O-alkyl”.
  • Alkylthio refers to the group “alkyl-S-”.
  • Alkylsulfinyl refers to the group “alkyl-S(O)-”.
  • Alkylsulfonyl refers to the group “alkyl-S(O) 2 -”.
  • Alkylsulfonylalkyl refers to -alkyl-S(O) 2 -alkyl.
  • Acyl refers to a group -C(O)R y , wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR y R z and an “N- amido” group which refers to the group -NR y C(O)R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or R y and R z are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.
  • Amino refers to the group -NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Aminoalkyl refers to the group “-alkyl-NR y R z ,” wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Amidino refers to -C(NR y )(NR z 2), wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.
  • Arylalkyl or “Aralkyl” refers to the group “aryl-alkyl-”.
  • Carbamoyl refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NR y R z and an “N-carbamoyl” group which refers to the group -NR y C(O)OR z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Carboxyl ester or “ester” refer to both -OC(O)R x and -C(O)OR x , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Cyanoalkyl refers to refers to an alkyl group as defined above, wherein one or more (e.g., one to three) hydrogen atoms are replaced by a cyano (-CN) group.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems.
  • the term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
  • Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
  • cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.
  • Cycloalkoxy refers to “-O-cycloalkyl.”
  • Cycloalkylalkyl refers to the group “cycloalkyl-alkyl-”.
  • Cycloalkylalkoxy refers to “-O-alkyl-cycloalkyl.”
  • “Hydrazino” refers to -NHNH 2 .
  • Imino refers to a group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Imido” refers to a group -C(O)NR y C(O)R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a halogen.
  • a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
  • haloalkyl examples include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to an alkoxy group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a halogen.
  • Hydroxyalkyl refers to an alkyl group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a hydroxy group.
  • “Heteroalkyl” refers to an alkyl group in which one or more (e.g., one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom.
  • heteroalkyl includes unbranched or branched saturated chain having carbon and heteroatoms.
  • 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR y -, -O- , -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkyl groups include, e.g., ethers (e.g., -CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , etc.), thioethers (e.g., -CH 2 SCH 3 , -CH(CH 3 )SCH 3 , - CH 2 CH 2 SCH 3 , -CH 2 CH 2 SCH 2 CH 2 SCH 3 , etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 , -CH(CH 3 )S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 3 , -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 , etc.), and amines (e.g., -CH 2 NR y CH 3 , -CH(CH 3 )NR y CH 3 ,
  • heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • “Heteroalkylene” refers to a divalent alkyl group (i.e., alkylene) in which one or more (e.g., one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
  • “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain.
  • the term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms.
  • 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkylene groups include, e.g., -CH 2 OCH 2 -, -CH(CH 3 )OCH 2 -, -CH 2 CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 CH 2 OCH 2 -, -CH 2 SCH 2 -, -CH(CH 3 )SCH 2 -, -CH 2 CH 2 SCH 2 -, -CH 2 CH 2 SCH 2 CH 2 SCH 2 -, -CH 2 S(O) 2 CH 2 -, -CH(CH 3 )S(O) 2 CH 2 -, -CH 2 CH 2 S(O) 2 CH 2 -, -CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 2 -, -CH 2 NR y CH 2 -, -CH(CH 3 )NR y CH 2 -, -CH 2 CH 2 NR y CH 2 -, -CH 2 CH 2 NR y CH 2 CH 2 NR y CH 2 -,
  • heteroalkylene includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • heteroalkylene does not include groups such as amides or other functional groups having an oxo present on one or more carbon atoms.
  • “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxide
  • fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings).
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”.
  • Heterocyclyl refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups.
  • Any non- aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.
  • ring carbon atoms i.e., C 2-20 heterocyclyl
  • 2 to 12 ring carbon atoms i.
  • heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-ox
  • heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
  • spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl.
  • fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • Heterocyclylalkyl refers to the group “heterocyclyl-alkyl-”.
  • Sulfonyl refers to the group -S(O) 2 R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • sulfonyl examples include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • “Sulfinyl” refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • sulfinyl examples include methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.
  • “Sulfonamido” refers to the groups -SO 2 NR y R z and -NR y SO 2 R z , where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • substituted means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroaryl
  • R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl.
  • substituted also means any of the above groups in which one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R g and R h and R i are taken together with the atoms to which they are attached form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms. Such impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein.
  • the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to three.
  • Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • isotopically labeled compounds have structures depicted herein, except that one or more (e.g., one to five or one to three) atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more (e.g., one to five or one to three) hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more (e.g., one to five or one to three) hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME).
  • isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F, 3 H, 11 C labeled compound may be useful for PET or SPECT or other imaging studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable.
  • physiologically acceptable salts include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH 2 (alkyl)), dialkyl amines (i.e., HN(alkyl) 2 ), trialkyl amines (i.e., N(alkyl) 3 ), substituted alkyl amines (i.e., NH 2 (substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl) 2 ), tri(substituted alkyl) amines (i.e., N(substituted alkyl) 3 ), alkenyl amines (i.e., NH 2 (alkenyl)),
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • hydrate refers to the complex formed by the combining of a compound described herein and water.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid and ethanolamine.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers.
  • the imidic acid containing compounds are understood to include their amide tautomers.
  • the compounds of the invention, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • Relative centers of the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).
  • Prodrugs means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V.
  • the compounds or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof are inhibitors of caspase-1.
  • compounds of Formula A-I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof wherein: n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2; R 1 is , , , , , R 2 is hydrogen or C 1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC 1-6 alkyl, and tetrazolyl, wherein each -C(O)OC 1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z 1a ; R 2’ is hydrogen, cyano, or C 1-6 alkyl substituted with one to six
  • a compound of Formula A-IA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2; R 1 is R 2 is hydrogen or C 1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC 1-6 alkyl, and tetrazolyl, wherein each -C(O)OC 1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z 1a ; R 3 is R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C 1-6 alkyl, C 2-6
  • m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. [0086] In certain embodiments, each R 9 is independently halo or C 1-6 alkyl. [0087] Also provided is a compound of Formula A-IB: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1 , R 4 , R 4’ , R 5 , R 6 , n, and X are independently as defined herein.
  • R 4 and R 4’ together with the atom to which they are attached form a C 3-10 cycloalkyl or heterocyclyl; wherein each is independently optionally substituted with one to six Z 1a .
  • R 4 and R 4’ together with the atom to which they are attached form a C 3-10 cycloalkyl.
  • R 4 and R 4’ together with the atom to which they are attached form a C 3-6 cycloalkyl.
  • R 4 and R 4’ together with the atom to which they are attached form a cyclopropyl.
  • a compound of Formula A-IC or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1 , R 4 , R 5 , R 6 , n, and X are independently as defined herein.
  • a compound of Formula A-II or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 2 , R 3 , R 4 , R 5 , R 6 , n, and X are independently as defined herein.
  • R 11 is hydrogen or fluoro.
  • R 12 is fluoro, chloro, cyano, or -O-aryl optionally substituted with one to five halo.
  • R 12 is fluoro.
  • R 12 is -O-aryl optionally substituted with one to five halo.
  • R 12 is [0098] Also provided is a compound of Formula A-IIC: . or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 2 , R 13 , R 4 , R 5 , R 6 , n, and X are independently as defined herein. [0099] In certain embodiments, R 13 is -C(O)N(R 8 ) 2 . [0100] In certain embodiments, R 13 is -C(O)NHR 8 .
  • R 13 is [0102] In certain embodiments, R 2 is C 1-6 alkyl substituted with -C(O)OC 1-6 alkyl. [0103] In certain embodiments, R 2 is C 1-6 alkyl substituted with -C(O)OC 2 alkyl. [0104] In certain embodiments, R 2 is -CH 2 C(O)OC 2 alkyl. [0105] In certain embodiments, the moiety is: , [0106] In certain embodiments, the moiety is:
  • a compound of Formula A-III or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 4 , R 5 , R 6 , n, and X are independently as defined herein.
  • a compound of Formula A-IIIA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 4 , R 5 , R 6 , n, and X are independently as defined herein.
  • a compound of Formula A-IV or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 7 , R 4 , R 5 , R 6 , n, and X are independently as defined herein.
  • a compound of Formula A-IVA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 7 , R 4 , R 5 , R 6 , n, and X are independently as defined herein.
  • a compound of Formula A-IVB or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 7 , R 4 , R 5 , R 6 , n, and X are independently as defined herein.
  • a compound of Formula A-IVC or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 7 , R 4 , R 5 , R 6 , n, and X are independently as defined herein.
  • R 7 is hydrogen or C 1-6 alkyl.
  • R 7 is ethyl.
  • R 5 is hydrogen, halo, or C 1-6 alkyl. In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is halo. In certain embodiments, R 5 is C 1-6 alkyl. In certain embodiments, R 5 is C 1-6 alkoxy. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is -O- CH 3 . [0116] In certain embodiments, R 5 is hydrogen and X is O or S.
  • a compound of Formula A-V or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1 , R 4 , R 5 , R 6 , R 9 , m, and n are independently as defined herein.
  • a compound of Formula A-VA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1 , R 4 , R 6 , and n are independently as defined herein.
  • Z 1a is halo or C 1-6 alkyl.
  • a compound of Formula A-VIA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1 , R 4 , R 6 , R 9 , m, and n are independently as defined herein.
  • a compound of Formula A-VIB or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1 , R 4 , R 6 , and n are independently as defined herein.
  • a compound of Formula A-VII or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1 , R 4 , R 6 , R 9 , m, and n are independently as defined herein.
  • a compound of Formula A-VIIA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R 1 , R 4 , R 6 , and n are independently as defined herein.
  • R 4 is C 1-6 alkyl optionally substituted by phenyl.
  • R 4 is methyl, ethyl, isopropyl, or benzyl.
  • n is 2.
  • each R 6 is independently halo or -N(R 16 ) 2 .
  • each R 6 is independently chloro or -NH 2 .
  • provided is a compound selected from Table A-1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Table A-1
  • a stereocenter refers to a single unknown isomer (or unassigned) configuration.
  • a compound of Formula B-I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; R 1 is R 11 is hydrogen, fluoro, chloro, cyano, -CF 3 , or aryl; wherein the aryl is independently optionally substituted with one to five halo; R 12 is hydrogen, fluoro, chloro, cyano, -CF 3 , aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R 13 is C 1-6 alkyl, -C(O)OR 8 , or -C(O)N(R 8 ) 2 ; R 2 is hydrogen or C 1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -
  • R 11 is hydrogen or fluoro.
  • R 12 is fluoro, chloro, cyano, or -O-aryl optionally substituted with one to five halo.
  • R 12 is fluoro, chloro, or cyano. [0139] In certain embodiments, R 12 is -O-aryl optionally substituted with one to five halo. [0140] In certain embodiments, R 12 is [0141] In certain embodiments, provided is a compound represented by Formula IV: wherein n, R 2 , R 3 , R 4 , R 5 , R 6 , and R 13 , are each independently as defined herein. [0142] In certain embodiments, R 13 is -C(O)OR 8 or -C(O)N(R 8 ) 2 . [0143] In certain embodiments, R 13 is -C(O)OR 8 or -C(O)NHR 8 .
  • R 13 is -C(O)OCH 3 or [0145]
  • R 2 is hydrogen or C 1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, and -C(O)OC 1-6 alkyl.
  • R 2 is hydrogen or C 1-6 alkyl substituted with -CH(OH)(CF 3 ), -C(O)OH, or -C(O)OC 2 alkyl.
  • R 2 is hydrogen, -CH 2 CH(OH)(CF 3 ), -CH 2 C(O)OH, or -CH 2 C(O)OC 2 alkyl.
  • the moiety is:
  • the moiety is: [0150] In certain embodiments, R 3 is hydrogen. [0151] In certain embodiments, R 3 is hydrogen and R 4 is , wherein m is 0 or 1. [0152] In certain embodiments, m is 0 or 1, and R 7 is C 1-6 haloalkyl. [0153] In certain embodiments, R 3 and R 4 together with the atoms to which they are attached form a ring selected from wherein each is optionally substituted by oxo or a C 3-6 spirocycle. [0154] In certain embodiments, R 3 and R 4 together with the atoms to which they are attached form a . [0155] In certain embodiments, n is 2.
  • each R 6 is independently halo or -N(R 16 ) 2 .
  • each R 6 is independently chloro or -NH 2 .
  • R 5 is C 1-6 alkyl.
  • R 5 is tert-butyl.
  • provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • Table B-1 [0161] In certain embodiments, provided is a compound selected from Table B-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Table B-2
  • Treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life and/or prolonging survival.
  • treating does not encompass preventing.
  • prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
  • terapéuticaally effective amount or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.
  • the methods described herein may be applied to cell populations in vivo or ex vivo.
  • “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual.
  • “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art.
  • the selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • a compound disclosed herein can be used to treat or lessen a disease or condition mediated, at least in part, by caspase-1, by administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof.
  • the disease or condition includes a chronic or acute form of a IL-1beta apoptosis-, IL-18-, or IFN- ⁇ -mediated disease, or an inflammatory, autoimmune, destructive bone, proliferative, infectious, or degenerative disease.
  • Exemplary diseases include, but are not limited to, chronic kidney disease, diabetic nephropathy, IgA nephropathy, uveitis, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, an excess dietary alcohol intake disease, necrotic diseases, a viral mediated disease, inflammatory peritonitis, osteoarthritis, pancreatitis (e.g., acute pancreatitis or chronic pancreatitis), asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, diabetes (e.g., juvenile diabetes, insulin-dependent diabetes mellitus (Type I)), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis
  • the IL-1 or apoptosis mediated inflammatory disease which may be treated includes, but is not limited to osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, or adult respiratory distress syndrome.
  • the IL-1 or apoptosis mediated autoimmune disease which may be treated includes, but is not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, insulin- dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, Crohn’s disease, psoriasis, atopic dermatitis, or graft vs. host disease.
  • the IL-1 or apoptosis mediated destructive bone disorders which may be treated include, but are not limited to, osteoporosis and multiple myeloma-related bone disorder.
  • the IL-1 or apoptosis mediated proliferative diseases which may be treated include, but are not limited to, leukemias and related disorders, such as myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi’s sarcoma, and multiple myeloma.
  • the IL-1 or apoptosis mediated infectious diseases which may be treated include, but are not limited to, sepsis, septic shock, or Shigellosis.
  • the IL-1 or apoptosis mediated degenerative or necrotic diseases which may be treated include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, and myocardial ischemia.
  • the degenerative disease is Alzheimer’s disease.
  • the IL-1 or apoptosis-mediated degenerative diseases which may be treated include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, or neurological damage due to stroke.
  • Other diseases having an inflammatory or apoptotic component may be treated by the disclosed compounds. Such diseases may be systemic diseases or diseases with effects localized in the liver or other organs and may be caused by, for example, excess dietary alcohol intake or viruses, such as HBV, HCV, HGV, yellow fever virus, dengue fever virus, or Japanese encephalitis virus.
  • the IL-18- or IFN- ⁇ -mediated diseases which may be treated include, but are not limited to, inflammatory, infectious, autoimmune, proliferative, neurodegenerative and necrotic conditions.
  • the IL-18- or IFN- ⁇ -mediated inflammatory diseases which may be treated include, but are not limited to osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cerebral ischemia, myocardial ischemia and adult respiratory distress syndrome.
  • the IL-18- or IFN- ⁇ -mediated infectious diseases which may be treated include, but are not limited to infectious hepatitis, sepsis, septic shock and Shigellosis.
  • the IL-18- or IFN- ⁇ -mediated autoimmune diseases which may be treated include, but are not limited to glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), juvenile diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple sclerosis, psoriasis, lichenplanus, graft vs.
  • a method of treating diabetic nephropathy comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof.
  • provided is a method of treating IgA nephropathy comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof.
  • a method of treating a renal disease comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof.
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • methods for treating a patient in need of dialysis or renal transplantation comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof.
  • Renal tubulointerstitial fibrosis characterized by ECM deposition, interstitial myofibroblast proliferation, and the infiltration of inflammatory mononuclear cells, is thought to play an important role in the pathogenesis of CKD. Therefore, preventing renal tubulointerstitial fibrosis remains a major target for clinicians.
  • a method of treating or preventing renal tubulointerstitial fibrosis comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof.
  • a method of treating or preventing neointimal hyperplasia (NH) in the arteries comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof.
  • One aspect of the present disclosure includes methods for treating a caspase-mediated disorder by administering a therapeutically effective amount of the disclosed compounds to a subject determined to be in need thereof.
  • the compounds and compositions described herein may also be useful in treating complications associated with coronary artery bypass grafts and as a component of immunotherapy for the treatment of various forms of cancer.
  • kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and suitable packaging.
  • a kit further includes instructions for use.
  • a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • compositions and modes of Administration [0193] Compounds provided herein are usually administered in the form of pharmaceutical compositions.
  • pharmaceutical compositions that contain one or more of the compounds described herein a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations.
  • Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof.
  • the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. 6.
  • Dosing [0202] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate.
  • a dosage of between 0.5 and 60 mg/kg may be appropriate. In some embodiments, a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. 7.
  • the compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. [0204] It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated.
  • process conditions i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J., Wiley- Interscience, and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers.
  • stereoisomers i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0207] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • compound A-I-3 (e.g., compounds of Formula A-II where R 2 is H) can be provided by contacting hydrazone compound A-I-1 with compound A-I-2 under standard amide coupling conditions. Coupling of compound A-I-3 with compound A-I-4 under standard nucleophilic substitution conditions provides compounds of Formula A-II.
  • Compound A-I-1 can be prepared from the corresponding ester compounds A-I-5 using hydrazine hydrate under standard reaction conditions.
  • compounds of Formula A-IV can be prepared from the corresponding ester compounds A-I-5 by coupling with compound A-I-6 under standard metal catalyzed coupling conditions.
  • each n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, and t are independently as defined herein, X is a leaving group (e.g., halo, such as bromo), and R 50 is an alkyl group (e.g., ethyl).
  • Scheme B-I [0213] Referring to Scheme B-I, compound B-I-3 (e.g., compounds of Formula B-I where R 2 is H) can be provided by contacting hydrazone compound B-I-1 with compound B-I-2 under standard amide coupling conditions. Coupling of compound B-I-3 with compound B-I-4 under standard nucleophilic substitution conditions provides compounds of Formula B-I.
  • Compound B-I-1 can be prepared from the corresponding ester compounds B-I-5 using hydrazine hydrate under standard reaction conditions.
  • Appropriate starting materials and reagents for the reactions shown in Scheme B-I can be purchased or prepared by methods known to one of skill in the art (e.g., see Examples below).
  • any compound shown in Scheme B-I it should be understood that various derivatives can be provided by functional group interconversion at any step.
  • the various substituents of Formula B-I-1, B-I-2, B-I-3, B-I-4, or B-I-5 are as defined herein.
  • stereoisomers i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. It should be appreciated that various isomers of Formula A-I or Formula B-Ican be separated as well.
  • Example A-1 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-1,2-dihydropyridin-3-yl)benzamide
  • Reagents and conditions (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) Pd(PPh 3 ) 4 , DMBA, CH 2 Cl 2 , 15 min
  • Example A-1B 3-Chloro-4-nitro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide
  • Example A-1C methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)propanoate [0221] To a stirred solution of Example A-1B (45 g, 153 mmol) dissolved in DMF (450 mL) was added cesium carbonate (125 g, 383 mmol) and methyl 2-bromopropanoate (17.2 mL, 153 mmol) at 0 0C. The reaction mixture was heated at 60 0C for 3 hours. The progress of the reaction was monitored by TLC and LCMS.
  • Example A-1D Methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanoate [0222] To a stirred solution of Example A-1C (30 g, 79 mmol) dissolved in ethanol (300 mL), water (150 mL) was added ammonium chloride (22.1 mL, 633 mmol) and Iron (20.6 g, 315 mmol). The reaction mixture was heated at 60 0C for 14 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite bed and residue was washed with methanol.
  • Example A-1E 2-(3-(4-Amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanoic acid [0223] To a stirred solution of Example A-1D (21 g, 60 mmol) dissolved in tetrahydrofuran (48 mL) and water (16 mL) was added lithium hydroxide monohydrate (7.56 g, 180 mmol) at rt. The reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS.
  • Example A-1E 1 g, 2.98 mmol
  • DMF 3 mL
  • DIPEA 1.04 mL, 5.96 mmol
  • EDCl 0.69 g, 3.57 mmol
  • HOBt 0.46 g, 2.98 mmol
  • the solution was stirred at 0 °C for 10 minutes and the solution from the above reaction was added dropwise to it.
  • the reaction mixture was stirred at rt for 4 h.
  • the reaction progress was monitored by TLC and LCMS.
  • Example A-5F 4-Amino-3-chloro-N-(1-(2-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-2-oxo-1-phenylethyl)-2- oxo-1,2-dihydropyridin-3-yl)benzamide (A-5) [0232]
  • the title compound (0.032 g) was prepared using the procedure described in Example A-1F, using Example A-5E (0.2 g, 0.50 mmol) in place of Example A-1E and purified by preparative HPLC Atlantis Prep C18 (19 ⁇ 100) mm; 5 ⁇ M column and water: acetonitrile as mobile phase (19 mL/ min flow rate) at RT 19.33 min.
  • EXAMPLE A-6 4-Amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxo-3- phenylpropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
  • Reagents and conditions (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) Pd(PPh 3 ) 4 , DMBA, CH 2 Cl 2 , 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h.
  • Example A-6F 4-Amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxo-3-phenylpropan-2- yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-6) [0237]
  • the title compound (0.03 g) was prepared using the procedure described in Example A-1F, using Example A-6E (0.15 g, 0.36 mmol) in place of Example A-1E and purified by preparative HPLC Inertsil ODS C18 (250 ⁇ 20) mm; 5 ⁇ M column, 5 mM Ammonium acetate in water: acetonitrile as mobile phase (19 ml/min flow rate) at RT 18.83 min.
  • EXAMPLE A-7 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxo-3- phenylpropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide and EXAMPLE A-8 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxo-3- phenylpropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide [0238] Purification of the Example A-6F by chiral prep-HPLC using CHIRALPACK IC (250 mm ⁇ 20 mm ⁇ 5 ⁇ M) column and Ethanol (100%) as mobile phase (20 mL/
  • EXAMPLE A-9 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-3-methyl-1-oxobutan- 2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide and EXAMPLE A-10 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-3-methyl-1-oxobutan- 2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
  • Reagents and conditions (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) Pd(PPh 3 ) 4 , DMBA, CH 2 Cl 2 , 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h, (g) Preparative separation.
  • Reagents and conditions (a) DMF, 130 °C, 16 h, (b) H 2 , Pd/C, EtOH, (c) TsCl, NaH, THF, 0 °C, 12 h, (d) I 2 , LDA, THF, -78 °C, (e) Pd(dpffCl 2 ).CH 2 Cl 2 , K 2 CO 3 , dioxane, H 2 O, 100 °C, 12 h, (f) 4 M HCl in dioxane, 70 °C, 12 h, (g) Cs 2 CO 3 , DMF, 60 °C, 8 h, (h) 20% NaOH, dioxane, 80 °C, 12 h, (i) (i) Pd(PPh 3 ) 4 , DMBA, CH 2 Cl 2 , 15 min, (ii) EDC, HOBt, DIPEA, CH 2 Cl 2 /DMF, 16
  • Example A-11B 7-Methoxy-1H-pyrrolo[2,3-c]pyridine [0247] A solution of Example A-11A (4 g, 17.9 mmol) in ethanol (400 mL) containing 10% Pd/C (357 mg) was shaken under hydrogen at 15 psi for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mass was filtered through celite bed and concentrated to get crude. The residue was purified by silica gel flash column chromatography using EtOAc: heptane (25:75) as a eluent and afforded 7-methoxy-1H-pyrrolo[2,3-c]pyridine (1 g).
  • Example A-11C 7-Methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine [0248] To a stirred solution of Example A-11B (3.7 g, 25 mmol) in dry THF (40 mL) was cooled to 0 °C added sodium hydride (1.44 g, 37.5 mmol) and stirred for 30 min at same temperature, then cooled to 0 °C added benzenesulfonyl chloride (3.84 mL, 30 mmol) continued to stirred at room temperature for 16 h.
  • Example A-11D 2-Iodo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine [0249] To a stirred solution of Example A-11C (3.1 g, 10.8 mmol) in dry THF (60 mL) was added lithium diisopropylamide (2.3 g, 21.5 mmol) at -78 °C and stirred for 30 min at -78 °C. To it iodine (5.46 g, 21.5 mmol) was added and the reaction mixture was then stirred at -78 °C for 5 h. The progress of the reaction was monitored by TLC and LC-MS.
  • Example A-11E 2-Chloro-4-(7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridin-2-yl)aniline [0250] To a stirred solution of Example A-11D (2 g, 3.86 mmol) in dioxane (32 mL) was added 2- chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.08 g, 4.25 mmol) and potassium carbonate (1.6 g, 11.6 mmol) in water (8 mL) purged with nitrogen for 5 minutes.
  • reaction mass was concentrated to remove solvent, and diluted with cold water (5 mL) aqueous phase was extracted with diethyl ether (2 ⁇ 10 mL), The aqueous layer was acidified with saturated citric acid in water (pH-6) followed by filtration afforded 2-(2-(4-amino-3- chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)propanoic acid (0.4 g) as pale yellow solid which was used in the next step without further purification.
  • Example A-11H 0.1 g, 0.30 mmol
  • dichloromethane/ DMF 5 mL/ 5 mL
  • DIPEA 0.16 mL, 0.90 mmol
  • 1H-1,2,3-benzotriazol-1-ol hydrate 0.046 g, 0.30 mmol
  • reaction mixture was diluted with dichloromethane (25 mL) and cold water (15 mL). After separation, aqueous phase was extracted with dichloromethane (2 ⁇ 20 mL). The combined organic phase was washed sequentially with aqueous saturated NaHCO 3 (15 mL), 2% citric acid solution (10 mL) and brine solution (15 mL), then dried over sodium sulphate, filtered and concentrated under vacuum.
  • EXAMPLE A-12 Ethyl N-acryloyl-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)- yl)propanamido)glycinate [0256] Reagents and conditions: (a) NH 2 NH 2 .H 2 O, EtOH, 80 °C, 16 h, (b) NMM, DMF, 0 °C-rt, 6 h, (c) NEt 3 , THF, 0 °C, 15 min.
  • EXAMPLE A-12A 4-Amino-3-chloro-N-(1-(1-hydrazineyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide [0257] To a stirred solution of Example A-1D (1 g, 2.86 mmol) in ethanol (30 mL) was added hydrazine hydrate (5.2 mL, 114 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. Reaction was monitored by TLC. Reaction mixture was distilled and diluted with water (10 mL).
  • EXAMPLE A-12B Ethyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)glycinate [0258] To a stirred solution of Example A-12A (0.3 g, 0.858 mmol) in DMF (10.0 mL), 4- methylmorpholine (0.26 mL, 0.283 mmol), and ethyl 2-bromoacetate (0.19 mL, 0.858 mmol) were added dropwise at 0 °C and the mixture was allowed to stir for 6 h at room temperature. The progress of the reaction was monitored by TLC and LCMS.
  • Example A-12C Ethyl N-acryloyl-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)glycinate (12) [0259] To a solution of Example A-12B (0.12 g, 0.275 mmol) in THF (10 mL) was cooled to 0 °C added triethylamine (0.056 mL, 0.413 mmol), prop-2-enoyl chloride (0.018 mL, 0.22 mmol) under a nitrogen atmosphere, and the reaction mixture was continued at same temperature for 15 min. The progress of the reaction was monitored by TLC and LCMS.
  • EXAMPLE A-13 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate [0260] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 3 h.
  • EXAMPLE A-13A Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate (A-13) [0261] To a solution of Example A-12B (0.3 g, 0.69 mmol) was added ethylbis(propan-2-yl)amine (0.36 mL, 2.06 mmol) in dimethylformamide (3.0 mL) was added HATU (0.31 g, 0.83 mmol) and under nitrogen atmosphere at 0 °C.
  • EXAMPLE A-14 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate and EXAMPLE A-15 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate [0262] Purification of Example A-13C by chiral prep-HPLC using CHIRALPACK IA (250 mm ⁇ 30 mm ⁇ 5 ⁇ M) column and ethanol and n-hexane (50:50) as mobile phase (40 mL/ min flow rate) afforded the title compound Example A-14 (0.02 g) at RT 8.78 min and title compound Example A-15 (0.02 g) at
  • EXAMPLE A-16 Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate [0263] Reagents and conditions: (a) EDCl, DIPEA, HOBt, CH 2 Cl 2 , 0 °C-rt, 16 h.
  • EXAMPLE A-16A Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate (A-16) [0264] To a stirred solution of 4-(benzylamino)-4-oxo-2-butenoic acid (0.21 g, 1.03 mmol) in dichloromethane (10 mL) ethylbis(propan-2-yl)amine (0.60 mL, 3.44 mmol) was added at 0 °C.
  • EXAMPLE A-17 Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate and EXAMPLE A-18 Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate [0265] Purification of the Example A-16A (0.09 g, 0.14 mmol) was performed by chiral prep-HPLC using CHIRALPACK IC (250 mm ⁇ 30 mm ⁇ 5 ⁇ M) column and Ethanol and n-Hexane (
  • EXAMPLE A-19B Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycinate (A-19) [0267] To a stirred solution of Example A-12B (0.3 g, 0.69 mmol) in dichloromethane (4 mL) were added triethylamine (0.48 mL, 3.44 mmol) and Example A-19A (0.22 g, 0.83 mmol) at room temperature and the mixture was allowed to react for 16 h at room temperature.
  • reaction mixture was diluted with dichloromethane (10 mL) and washed with water (10 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by flash column chromatography using methanol: dichloromethane system (0-3%) to get product (0.24 g).
  • EXAMPLE A-22 Ethyl N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(2-fluoroacetyl)glycinate [0269] Reagents and conditions: (a) EDC, HOBt, NEt 3 , CH 2 Cl 2 , 0 °C-rt, 12 h, (b) HATU, DIPEA, DMF, 0 °C-rt, 3 h.
  • EXAMPLE A-22A Ethyl (2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)glycinate [0270] To a stirred solution Example A-11H (0.3 g, 0.90 mmol) in dichloromethane (10 mL) at 0 °C triethylamine (0.50 mL, 3.62 mmol), EDC (0.21 g, 1.36 mmol), HOBt (0.21 g, 1.36 mmol) and ethyl 2- hydrazinylacetate hydrochloride (0.14 g, 0.90 mmol) were added and reaction mixture was stirred at rt for 12 h.
  • EXAMPLE A-22B Ethyl N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(2-fluoroacetyl)glycinate (A-22) [0271] The title compound (0.035 g) was prepared using the procedure described in Example A-13C, using Example A-22A (0.11 g, 0.26 mmol) in place of Example A-12B.
  • EXAMPLE A-24 Ethyl N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(2-fluoroacetyl)glycinate [0272] Purification of the Example A-22B (0.030 g, 0.059 mmol) by chiral prep-HPLC using CHIRALPACK IC (100 mm ⁇ 4.6 mm ⁇ 3 ⁇ M) column and n-hexane: ethanol (70:30) as mobile phase (30 mL/ min flow rate) afforded title compound Example A-23 (0.006 g) at RT 22.44 min and title compound Example A-24 (0.006 g) at RT 26.42 min.
  • EXAMPLE A-25 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycinate and EXAMPLE A-26 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycinate [0273] Reagents and conditions: (a) SOCl 2 , dioxane, 80 °C, 90 min.
  • EXAMPLE A-25B Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycinate [0275]
  • the title compound was prepared using the procedure described in Example A-19B, using Example A-12B (0.5 g, 1.15 mmol) and Example A-25A in place of Example A-19A. Crude compound was purified with flash column chromatography using ethyl acetate: n-hexane system (0-40%) and afforded the title compound (0.17 g).
  • EXAMPLE A-27B Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycinate (A-27) [0279] The title compound was prepared using the procedure described in Example A-19B, using Example A-12B (0.45 g, 1.03 mmol) and Example A-27A in place of Example A-19A.
  • EXAMPLE A-28 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)butanamido)-N-(2- fluoroacetyl)glycinate [0280] Reagents and conditions: (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) NH 2 NH 2 .H 2 O, EtOH, 80 °C, 16 h, (f) NMM, DMF, 0 °C-rt, 6 h, (g) HATU, DIPEA, DMF, 0 °C-rt, 3 h.
  • EXAMPLE A-28F Ethyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)butanamido)glycinate [0284]
  • the title compound (0.18 g) was prepared using the procedure described in Example A-12B, using Example A-28E (0.3 g, 0.83 mmol) in place of Example A-12A.
  • Crude compound was purified with preparative HPLC using Inertsil ODS C18 (20 ⁇ 250) mm; 5 ⁇ M column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/min flow rate) at RT 16.66 min.
  • EXAMPLE A-29 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycinate and EXAMPLE A-30 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycinate [0286]
  • the stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration).
  • Example A-27 Purification of the Example A-27 by chiral prep-HPLC using CHIRALPACK IC (250 mm ⁇ 20 mm ⁇ 5 ⁇ M) column and n-Hexane: EtOH (50:50) as mobile phase (19 mL/ min flow rate) and afforded the Example A-29 (0.0479 g) at RT 3.58 min and Example A-30 (0.0471 g) at RT 5.67 min.
  • EXAMPLE A-31 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate [0287] Reagents and conditions: (a) NH 2 NH 2 .H 2 O, EtOH, 80 °C, 16 h, (b) NMM, DMF, 0 °C-rt, 6 h, (c) HATU, DIPEA, DMF, 0 °C-rt, 3 h.
  • EXAMPLE A-31A 4-amino-3-chloro-N-(1-(1-hydrazineyl-3-methyl-1-oxobutan-2-yl)-2-oxo-1,2-dihydropyridin-3- yl)benzamide [0288]
  • the title compound (1.2 g) was prepared using the procedure described in Example A-12A, using Example A-9D (1.9 g, 4.9 mmol) in place of Example A-1D.
  • EXAMPLE A-31B ethyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate [0289]
  • the title compound (1.0 g) was prepared using the procedure described in Example A-12B, using Example A-31A (1.2 g, 3.0 mmol) in place of Example A-12A.
  • Reagents and conditions (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) Pd(PPh 3 ) 4 , DMBA, CH 2 Cl 2 , 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h.
  • EXAMPLE A-32A 3-chloro-N-(2-methoxy-5-methylpyridin-3-yl)-4-nitrobenzamide
  • the title compound (1.6 g) was prepared using the procedure described in Example A-1A, using 2-methoxy-5-methylpyridin-3-amine (1.0 g, 7.1 mmol) in place of 2-methoxypyridin-3-amine.
  • EXAMPLE A-32B 3-chloro-N-(5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-nitrobenzamide
  • the title compound (1.5 g) was prepared using the procedure described in Example A-1B, using Example A-32A (1.6 g, 4.8 mmol) in place of Example A-1A.
  • Crude product was purified with preparative HPLC using X Bridge C18 (19 ⁇ 250) mm; 5 ⁇ M column and 1 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 15.73 min.
  • EXAMPLE A-33 Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4- (piperidin-1-yl)but-2-enoyl)glycinate [0298] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 16 h.
  • Reagents and conditions (a) DMF, 0 °C-rt, 3 h, (b) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (c) TFA, DCM, 0 °C, 30 min.
  • Example A-34A tert-butyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)glycinate [0301] To a stirred solution of Example A-12A (1.0 g, 2.86 mmol) in DMF (10.0 mL), tert-butyl 2- bromoacetate (5.0 mL, 25.0 mmol) was added dropwise at 0 °C and the mixture was allowed to stir for 3 h at room temperature. The progress of the reaction was monitored by TLC and LCMS.
  • reaction mixture was evaporated under reduced pressure to get the crude product, which was subjected to preparative HPLC purification using Inertsil C18 (19 ⁇ 250) mm; 5 ⁇ M column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (15 mL/ min flow rate) to afford N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-fluoroacetyl)glycine (0.005 g) at RT 19.38 min.
  • EXAMPLE A-35 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- chloroacetyl)glycinate [0304] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 16 h.
  • EXAMPLE A-35A Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- chloroacetyl)glycinate (A-35) [0305] To a solution of 12B (0.3 g, 0.69 mmol) in DMF (10 mL) was added ethylbis(propan-2-yl)amine (0.26 mL, 1.38 mmol) and HATU (0.39 g, 1.03 mmol) and under nitrogen atmosphere at 0 °C. Then 2- chloroacetic acid (0.19 g, 2.06 mmol) was added.
  • the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS.
  • the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 ⁇ 10 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude product, which was subjected to preparative HPLC purification using X Select (19 ⁇ 250) mm; 5 ⁇ M column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (18 mL/ min flow rate) and afforded ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-chloroacetyl)glycinate (0.0082 g) at RT 16.81 min.
  • EXAMPLE A-36 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine [0306] Reagents and conditions: (a) Me 3 SnOH, DCE, 80 °C, 12 h EXAMPLE A-36A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine (36) [0307] To a stirred solution of Example A-29 (0.0022 g, 0.036mmol) in DCE (2.0 mL) was added trimethyltin hydroxide (0.0033 g, 0.18 mmol) at rt.
  • EXAMPLE A-37 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine [0308] Reagents and conditions: (a) Me 3 SnOH, DCE, 80 °C, 12 h EXAMPLE A-37A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine (A-37) [0309] The title compound (0.0055 g) was prepared using the procedure described in Example A-36A, using Example A-30 (0.16 g, 0.45 mmol) in place of Example A-29.
  • EXAMPLE A-38 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine [0310] Reagents and conditions: (a) EDC.HCl, HOBt, DIPEA, CH 2 Cl 2 , DMF 0 °C-rt, 16 h.
  • Reaction mixture was quenched in cold water (15 mL) and extracted with dichloromethane (10 mL), washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum to afford crude product. It was then purified by prep-HPLC using X Select C18 (19 ⁇ 250) mm; 5 ⁇ M column and water and acetonitrile as mobile phase (18 mL/ min flow rate) to afford the title compound (0.01 g) at RT of 15.38 min.
  • EXAMPLE A-39 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycine and EXAMPLE A-40 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycine
  • EXAMPLE A-42 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide and EXAMPLE A-43 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide
  • Reagents and conditions (a) T3P, TEA, DCM, 0 °C-rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) LiOH, THF/H 2 O (3:1), rt, 6 h, (f) (i) Pd(PPh 3 ) 4 , DMBA, CH 2 Cl 2 , 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h, (g) Chiral preparative HPLC separation.
  • Example A-42G 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-42) and 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-43) [0324] The crude product of Example A-42F was purified by preparative HPLC X Select CSH C18 (250 ⁇ 20) mm; 5 ⁇ M column, 5 mM Ammonium acetate in water: aceton
  • Example A-34A (0.33 g, 0.647 mmol) was subsequently added to the reaction mixture. It was then stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (20 mL) and residue was extracted with ethyl acetate (20 mL ⁇ 2 times). The combined organic layer was washed with brine (10 mL ⁇ 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-30%).
  • reaction mixture was stirred at 0 0C for 2 h.
  • the reaction progress was monitored by TLC and LCMS.
  • the reaction mixture was concentrated under vacuum, washed with diethyl ether and dried under vacuum to afford 3-chloro-4- nitro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide (1 g) as brown solid, which was used in the next step without further purification.
  • reaction mixture was stirred at rt for 5 h.
  • the reaction was monitored by TLC and LCMS.
  • the reaction mixture was quenched with cold water (40 mL) and residue was extracted with DCM (20 mL ⁇ 2 times).
  • the combined organic layer was washed with brine (15 mL ⁇ 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-40%).
  • EXAMPLE A-45D ethyl (2S,4R)-1-acryloyl-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)- yl)propanamido)pyrrolidine-2-carboxylate (A-45) [0332] To a stirred solution of Example A-45C (0.13 g, 0.23 mmol) in mixture of water (3.5 mL) and tetrahydrofuran (6.5 mL) was added triethylamine (0.1 mL, 0.7 mmol). Reaction mixture was stirred at 60 °C for 16 hours. The progress of the reaction was monitored with TLC and LCMS.
  • reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL ⁇ 3 times). The organic layer was washed with brine (10 mL ⁇ 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified with preparative HPLC using Zorbax Eclipse C18 (21 ⁇ 150) mm; 5 ⁇ M column and 5% ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 9.65 min. to afford the title compound (0.013g) at RT of 9.65 min.
  • EXAMPLE A-46 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-4- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide and EXAMPLE A-47 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-4- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide
  • Reagents and conditions (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) Pd(PPh 3 ) 4 , DMBA, CH 2 Cl 2 , 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h, (g) Chiral preparative HPLC separation.
  • EXAMPLE A-48 Ethyl (2S,4S)-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-1-((E)-4- (benzylamino)-4-oxobut-2-enoyl)pyrrolidine-2-carboxylate [0341] Reagents and conditions: (a) T3P, DIPEA, DCM, DMF, 0 °C-rt, 5 h.
  • EXAMPLE A-48A Ethyl (2S,4S)-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-1-((E)-4- (benzylamino)-4-oxobut-2-enoyl)pyrrolidine-2-carboxylate (A-48) [0342]
  • the title compound was prepared using the procedure described in Example A-45C, using (E)-4- (benzylamino)-4-oxobut-2-enoic acid (0.4 g, 1.95 mmol) in place of 3-chloropropanoic acid.
  • Crude product was purified with preparative HPLC using X-Select C18 (19 ⁇ 250) mm; 5 ⁇ M column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 16.82 min.
  • Example A-33A Purification of the Example A-33A by chiral prep-HPLC using CHIRALPACK IA (250 mm ⁇ 20 mm ⁇ 5 ⁇ M) column and EtOH as mobile phase (10 mL/ min flow rate) and afforded the Example A-50A (0.04 g) at RT 14.83 min and Example A-50B (0.034 g) at RT 21.79 min.
  • Example A-44B Purification of the Example A-44B by chiral prep-HPLC using CHIRALPACK IC (250 mm ⁇ 20 mm ⁇ 5 ⁇ M) column and n-Hexane: EtOH (70:30) as mobile phase (20 mL/ min flow rate) and afforded the Example A-52 (0.018 g) at RT 8.39 min and Example A-53 (0.0135 g) at RT 11.08 min.
  • EXAMPLE A-54 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide and EXAMPLE A-55 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide [0356] The stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration).
  • Example A-43 Purification of the Example A-43 by chiral prep-HPLC using CHIRALPACK IA (250 mm ⁇ 30 mm ⁇ 5 ⁇ M) column and n-Hexane: IPA (70:30) as mobile phase (40 mL/ min flow rate) and afforded the Example A-54 (0.025 g) at RT 7.249 min and Example A-55 (0.033 g) at RT 10.388 min.
  • EXAMPLE A-56 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-2-methyl-1- oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
  • Reagents and conditions (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) Cs 2 CO 3 , DMF, 60 0C, 16 h, (d) LiOH, THF/H 2 O (3:1), rt, 16 h, (e) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 4 h.
  • EXAMPLE A-56A 4-amino-3-chloro-N-(2-methoxypyridin-3-yl)benzamide [0358] To a stirred solution of 4-amino-3-chlorobenzoic acid (20.0 g, 117.0 mmol) in DMF (200 mL) was added N,N-Diisopropylethylamine (60.9 mL, 350.0 mmol), HATU (67.0 g, 175.0 mmol) and 2- methoxypyridin-3-amine (17.4 g, 140.0 mmol) sequentially over a period of 10-15 min. The reaction mixture was heated at 60 °C for 16 h. The reaction progress was monitored by TLC and LCMS.
  • EXAMPLE A-56B 4-amino-3-chloro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide [0359] The title compound (20.0 g) was prepared using the procedure described in Example A-1B, using Example A-56A (25.0 g, 90.0 mmol) in place of Example A-1A.
  • reaction was continued for 16 hours. Upon completion, reaction mixture was filtered through a celite pad and the filtrate was evaporated to near dryness. Separately to a solution of Example A-56D (0.1 g, 0.28 mmol) in DMF (5 mL) was added EDC (0.08 g, 0.43 mmol), HOBt (0.046 g, 0.28 mmol). The solution was stirred at 0 °C for 10 minutes and the solution from the above reaction was added dropwise to it. The reaction mixture was stirred at rt for 4 h. The reaction progress was monitored by TLC and LCMS.
  • Crude product was purified with preparative HPLC using X-Select C18 (19 ⁇ 250) mm; 5 ⁇ M column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 15.25 min.
  • EXAMPLE A-58 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide and EXAMPLE A-59 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide [0367] The stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration).
  • Example A-42 Purification of the Example A-42 by chiral prep-HPLC using CHIRALPACK IA (250 mm ⁇ 30 mm ⁇ 5 ⁇ M) column and MTBE: ACN (80:20) as mobile phase (18 mL/ min flow rate) and afforded the Example A-58 (0.025 g) at RT 8.106 min and Example A-59 (0.052g) at RT 11.138 min.
  • EXAMPLE A-60A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycine (A-60) [0369]
  • the title compound (0.012 g) was prepared using the procedure described in Example A-36A, using Example A-21 (0.05 g, 0.043 mmol) in place of Example A-29.
  • Crude product was purified with preparative HPLC using X-Select C18 (19 ⁇ 250) mm; 5 ⁇ M column and water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 8.15 min.
  • EXAMPLE A-62 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate and EXAMPLE A-63 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate [0372]
  • the stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration).
  • Example A-31C Purification of the Example A-31C by chiral prep-HPLC using CHIRALPACK IG (250 mm ⁇ 20 mm ⁇ 5 ⁇ M) column and n-Hexane: IPA (50:50) as mobile phase (20 mL/ min flow rate) and afforded the Example A-62 (0.36 g) at RT 3.88 min and Example A-63 (0.35 g) at RT 7.88 min.
  • Reagents and conditions (a) KF, DMF, rt, 16 h, (b) NaBH 4 , MeOH, THF, 0 0C-rt, 3 h, (c) Pd-C, EtOAc, rt, 3 h, (d) EDC, HOBt, DCM, 0 °C-rt, 14 h, (e) IBX, EtOAc, 80 °C, 4 h, (f) TFA, DCM, 0 °C-rt, 2 h, (g) Chiral preparative HPLC separation.
  • EXAMPLE A-64D tert-butyl 3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-hydroxy-5- (2,3,5,6-tetrafluorophenoxy)pentanoate [0377] To a solution of Example A-1E (0.5 g, 1.49 mmol) in DCM (10 mL) was added EDC (0.35 g, 2.24 mmol) and HOBt (0.34 g, 2.24 mmol). The solution was stirred at 0 °C for 10 minutes and then Example A-64C (0.53 g, 1.49 mmol) was added to it.
  • reaction mixture was stirred at rt for 14 h.
  • the reaction progress was monitored by TLC and LCMS.
  • the solvent of reaction mixture was dried under vacuum and the residue was diluted with water (20 mL) then extracted with ethyl acetate (3 times ⁇ 20 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 0-50% ethyl acetate/hexane.
  • reaction mixture was washed with water (2 times ⁇ 20 mL). Organic layer was separated, dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 20-50% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford tert-butyl (3S)-3-(2-(3-(4-amino-3-chlorobenzamido)- 2-oxopyridin-1(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoate (0.24 g) as white solid.
  • Example A-64G 3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoic acid (A-64) and 3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoic acid (A-65) [0380]
  • the product of Example A-64F was purified by preparative chiral HPLC using Chiralpack IG (250 ⁇ 30) mm; 5 ⁇ M column and n-hexane: IPA (50:50) as mobile phase (19 mL/ min flow rate) and afforded the Example A-64 (0.022g) at RT 6.
  • EXAMPLE A-66A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycine (A-66) [0382]
  • the title compound (0.006 g) was prepared using the procedure described in Example A-36A, using Example A-63 (0.03 g, 0.057 mmol) in place of Example A-29.
  • Crude product was purified with preparative HPLC using Sunfire C18 (19 ⁇ 250) mm; 5 ⁇ M column and 1% formic acid in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 10.2 min.
  • EXAMPLE A-69A methyl 1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate [0388] To a stirred solution of Example A-56B (2.0 g, 7.58 mmol) dissolved in DMF (30 mL) was added potassium carbonate (5.24 g, 37.9 mmol) and methyl 2,4-dibromobutanoate (2.74 mL, 11.4 mmol) at rt. The reaction mixture was stirred for 48 hours. The progress of the reaction was monitored by TLC and LCMS.
  • EXAMPLE A-69B 1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid [0389]
  • the title compound (0.25 g) was prepared using the procedure described in Example A-1E, using Example A-69A (0.4 g, 1.11 mmol) in place of Example A-1D.
  • Crude product was purified with preparative HPLC using X-Bridge C18 (19 ⁇ 250) mm; 5 ⁇ M column and 1% formic acid in water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 12.89 min.
  • EXAMPLE A-71 Ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate and EXAMPLE A-72 Ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate
  • Reagents and conditions (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) LiOH, THF/H 2 O (3:1), rt, 16 h, (e) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 16 h, (f) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (g) Chiral preparative HPLC separation.
  • Example A-71E ethyl (2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate [0398] To a solution of Example A-71D (0.25 g, 0.71 mmol) in DMF (5 mL) was added DIPEA (0.44 mL, 2.2 mmol), EDCl (0.24 g, 1.3 mmol), HOBt (0.2 g, 1.3 mmol). The solution was stirred at 0 °C for 10 minutes and then was added ethyl 2-hydrazinylacetate hydrochloride (0.2 mg, 1.27 mmol).
  • reaction mixture was stirred at rt for 16 h.
  • the reaction progress was monitored by TLC and LCMS.
  • the solvent of reaction mixture was dried under vacuum and the residue was diluted with water (15 mL) then extracted with ethyl acetate (3 ⁇ 10 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product.
  • the compound was then purified by flash column chromatography using 40-60% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford ethyl (2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate (0.2 g).
  • Example A-71G ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-71) and ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-72) [0400]
  • the product of Example A-71F was purified by preparative chiral HPLC using Chiralpack IA (250 ⁇ 30) mm; 5 ⁇ M column and hexane: IPA (50:50) as mobile phase (40 mL/ min flow rate) and afforded the Example A-71 (0.015 g) at RT 11.282 min and Example A-
  • Reagents and conditions (a) K 2 CO 3 , DMF, 60 0C, 16 h, (b) LiOH, THF/H 2 O (3:1), rt, 16 h, (c) (i) H 2 , Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 4 h, (d) Chiral preparative HPLC separation.
  • Example A-74D N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-1H-indole-2-carboxamide (A-74) and N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-1H-indole-2-carboxamide (A-75) [0407] The product of Example A-74C was purified by preparative chiral HPLC using Chiralpack IG (250 ⁇ 30) mm; 5 ⁇ M column and MTBE: IPA (80:20) as mobile phase (40 mL/ min
  • EXAMPLE A-76 Ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)- N-(2-fluoroacetyl)glycinate and EXAMPLE A-77 Ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)- N-(2-fluoroacetyl)glycinate
  • Reagents and conditions (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) K 2 CO 3 , DMF, 60 0C, 3 h, (d) LiOH, THF/H 2 O (3:1), rt, 16 h, (e) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 16 h, (f) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (g) Chiral preparative HPLC separation.
  • EXAMPLE A-76A 7-chloro-N-(2-methoxypyridin-3-yl)-1H-indole-5-carboxamide
  • the title compound (1.8 g) was prepared using the procedure described in Example A-56A, using 7-chloro-1H-indole-5-carboxylic acid (3.0 g, 15.3 mmol) in place of 4-amino-3-chlorobenzoic acid.
  • EXAMPLE A-76C methyl 2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoate
  • the title compound (1.1 g) was prepared using the procedure described in Example A-69A, using Example A-76B (1.8 g, 6.2 mmol) in place of Example A-1B and methyl 2-bromo-3-methylbutanoate (1.11 mL, 7.65 mmol)
  • EXAMPLE A-76D 2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoic acid
  • the title compound (0.8 g) was prepared using the procedure described in Example A-1E, using Example A-76C (1.0 g, 2.49 mmol) in place of Example A-1D.
  • Example A-76G ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-76) and ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-77) [0415] The product of Example A-76F was purified by preparative chiral HPLC using Chiralpack IC (250 ⁇ 30) mm; 5 ⁇ M column and n-hexane: IPA (50:50) as mobile phase (40 mL/ min flow rate) and afforded the Example A-76 (0.034
  • Example A-78C butyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-78) and butyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-79) [0419] The product of Example A-78B was purified by preparative chiral HPLC using Chiralpack IG (250 ⁇ 30) mm; 5 ⁇ M column and n-hexane: IPA (50:50) as mobile phase (19 mL/ min flow rate) and afforded the Example A-78 (0.005 g) at RT 8.089 min and Example A-79
  • EXAMPLE A-81 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3- methylbutanamido)-N-(2-fluoroacetyl)glycinate and EXAMPLE A-82 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3- methylbutanamido)-N-(2-fluoroacetyl)glycinate
  • Reagents and conditions (a) K 2 CO 3 , DMF, 60 0C, 3 h, (b) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (c) LiOH, THF/H 2 O (3:1), rt, 16 h, (d) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 16 h, (e) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (f) Chiral preparative HPLC separation.
  • EXAMPLE A-81A methyl 2-(3-(3-chloro-4-nitrobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanoate
  • the title compound (2.5 g) was prepared using the procedure described in Example A-69A, using Example A-42B (5.0 g, 16.0 mmol) in place of Example A-1B and methyl 2-bromo-3-methylbutanoate (3.13 mL, 16.0 mmol)
  • EXAMPLE A-81B methyl 2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanoate
  • the title compound (2.2 g) was prepared using the procedure described in Example A-1D, using Example A-81A (2.5 g, 5.87 mmol) in place of Example A-1C.
  • Example A-81F ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-81) and ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-82) [0428]
  • the product of Example A-81E was purified by preparative chiral HPLC using Chiralpack IG (250 ⁇ 30) mm; 5 ⁇ M column and n-hexane: IPA (50:50) as mobile phase (40 mL/ min flow rate) and afforded the Example A-81 (0.23g)
  • Reagents and conditions (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) LiOH, THF/H 2 O (3:1), rt, 16 h, (e) (i) H 2 , Pd-C, EtOAc, rt, 16 h, (ii) DCC, HOBt, DCM, 4 h, (f) Chiral preparative HPLC separation.
  • EXAMPLE A-83A 5-fluoro-N-(2-methoxy-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide
  • the title compound (3.0 g) was prepared using the procedure described in Example A-56A, using 5-fluoro-1H-indole-2-carboxylic acid (2.5 g, 14.0 mmol) in place of 4-amino-3-chlorobenzoic acid.
  • reaction was continued for 16 hours. Upon completion, reaction mixture was filtered through a celite pad and the filtrate was evaporated to near dryness. Separately to a solution of Example A-83D (0.28 g, 0.82 mmol) in DCM (10 mL) was added DCC (0.25 g, 1.22 mmol), HOBt (0.18 g, 1.22 mmol). The solution was stirred at 0 °C for 10 minutes and the solution from the above reaction was added dropwise to it. The reaction mixture was stirred at rt for 2 h. The reaction progress was monitored by TLC and LCMS.
  • reaction mixture was dried under vacuum and the residue was diluted with water (10 mL) then extracted with ethyl acetate (3 ⁇ 10 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 10-40% ethyl acetate/hexane.
  • EXAMPLE A-85 4-amino-N-(5-bromo-1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2- yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-chlorobenzamide and EXAMPLE A-86 4-amino-N-(5-bromo-1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2- yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-chlorobenzamide
  • Reagents and conditions (a) T3P, TEA, DCM, 0 °C-rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) Cs 2 CO 3 , DMF, 60 0C, 3 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) H 2 , Pd-C, EtOAc, rt, 16 h, (ii) EEDQ, DCM, 0 °C-rt, 4 h, (g) Chiral preparative HPLC separation.
  • reaction was continued for 16 hours. Upon completion, reaction mixture was filtered through a celite pad and the filtrate was evaporated to near dryness. Separately to a solution of Example A-85E (0.6 g, 1.45 mmol) in DMF (15 mL) was added ethyl 2-ethoxy-1,2- dihydroquinoline-1-carboxylate (0.72 g, 2.89 mmol). The solution was stirred at 0 °C for 10 minutes and the solution from the above reaction was added dropwise to it. The reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS.
  • reaction mixture was diluted with water (40 mL) then extracted with ethyl acetate (3 ⁇ 20 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 50-60% ethyl acetate/hexane.
  • Reagents and conditions (a) T3P, TEA, DCM, 0 °C-rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) K 2 CO 3 , DMF, rt, 16 h, (d) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) H 2 , Pd-C, EtOAc, rt, 16 h, (ii) DCC, HOBt, DCM, 0 °C-rt, 4 h.
  • Reagents and conditions (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) K 2 CO 3 , DMF, rt, 30 h, (d) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) H 2 , Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 0 °C-rt, 4 h.
  • EXAMPLE A-88A 4-amino-3-fluoro-N-(2-methoxypyridin-3-yl)benzamide
  • the title compound (2.0 g) was prepared using the procedure described in Example A-56A, using 4-amino-3-fluorobenzoic acid (2.0 g, 12.9 mmol) in place of 4-amino-3-chlorobenzoic acid.
  • EXAMPLE A-88B 4-amino-3-fluoro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide
  • the title compound (1.7 g) was prepared using the procedure described in Example A-1B, using Example A-88A (2.0 g, 7.6 mmol) in place of Example A-1A.
  • EXAMPLE A-88D 1-(3-(4-amino-3-fluorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid [0454]
  • the title compound (0.3 g) was prepared using the procedure described in Example A-1E, using Example A-88C (0.4 g, 1.16 mmol) in place of Example A-1D.
  • Reagents and conditions (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) K 2 CO 3 , DMF, rt, 30 h, (d) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) H 2 , Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 0 °C-rt, 4 h.
  • EXAMPLE A-90 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)benzamide and EXAMPLE A-91 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)benzamide
  • Reagents and conditions (a) (i) (COCl) 2 , DMF, DCM, 0 °C-rt, 1 h, (ii) TEA, THF, rt 1 h, (b) 4M HCl in dioxane, dioxane, 70 0C, 16 h, (c) K 2 CO 3 , DMF, rt, 4 h, (d) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (e) LiOH, THF/H 2 O (3:1), rt, 2 h, (f) (i) H 2 , Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 0 °C-rt, 4 h, (g) Chiral preparative HPLC separation.
  • reaction mixture was evaporated to dryness, diluted with water (50 mL) then extracted with ethyl acetate (3 times ⁇ 25 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 10-40% 3-chloro-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4- nitrobenzamide (9.0 g) as white solid.
  • Reagents and conditions (a) PPh 3 , DCM, 0 °C-rt, 16 h, (b) NaH, DMSO, 0 °C-rt, 3 h, (c) Iron, NH 4 Cl, EtOH/H 2 O (2:1), 60 0C, 14 h, (d) LiOH, THF/H 2 O (3:1), rt, 16 h, (f) (i) H 2 , Pd-C, EtOAc, rt, 16 h, (ii) DCC, HOBt, DCM, 0 °C-rt, 4 h.
  • reaction mixture was evaporated to dryness, diluted with water (150 mL) then extracted with ethyl acetate (3 times ⁇ 50 mL), combined organic layer was dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 0-30% to afford methyl 2-(3-(3-chloro-4- nitrobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)acrylate (5.0 g) as white solid.
  • Crude product was purified with preparative HPLC using X-Select CSH C18 (19 ⁇ 250) mm; 5 ⁇ M column and water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 16.542 min.
  • EXAMPLE A-94 Ethyl (S)-3-(1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1- carboxamido)-3-cyanopropanoate [0482] Reagents and conditions: (a) (i) DBU, DMF, 0 °C-rt, 1 h, (ii) HATU, DIPEA, 0 °C-rt, 16 h EXAMPLE A-94A Ethyl (S)-3-(1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxamido)-3- cyanopropanoate (A-94) [0483] To a stirred solution of ethyl (S)-3-cyano-3-[(9H-fluoren-9-
  • Example A-69B (0.02 g, 0.12 mmol) in DMF (2 mL) was added N,N- Diisopropylethylamine (0.15 mL, 0.086 mmol), HATU (0.033 g, 0.086 mmol) and after 15 min, the above reaction mixture was added to it. This was then stirred for 16 h at rt. Reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (10 mL) and residue was extracted with ethyl acetate (10 mL ⁇ 2 times).
  • reaction mixture was allowed to come to ambient temperature while stirring and finally (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (8.4, 46.6 mmol) was added to the reaction mixture. Reaction was continued until both the starting materials were consumed and upon completion the reaction mixture was diluted CH 2 CL 2 (60 mL) and washed with water and brine (2 ⁇ 100 mL each). CH 2 CL 2 layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material which was triturated and recrystallized from hexane to afford the title compound (3.2 g).
  • Example B-1B (S)-2-(4-Amino-3-chlorobenzamido)-3,3-dimethylbutanoic acid [0487] To a stirred solution of Example B-1A (3.2 g, 10.4 mmol) in THF (25 mL) and water (5 mL) was added lithium hydroxide (0.51 g, 20.8 mmol). The reaction mixture was stirred at an ambient temperature for overnight, concentrated to a minimum volume, and the residue was diluted with water (10 mL). The pH of the aqueous phase was adjusted to 1 by the addition of HCl (aq) (1.0 M) resulting in a thick precipitate that was collected by filtration and dried to afford the title compound (2.8 g).
  • Example B-1D N-((2S)-1-((2-(2-acryloylhydrazineyl)-2-oxo-1-phenylethyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)-4- amino-3-chlorobenzamide (B-1) [0490] To a stirred solution of Example B-1D (0.15 g, 0.3 mmol) at 0 °C in DMF (5 mL) was added propylphosphonic anhydride (50% wt solution in ethyl acetate) (0.1 mL, 0.4 mmol) and DIPEA (0.18 mL, 1.0 mmol).
  • EXAMPLE B-2 Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- phenylacetamido)glycinate [0491] Reagents and conditions: (a) Ethyl 2-bromoacetate, NMM, DMF, 0 °C-rt, 16 h; (b) acryloyl chloride, Et 3 N, THF, 0 °C-rt, 1 h.
  • EXAMPLE B-2A Ethyl (2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)glycinate [0492] To a stirred solution of Example B-1D (3.0 g, 7.0 mmol) in DMF (30 mL) was added 4- methylmorpholine (2.3 mL, 20.0 mmol). Reaction mixture was cooled to 0 °C and ethyl 2-bromoacetate (3.0 mL, 20.0 mmol) was added slowly.
  • EXAMPLE B-2B Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- phenylacetamido)glycinate (B-2) [0493] To a stirred solution of Example B-2A (0.5 g, 0.9 mmol) in THF (10 mL) at 0 °C was successively added triethyl amine (0.4 mL, 2.9 mmol) and acryloyl chloride (0.08 mL, 0.9 mmol). Reaction mixture was stirred and allowed to come to room temperature over a period of one hour.
  • EXAMPLE B-3 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-cyanoacetyl)glycinate [0494] Reagents and conditions: (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 18 h.
  • EXAMPLE B-5 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-fluoroacetyl)glycinate [0497] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 4 h.
  • Example B-2A (0.12 g, 0.2 mmol) and sodium 2-fluoroacetate (0.034 g, 0.3 mmol) in DMF (5 mL) at 0 °C was consecutively added HATU (0.1 g, 0.3 mmol) and DIPEA (0.1 mL, 0.7 mmol). Reaction mixture was stirred and allowed to come to room temperature over a period of four hours. Upon completion, it was diluted with ethyl acetate (15 mL) and washed with ice-cold water and brine (2 ⁇ 20 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material.
  • EXAMPLE B-7 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- ((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate [0500] Reagents and conditions: (a) (CO) 2 Cl 2 , CH 2 Cl 2 , 0 °C-rt, 4 h, (b) Et 3 N, CH 2 Cl 2 , rt, 2 h, (c) LiOH, THF/H 2 O (5:1), rt, 8 h; (d) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h.
  • Example B-7A (11.0 g, 74.7 mmol) was added to the reaction mixture and the reaction was continued for 2 hours at an ambient temperature. Upon completion, reaction mixture was diluted with DCM (100 mL) and washed with water (2 ⁇ 150 mL). Organic layer was separated, dried with sodium sulphate and concentrated in vacuo to get the crude, which was then purified by flash column chromatography using 40% ethyl acetate in hexane to get Methyl (E)-4-(benzylamino)-4-oxobut-2-enoate (9.2 g).
  • EXAMPLE B-7D Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- (benzylamino)-4-oxobut-2-enoyl)glycinate (B-7) [0504] To a stirred solution of Example B-7C (0.15 g, 0.7 mmol) in N,N dimethyl formamide (10 mL) at 0 °C was added EDCl (0.3 g, 1.5 mmol) and HOBt (0.1 g, 0.7 mmol).
  • EXAMPLE B-8 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- ((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate [0505] During the preparative HPLC purification of Example B-7D, the title compound (0.008 g) was isolated at RT 24.06 min.
  • EXAMPLE B-9 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-(perfluorophenoxy)acetyl)glycinate [0506] Reagents and conditions: (a) (i) SOCl 2 , dioxane, 105 °C, 1 h, (ii) Et 3 N, CH 2 Cl 2 , rt, 16 h.
  • EXAMPLE B-10 Ethyl N-((S)-2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)- N-(2-(perfluorophenoxy)acetyl)glycinate and EXAMPLE B-11 Ethyl N-((R)-2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)- N-(2-(perfluorophenoxy)acetyl)glycinate [0508] Preparative HPLC purification of Example B-9 by using XSELECT C18 (19 mm X 250 mm X 5 ⁇ M) and 5mM ammonium acetate in water and MeCN as mobile phase (19 mL/ min flow rate) and afforded the title compound (10) (0.02 g) at RT
  • Example B-12C N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- (benzylamino)-4-oxobut-2-enoyl)glycine (B-12) [0512] To a stirred solution of Example B-12B (0.25 g, 0.3 mmol) in dichloromethane at 0 °C was dropwise added trifluoroacetic acid (2.5 mL, 32.7 mmol). Reaction mixture was stirred for couple of hours while the reaction temperature was allowed to come to room temperature.
  • trifluoroacetic acid 2.5 mL, 32.7 mmol
  • reaction mixture was evaporated to dryness to get the crude.
  • EXAMPLE B-13 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- (benzylamino)-4-oxobut-2-enoyl)glycine [0513] During the preparative HPLC purification of Example B-12C, the title compound (0.02 g) was isolated at RT 14.12 min.
  • EXAMPLE B-14 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-fluoroacetyl)glycinate [0514] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 4 h; (b) TFA, CH 2 Cl 2 , 0 °C-rt, 2 h.
  • EXAMPLE B-14B Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacetyl)glycinate (B-14) [0516] Following the procedure described in Example B-12C and using Example B-14A (0.1 g, 0.17 mmol) in place of Example B-12B the crude product was obtained.
  • EXAMPLE B-16 Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)glycinate [0518] Reagents and conditions: (a) SOCl 2 , MeOH, 0 °C- rt, 16 h; (b) T3P, DIPEA, DMF, 0 °C-rt, 14 h; (c) Hydrazine hydrate, EtOH, 80 °C, 14 h; (d) Ethyl 2-bromoacetate, NMM, DMF, 0 °C-rt, 16 h; (e) acryloyl chloride, Et 3 N, THF, 0 °C-rt, 1 h.
  • EXAMPLE B-16D Ethyl (2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)glycinate [0522]
  • the title compound (7.4 g) was prepared using the procedure described in Example B-2A, using Example B-16C (13.0 g, 26.0 mmol) in place of Example B-45A.
  • EXAMPLE B-16E Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)glycinate (B-16) [0523] Following the procedure described in Example B-2B and using Example B-16D (0.1 g, 0.16 mmol) in place of Example B-2A the crude product was obtained.
  • EXAMPLE B-17 Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- cyclopropylacetamido)glycinate
  • Reagents and conditions (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h; (b) Hydrazine hydrate, EtOH, 80 °C, 14 h; (c) Ethyl 2-bromoacetate, NMM, DMF, 0 °C-rt, 16 h; (d) acryloyl chloride, Et 3 N, THF, 0 °C-rt, 1 h.
  • EXAMPLE B-17B 4-Amino-3-chloro-N-((2S)-1-((1-cyclopropyl-2-hydrazineyl-2-oxoethyl)amino)-3,3-dimethyl-1-oxobutan- 2-yl)benzamide [0526]
  • the title compound (1.2 g) was prepared using the procedure described in Example B-1D, using Example B-17A (2.0 g, 5.1 mmol) in place of Example B-1C.
  • EXAMPLE B-17C Ethyl (2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- cyclopropylacetamido)glycinate [0527]
  • the title compound (0.4 g) was prepared using the procedure described in Example B-2A, using Example B-17B (1.2 g, 2.5 mmol) in place of Example B-1D.
  • EXAMPLE B-17D Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- cyclopropylacetamido)glycinate (B-17) [0528] Following the procedure described in Example B-2B and using Example B-17C (0.2 g, 0.4 mmol) in place of Example B-2A the crude product was obtained.
  • Reagents and conditions (a) (i) SOCl 2 , dioxane, 105 °C, 1 h, (ii) Et 3 N, CH 2 Cl 2 , rt, 16 h; (b) TFA, CH 2 Cl 2 , 0 °C-rt, 2 h.
  • Example B-18B N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- (perfluorophenoxy)acetyl)glycine (B-18) [0531] Following the procedure described in Example B-12C and using Example B-18A (0.08 g, 0.1 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using SunFire C18 (19 X 250) mm; 5 ⁇ M column and water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.01 g) at RT 20.85 min.
  • EXAMPLE B-19 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-(2,3,5,6-tetrafluorophenoxy)acetyl)glycinate [0532] Reagents and conditions: (a) (i) SOCl 2 , dioxane, 105 °C, 1 h, (ii) Et 3 N, CH 2 Cl 2 , rt, 16 h.
  • EXAMPLE B-20 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-(2,3,5,6-tetrafluorophenoxy)acetyl)glycinate [0534] During the preparative HPLC purification of Example B-19, the title compound (0.01 g) was isolated at RT 32.90 min.
  • EXAMPLE B-22 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacryloyl)glycine [0538] Reagents and conditions: (a) BOP, DIPEA, DMF, 0 °C-rt, 14 h; (b) TFA, CH 2 Cl 2 , 0 °C-rt, 2 h.
  • EXAMPLE B-22A tert-Butyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacryloyl)glycinate [0539] To a stirred solution of Example B-12A (0.35 g, 0.6 mmol) and 2-fluoroacrylic acid (0.09 g, 1.0 mmol) in DMF (10 mL) at 0 °C was subsequently added BOP (0.4 g, 1.0 mmol) and DIPEA (0.3 mL, 1.9 mmol).
  • Example B-22B N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacryloyl)glycine (B-22) [0540] Following the procedure described in Example B-12C and using Example B-22A (0.15 g, 0.2 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using SunFire C18 (19 X 250) mm; 5 ⁇ M column and water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.008 g) at RT 17.25 min.
  • EXAMPLE B-23 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacryloyl)glycine [0541] During the preparative HPLC purification of Example B-22B, the title compound (0.02 g) was isolated at RT 12.26 min. EXAMPLE B-24 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)- but-2-enoyl)glycine
  • Reagents and conditions (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h; (b) TFA, CH 2 Cl 2 , 0 °C- rt, 2 h.
  • EXAMPLE B-26 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- chloroacetyl)glycine [0546] Reagents and conditions: (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h; (b) TFA, CH 2 Cl 2 , 0 °C- rt, 2 h.
  • reaction mixture was allowed to stir for couple of hours while allowing to worm to room temperature gradually. Upon completion, reaction mixture was diluted with ethyl acetate and washed with water and brine (2 ⁇ 20 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material which was purified by flash chromatography on silica gel (0-40% ethyl acetate in hexane) afforded the title compound (0.13 g).
  • EXAMPLE B-29A 4-Amino-3-chloro-N-((2S)-3,3-dimethyl-1-oxo-1-((2-oxo-1-phenyl-2-(2-(3,3,3-trifluoro-2- oxopropyl)hydrazineyl)ethyl)amino)butan-2-yl)benzamide [0553] To a stirred solution of Example B-1D (0.5 g, 1.2 mmol) in DMF (15 mL) was added 4- methylmorpholine (0.2 mL, 1.2 mmol).
  • EXAMPLE B-29B 4-Amino-3-chloro-N-((2S)-3,3-dimethyl-1-oxo-1-((2-oxo-1-phenyl-2-(2-(3,3,3-trifluoro-2- hydroxypropyl)hydrazineyl)ethyl)amino)butan-2-yl)benzamide [0554] To a stirred solution of Example B-29A (0.23 g, 0.4 mmol) in THF (10 mL) was added sodium borohydride (0.03 g, 0.8 mmol). Reaction mixture was heated to 40 °C and methanol (1 mL) was added.
  • Example B-29B (0.1 g, 0.16 mmol) was added to it. After 6 hours of stirring, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with ice-cold water and brine (2 ⁇ 15 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by prep-HPLC using XSelect C18 (19 X 250) mm; 5 ⁇ M column and 5mM ammonium acetate in water and MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.005 g) at RT 25.01 min.
  • EXAMPLE B-31 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-fluoroacetyl)glycinate [0558] During the preparative HPLC purification of Example B-30, the title compound (0.025 g) was isolated at RT 20.32 min.
  • EXAMPLE B-32 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate [0559] Reagents and conditions: (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h. [0560] Following the procedure described in Example B-7D and using Example B-16D (0.3 g, 0.5 mmol) in place of Example B-2A the crude product was obtained.
  • EXAMPLE B-33 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate [0561] During the preparative HPLC purification of Example B-32, the title compound (0.035 g) was isolated at RT 21.62 min.
  • EXAMPLE B-34 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-(perfluorophenoxy)acetyl)glycinate [0562] Reagents and conditions: (a) (i) SOCl 2 , dioxane, 105 °C, 1 h, (ii) Et 3 N, CH 2 Cl 2 , rt, 16 h.
  • Example B-2A Following the procedure described in Example B-9 and using Example B-16D (0.3 g, 0.5 mmol) in place of Example B-2A the crude product was obtained. Purification of the residue by prep-HPLC using X-Select C18 (19 X 250) mm; 5 ⁇ M column and 5 mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.01 g) at RT 20.44 min.
  • EXAMPLE B-35 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-(perfluorophenoxy)acetyl)glycinate [0564] During the preparative HPLC purification of Example B-34, the title compound (0.04 g) was isolated at RT 22.61 min.
  • EXAMPLE B-36 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-(2,3,5,6-tetrafluorophenoxy)acetyl)glycinate [0565] Reagents and conditions: (a) (i) SOCl 2 , dioxane, 105 °C, 1 h, (ii) Et 3 N, CH 2 Cl 2 , rt, 16 h.
  • Example B-2A Following the procedure described in Example B-9 and using Example B-16D (0.3 g, 0.5 mmol) in place of Example B-2A the crude product was obtained. Purification of the residue by prep-HPLC using X-Select C18 (19 X 250) mm; 5 ⁇ M column and 5 mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.01 g) at RT 16.70 min.
  • EXAMPLE B-37 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-(2,3,5,6-tetrafluorophenoxy)acetyl)glycinate [0567] During the preparative HPLC purification of Example B-36, the title compound (0.01 g) was isolated at RT 17.22 min.
  • EXAMPLE B-38 Ethyl N-(1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)- N-((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate
  • Reagents and conditions (a) HATU, DIPEA, DMF, 0 °C-rt, 14 h; (b) LiOH, THF/H 2 O (5:1), rt, 8 h; (c) Ethyl 2-hydrazinylacetate hydrochloride, HATU, DIPEA, DMF, 0 °C-rt, 14 h; (d) T3P, DIPEA, DMF, 0 °C-rt, 14 h.
  • Example B-38A Methyl ((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-L-prolinate [0569] To a stirred solution of Example B-1B (4.0 g, 14.0 mmol) in N,N dimethyl formamide (20 mL) at 0 °C was added HATU (7.0 g, 18.0 mmol) and DIPEA (7.3 mL, 42.0 mmol). Subsequently after 10 minutes, methyl L-prolinate hydrochloride (2.6 g, 15.0 mmol) was added.
  • Example B-38B ((S)-2-(4-Amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)proline [0570] To a stirred solution of Example B-38A (5.0 g, 12.6 mmol) in THF (50 mL) and water (10 mL) was added lithium hydroxide (1.1 g, 42.0 mmol). The reaction mixture was stirred at an ambient temperature for overnight, concentrated to a minimum volume, and the residue was diluted with water (10 mL). The pH of the aqueous phase was adjusted to 1 by the addition of HCl (aq) (1.0 M) resulting in a thick precipitate that was collected by filtration and dried to afford the title compound (4.0 g).
  • EXAMPLE B-38C Ethyl (1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)pyrrolidine-2- carboxamido)glycinate [0571] To a stirred solution of Example B-38B (0.5 g, 1.3 mmol) in N,N dimethyl formamide (10 mL) at 0 °C was added HATU (0.75 g, 2.0 mmol) and DIPEA (0.7 mL, 4.0 mmol). Subsequently after 10 minutes, ethyl 2-hydrazinylacetate hydrochloride (0.3 g, 2.0 mmol) was added.
  • EXAMPLE B-38D Ethyl N-(1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-N- ((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate (B-38) [0572] To a solution of Example B-38C (0.3 g, 0.6 mmol) in DMF (10 mL) at 0 0C was added propylphosphonic anhydride (50% wt solution in ethyl acetate) (0.8 mL, 1.2 mmol) and DIPEA (0.3 mL, 1.8 mmol).
  • Example B-7C (0.25 g, 1.2 mmol) was added to the solution. After overnight stirring, the reaction mixture was diluted with ethyl acetate (30.0 mL) and washed with ice- cold water and brine (2 ⁇ 50 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by prep-HPLC using X Select CSH C18 (19 X 250) mm; 5 ⁇ M column and 5 mM ammonium acetate in water and MeCN as mobile phase (19 mL/min flow rate) afforded the title compound (0.03 g) at RT 18.72 min.
  • IL-1, IL-18 and NLRP3 inflammasome activity regulates pyroptosis and promotes fibrosis.
  • the IL-1 ⁇ and IL-18 cause inflammation and kidney fibrosis.
  • Inhibition of IL-1 ⁇ and reversal of pyroptosis will block or reverse phenotypic changes associated with CKD.
  • Direct correlation between inflammasome activation, including caspase-1, IL-1 ⁇ and IL-18 and severity of proteinuria was observed in kidney patients.
  • Pyroptosis is an inflammatory form of programmed cell death driven by inflammatory caspase-1, caspase-4 and caspase-5 in humans following infection or cellular damage.
  • IL-1 ⁇ release assay measures the levels of IL-1 ⁇ secreted from the LPS and nigericin induced THP-1 cells. These inducers activate inflammasome pathway in THP-1 cells. Upon inflammasome activation, pro-caspase-1 is converted to caspase-1 which further processes pro-IL-1 ⁇ to its bioactive IL- 1 ⁇ that is secreted out of the cells.
  • THP-1 cells stimulated with the LPS (Lipopolysaccharides from Escherichia coli O111:B4) and nigericin (Catalogue number N7143) were treated with compounds at various concentration doses and the inhibition of IL-1 ⁇ levels secreted into the media supernatant is measured by ELISA (Human IL 1 ⁇ ELISA kit Cat no: 557953; BD Biosciences).
  • ELISA Human IL 1 ⁇ ELISA kit Cat no: 557953; BD Biosciences.
  • Pyroptosis is an inflammatory form of program cell death that depends on the formation of plasma membrane pores by members of the gasdermin (GSDM) protein family, as a consequence of caspase-1 activation via inflammasomes. Pyroptosis occurs as the result of membranous pore formation and cytoplasmic swelling, and leakage of cytosolic contents.
  • THP-1 cells stimulated with the LPS (Lipopolysaccharides from Escherichia coli O111:B4) and nigericin (Catalogue number N7143) are treated with compounds at various concentration doses and the inhibition of pyroptosis is measured by evaluation of levels of cellular ATP as an indirect measure of cell viability using Cell-Titer-gloTM reagent.
  • 20,000 cells per well of THP-1 were seeded in 35 ⁇ L RPMI media in a 384-well white plate. 5 ⁇ L of compound was added and incubated for 1 hour. 5 ⁇ L of LPS (300 ng/mL) was added to the cells according to the plate map and the plate was incubated for 1 hour at 37 °C.5 ⁇ L of Nigericin was added all the wells except control and blank wells, and it was incubated for 2 hours at 37 °C. After incubation, plate was brought to room temperature for 5 minutes. 25 ⁇ L of CellTiter-Glo was added and the plate was incubated for 30 minutes on plate shaker covered with aluminium foil (protected from light).

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Abstract

The present disclosure relates generally to small molecule modulators of caspase 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof, and methods of making and using thereof.

Description

COMPOUNDS, COMPOSITIONS, AND METHODS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Numbers 63/338,838, filed May 5, 2022, 63/338,840, filed May 5, 2022, and 63/497,165, filed April 19, 2023, each of which is incorporated by reference in its entirety. FIELD [0002] The present disclosure relates generally to small molecule modulators of caspase 1 and their use as therapeutic agents. BACKGROUND [0003] Caspases are conserved family of aspartic acid-directed cysteinyl proteases that have essential functions in apoptosis, inflammation, cell survival, proliferation and differentiation. Caspases are cysteine proteases so named due to strict specificity for cleaving peptide sequences C-terminal to aspartic acids residues. Currently, 12 caspase isozymes have been identified in humans with numerous reported activities. Caspases are often subcategorized as either pro-apoptotic or pro-inflammatory enzymes. A prominent member of the pro-inflammatory class is caspase 1 (also known as interleukin-converting enzyme or ICE) which is responsible for the proteolytic activation of interleukin (IL)-1β and IL-18. IL-1β and IL-18 are cytokines that play a major role in the immune response and within numerous autoimmune and inflammatory diseases. Caspase 1 is constitutively and inducibly expressed in immune response elements such as T cells, macrophages and neutrophils. DESCRIPTION [0004] Provided herein are compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, that are useful in treating and/or preventing diseases mediated, at least in part, by caspase 1. [0005] Provided herein are compounds of Formula A-I:
Figure imgf000002_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2;
Figure imgf000003_0001
R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R2’ is hydrogen, cyano, or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R3 is
Figure imgf000003_0002
R4 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R4’ is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; or R4 and R4’ together with the atom to which they are attached form a C3-10 cycloalkyl or heterocyclyl; wherein each is independently optionally substituted with one to six Z1a; R5 is hydrogen, halo, C1-6 alkyl, or C1-6 alkoxy; X is O or S; or R5 and X together with the atoms to which they are attached form a 5-membered heteroaryl; wherein the 5-membered heteroaryl is independently optionally substituted with one to six Z1a; each R6 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R6 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; R7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R8 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R8 together with the nitrogen atom to which they are attached form a heterocyclyl; which is optionally substituted with one to six Z1a; each R9 is independently halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR10, -N(R10)2, -C(O)R10, -C(O)OR10, -OC(O)R10, -C(O)N(R10)2, -NR10C(O)R10, -OC(O)N(R10)2, -NR10C(O)OR10, -S(O)0-2R10, -NR10S(O)1-2R10, -NR10C(O)N(R10)2, or -NR10S(O)1-2N(R10)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R10 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R11 is hydrogen, fluoro, chloro, cyano, -CF3, or aryl; wherein the aryl is independently optionally substituted with one to five halo; R12 is hydrogen, fluoro, chloro, cyano, -CF3, aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R13 is C1-6 alkyl, -C(O)OR8, or -C(O)N(R8)2; each R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -OC(O)NH-, -OC(O)N(C1-6 alkyl)-, -OC(O)N(C2-6 alkenyl)-, -OC(O)N(C2-6 alkynyl)-, -OC(O)N(C1-6 haloalkyl)-, -OC(O)N(C3-10 cycloalkyl)-, -OC(O)N(heterocyclyl)- , -OC(O)N(aryl)-, -OC(O)N(heteroaryl)-, -NHC(O)-, -N(C1-6 alkyl)C(O)-, -N(C2-6 alkenyl)C(O)-, -N(C2-6 alkynyl)C(O)-, -N(C1-6 haloalkyl)C(O)-, -N(C3-10 cycloalkyl)C(O)-, -N(heterocyclyl)C(O)-, -N(aryl)C(O)-, -N(heteroaryl)C(O)-, -NHC(O)O-, -N(C1-6 alkyl)C(O)O-, -N(C2-6 alkenyl)C(O)O-, -N(C2-6 alkynyl)C(O)O-, -N(C1-6 haloalkyl)C(O)O-, -N(C3-10 cycloalkyl)C(O)O-, -N(heterocyclyl)C(O)O- , -N(aryl)C(O)O-, -N(heteroaryl)C(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)NH-, -S(O)2NH-, -NHS(O)NH-, or -NHS(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b and L is further independently optionally substituted with one to six halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0006] Provided herein are compounds of Formula A-I:
Figure imgf000005_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2; R1 is
Figure imgf000006_0001
R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R3 is
Figure imgf000006_0002
R4 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R5 is hydrogen, halo, C1-6 alkyl, or C1-6 alkoxy; X is O or S; or R5 and X together with the atoms to which they are attached form a 5-membered heteroaryl; wherein the 5-membered heteroaryl is independently optionally substituted with Z1a; each R6 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R6 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; R7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R8 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R9 is independently halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR10, -N(R10)2, -C(O)R10, -C(O)OR10, -OC(O)R10, -C(O)N(R10)2, -NR10C(O)R10, -OC(O)N(R10)2, -NR10C(O)OR10, -S(O)0-2R10, -NR10S(O)1-2R10, -NR10C(O)N(R10)2, or -NR10S(O)1-2N(R10)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R10 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R11 is hydrogen, fluoro, chloro, cyano, -CF3, or aryl; wherein the aryl is independently optionally substituted with one to five halo; R12 is hydrogen, fluoro, chloro, cyano, -CF3, aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R13 is C1-6 alkyl, -C(O)OR8, or -C(O)N(R8)2; each R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -OC(O)NH-, -OC(O)N(C1-6 alkyl)-, -OC(O)N(C2-6 alkenyl)-, -OC(O)N(C2-6 alkynyl)-, -OC(O)N(C1-6 haloalkyl)-, -OC(O)N(C3-10 cycloalkyl)-, -OC(O)N(heterocyclyl)- , -OC(O)N(aryl)-, -OC(O)N(heteroaryl)-, -NHC(O)-, -N(C1-6 alkyl)C(O)-, -N(C2-6 alkenyl)C(O)-, -N(C2-6 alkynyl)C(O)-, -N(C1-6 haloalkyl)C(O)-, -N(C3-10 cycloalkyl)C(O)-, -N(heterocyclyl)C(O)-, -N(aryl)C(O)-, -N(heteroaryl)C(O)-, -NHC(O)O-, -N(C1-6 alkyl)C(O)O-, -N(C2-6 alkenyl)C(O)O-, -N(C2-6 alkynyl)C(O)O-, -N(C1-6 haloalkyl)C(O)O-, -N(C3-10 cycloalkyl)C(O)O-, -N(heterocyclyl)C(O)O- , -N(aryl)C(O)O-, -N(heteroaryl)C(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)NH-, -S(O)2NH-, -NHS(O)NH-, or -NHS(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b and L is further independently optionally substituted with one to six halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0007] Provided herein are compounds of Formula B-I:
Figure imgf000008_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; R1 is
Figure imgf000008_0002
R11 is hydrogen, fluoro, chloro, cyano, -CF3, or aryl; wherein the aryl is independently optionally substituted with one to five halo; R12 is hydrogen, fluoro, chloro, cyano, -CF3, aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R13 is C1-6 alkyl, -C(O)OR8, or -C(O)N(R8)2; R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; R4 is
Figure imgf000009_0002
wherein m is 0, 1, 2, 3, 4, or 5; or R3 and R4 together with the atoms to which they are attached form a ring selected from
Figure imgf000009_0001
wherein each is optionally substituted by oxo or a C3-6 spirocycle; R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R6 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R6 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R7 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR17, -N(R17)2, -C(O)R17, -C(O)OR17, -OC(O)R17, -C(O)N(R17)2, -NR17C(O)R17, -OC(O)N(R17)2, -NR17C(O)OR17, -S(O)0-2R17, -NR17S(O)1-2R17, -NR17C(O)N(R17)2, or -NR17S(O)1-2N(R17)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R5 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R8 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR10, -N(R10)2, -C(O)R10, -C(O)OR10, -OC(O)R10, -C(O)N(R10)2, -NR10C(O)R10, -OC(O)N(R10)2, -NR10C(O)OR10, -S(O)0-2R10, -NR10S(O)1-2R10, -NR10C(O)N(R10)2, or -NR10S(O)1-2N(R10)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R10 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -OC(O)NH-, -OC(O)N(C1-6 alkyl)-, -OC(O)N(C2-6 alkenyl)-, -OC(O)N(C2-6 alkynyl)-, -OC(O)N(C1-6 haloalkyl)-, -OC(O)N(C3-10 cycloalkyl)-, -OC(O)N(heterocyclyl)- , -OC(O)N(aryl)-, -OC(O)N(heteroaryl)-, -NHC(O)-, -N(C1-6 alkyl)C(O)-, -N(C2-6 alkenyl)C(O)-, -N(C2-6 alkynyl)C(O)-, -N(C1-6 haloalkyl)C(O)-, -N(C3-10 cycloalkyl)C(O)-, -N(heterocyclyl)C(O)-, -N(aryl)C(O)-, -N(heteroaryl)C(O)-, -NHC(O)O-, -N(C1-6 alkyl)C(O)O-, -N(C2-6 alkenyl)C(O)O-, -N(C2-6 alkynyl)C(O)O-, -N(C1-6 haloalkyl)C(O)O-, -N(C3-10 cycloalkyl)C(O)O-, -N(heterocyclyl)C(O)O- , -N(aryl)C(O)O-, -N(heteroaryl)C(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)NH-, -S(O)2NH-, -NHS(O)NH-, or -NHS(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b and L is further independently optionally substituted with one to six halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0008] In another embodiment, provided is a compound of Table A-l or Table A-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
[0009] In another embodiment, provided is a compound of Table B-l or Table B-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
[0010] In another embodiment, provided is a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier.
[0011] In another embodiment, provided is a method for treating a disease or condition, at least in part, by a caspase 1 inhibitor, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
[0012] In another embodiment, provided is a method for treating a disease or condition, at least in part, by inhibiting caspase 1 , the method comprising administering an effective amount of the pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof.
[0013] The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds. The disclosure further provides compounds or compositions thereof for use in a method of treating a disease, disorder, or condition that is mediated, at least in part, by caspase 1. Moreover, the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease, disorder, or condition selected from chronic kidney disease, diabetic nephropathy, IgA nephropathy, uveitis, an excess dietary alcohol intake disease, a necrotic disease, a viral mediated disease, inflammatory peritonitis, osteoarthritis, pancreatitis (e.g., acute pancreatitis or chronic pancreatitis), asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, diabetes (e.g., juvenile diabetes, insulin-dependent diabetes mellitus (Type I)), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn’s disease, psoriasis, atopic dermatitis, scarring, graft vs. host disease, organ transplant rejection, osteoporosis, multiple myeloma-related bone disorder, leukemias and related disorders, myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi’s sarcoma, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Kennedy’s disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute or chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, coronary artery bypass graft, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV- or AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, various forms of liver disease, infectious hepatitis, hepatitis-B, hepatitis- C, hepatitis-G, yellow fever, dengue fever, Japanese encephalitis, lichenplanus, acute dermatomyositis, eczema, primary cirrhosis, Behcet’s disease, atopic skin disease, pure red cell aplasia, aplastic anemia, nephrotic syndrome, renal disease, renal tubulointerstitial fibrosis, neointimal hyperplasia (NH) in the arteries, polyaptic kidney disease, H. pylori-associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, and meningitis. [0014] In another embodiment, provided is a method for treating a disease, disorder, or condition selected from chronic kidney disease, diabetic nephropathy, and IgA nephropathy by inhibiting caspase 1. In certain embodiments, the method comprising administering an effective amount of a compound which inhibits caspase 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof. [0015] In certain embodiments, provided is a method for treating chronic kidney disease, diabetic nephropathy, or IgA nephropathy, comprising administering an effective amount of a compound of Table A-1 or Table A-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof. [0016] In certain embodiments, provided is a method for treating chronic kidney disease, diabetic nephropathy, or IgA nephropathy, comprising administering an effective amount of a compound of Table B-1 or Table B-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a pharmaceutically acceptable carrier, to a subject in need thereof. DETAILED DESCRIPTION [0017] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. 1. Definitions [0018] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. [0019] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named. [0020] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. [0021] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art. [0022] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., - CH2CH(CH3)2) and tert-butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3), and isopropyl (i.e., -CH(CH3)2). [0023] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group, or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. [0024] “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl). [0025] “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond. [0026] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. [0027] “Alkoxyalkyl” refers to the group “alkyl-O-alkyl”. [0028] “Alkylthio” refers to the group “alkyl-S-”. “Alkylsulfinyl” refers to the group “alkyl-S(O)-”. “Alkylsulfonyl” refers to the group “alkyl-S(O)2-”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyl. [0029] “Acyl” refers to a group -C(O)Ry, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl. [0030] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRz and an “N- amido” group which refers to the group -NRyC(O)Rz, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or Ry and Rz are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein. [0031] “Amino” refers to the group -NRyRz wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0032] “Aminoalkyl” refers to the group “-alkyl-NRyRz,” wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0033] “Amidino” refers to -C(NRy)(NRz2), wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0034] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl. [0035] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”. [0036] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRz and an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0037] “Carboxyl ester” or “ester” refer to both -OC(O)Rx and -C(O)ORx, wherein Rx is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0038] “Cyanoalkyl” refers to refers to an alkyl group as defined above, wherein one or more (e.g., one to three) hydrogen atoms are replaced by a cyano (-CN) group. [0039] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl. [0040] “Cycloalkoxy” refers to “-O-cycloalkyl.” [0041] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”. [0042] “Cycloalkylalkoxy” refers to “-O-alkyl-cycloalkyl.” [0043] “Guanidino” refers to -NRyC(=NRz)(NRyRz), wherein each Ry and Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0044] “Hydrazino” refers to -NHNH2. [0045] “Imino” refers to a group -C(NRy)Rz, wherein Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0046] “Imido” refers to a group -C(O)NRyC(O)Rz, wherein Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0047] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo. [0048] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. [0049] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a halogen. [0050] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a hydroxy group. [0051] “Heteroalkyl” refers to an alkyl group in which one or more (e.g., one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O- , -S-, -S(O)-, -S(O)2-, and the like, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, - CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyCH3, etc., where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. [0052] “Heteroalkylene” refers to a divalent alkyl group (i.e., alkylene) in which one or more (e.g., one to five or one to three) of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain. The term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkylene groups include, e.g., -CH2OCH2-, -CH(CH3)OCH2-, -CH2CH2OCH2-, -CH2CH2OCH2CH2OCH2-, -CH2SCH2-, -CH(CH3)SCH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2SCH2-, -CH2S(O)2CH2-, -CH(CH3)S(O)2CH2-, -CH2CH2S(O)2CH2-, -CH2CH2S(O)2CH2CH2OCH2-, -CH2NRyCH2-, -CH(CH3)NRyCH2-, -CH2CH2NRyCH2-, -CH2CH2NRyCH2CH2NRyCH2-, etc., where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkylene includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. As used herein, the term “heteroalkylene” does not include groups such as amides or other functional groups having an oxo present on one or more carbon atoms. [0053] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. [0054] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”. [0055] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro, and may comprise one or more (e.g., one to three or one or two) oxo (=O) or N-oxide (-O-) moieties. Any non- aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system. [0056] “Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-”. [0057] “Oxime” refers to the group -CRy(=NOH) wherein Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0058] “Sulfonyl” refers to the group -S(O)2Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl. [0059] “Sulfinyl” refers to the group -S(O)Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl. [0060] “Sulfonamido” refers to the groups -SO2NRyRz and -NRySO2Rz, where Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. [0061] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more (e.g., one to five or one to three) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. [0062] In certain embodiments, Ry and Rz as used herein are optionally substituted. In certain embodiments, Ry and Rz as used herein are unsubstituted. [0063] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, sulfinic acid, sulfonic acid, sulfonamido, thiol, thioxo, N-oxide, or -Si(Ry)3 wherein each Ry is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. [0064] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more (e.g., one to five or one to three) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgS(=O)1-2Rh, -C(=O)Rg, -C(=O)ORg, -OC(=O)ORg, -OC(=O)Rg, -C(=O)NRgRh, -OC(=O)NRgRh, -ORg, -SRg, -S(=O)Rg, -S(=O)2Rg, -OS(=O)1-2Rg, -S(=O)1-2ORg, -NRgS(=O)1-2NRgRh, =NSO2Rg, =NORg, -S(=O)1-2NRgRh, -SF5, -SCF3, or -OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., one to five or one to three) hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., one to five or one to three) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of Rg and Rh and Ri are taken together with the atoms to which they are attached form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy. [0065] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. [0066] In certain embodiments, as used herein, the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to three. [0067] Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more (e.g., one to five or one to three) atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H and 14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. [0068] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more (e.g., one to five or one to three) hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more (e.g., one to five or one to three) hydrogens have been replaced by deuterium. [0069] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18F, 3H, 11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein. [0070] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. [0071] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. [0072] Provided are also or a pharmaceutically acceptable salt, isotopically enriched analog, deuterated analog, stereoisomer, mixture of stereoisomers, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. [0073] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. [0074] The term “hydrate” refers to the complex formed by the combining of a compound described herein and water. [0075] A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid and ethanolamine. [0076] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers. [0077] The compounds of the invention, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [0078] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. [0079] “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. [0080] Relative centers of the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines). [0081] “Prodrugs” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety. 2. Compounds [0082] Provided herein are compounds, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, that are modulators of caspase-1. In certain embodiments, the compounds or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof are inhibitors of caspase-1. [0083] Provided herein are compounds of Formula A-I:
Figure imgf000024_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2; R1 is
Figure imgf000024_0002
, , , , ,
Figure imgf000024_0003
R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R2’ is hydrogen, cyano, or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R3 is
Figure imgf000024_0004
R4 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R4’ is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; or R4 and R4’ together with the atom to which they are attached form a C3-10 cycloalkyl or heterocyclyl; wherein each is independently optionally substituted with one to six Z1a; R5 is hydrogen, halo, C1-6 alkyl, or C1-6 alkoxy; X is O or S; or R5 and X together with the atoms to which they are attached form a 5-membered heteroaryl; wherein the 5-membered heteroaryl is independently optionally substituted with one to six Z1a; each R6 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R6 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; R7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R8 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R8 together with the nitrogen atom to which they are attached form a heterocyclyl; which is optionally substituted with one to six Z1a; each R9 is independently halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR10, -N(R10)2, -C(O)R10, -C(O)OR10, -OC(O)R10, -C(O)N(R10)2, -NR10C(O)R10, -OC(O)N(R10)2, -NR10C(O)OR10, -S(O)0-2R10, -NR10S(O)1-2R10, -NR10C(O)N(R10)2, or -NR10S(O)1-2N(R10)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R10 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R11 is hydrogen, fluoro, chloro, cyano, -CF3, or aryl; wherein the aryl is independently optionally substituted with one to five halo; R12 is hydrogen, fluoro, chloro, cyano, -CF3, aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R13 is C1-6 alkyl, -C(O)OR8, or -C(O)N(R8)2; each R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -OC(O)NH-, -OC(O)N(C1-6 alkyl)-, -OC(O)N(C2-6 alkenyl)-, -OC(O)N(C2-6 alkynyl)-, -OC(O)N(C1-6 haloalkyl)-, -OC(O)N(C3-10 cycloalkyl)-, -OC(O)N(heterocyclyl)- , -OC(O)N(aryl)-, -OC(O)N(heteroaryl)-, -NHC(O)-, -N(C1-6 alkyl)C(O)-, -N(C2-6 alkenyl)C(O)-, -N(C2-6 alkynyl)C(O)-, -N(C1-6 haloalkyl)C(O)-, -N(C3-10 cycloalkyl)C(O)-, -N(heterocyclyl)C(O)-, -N(aryl)C(O)-, -N(heteroaryl)C(O)-, -NHC(O)O-, -N(C1-6 alkyl)C(O)O-, -N(C2-6 alkenyl)C(O)O-, -N(C2-6 alkynyl)C(O)O-, -N(C1-6 haloalkyl)C(O)O-, -N(C3-10 cycloalkyl)C(O)O-, -N(heterocyclyl)C(O)O- , -N(aryl)C(O)O-, -N(heteroaryl)C(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)NH-, -S(O)2NH-, -NHS(O)NH-, or -NHS(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b and L is further independently optionally substituted with one to six halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0084] In certain embodiments, provided is a compound of Formula A-IA:
Figure imgf000027_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2; R1 is
Figure imgf000027_0002
R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R3 is
Figure imgf000027_0003
R4 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R5 is hydrogen, halo, C1-6 alkyl, or C1-6 alkoxy; X is O or S; or R5 and X together with the atoms to which they are attached form a 5-membered heteroaryl; wherein the 5-membered heteroaryl is independently optionally substituted with Z1a; each R6 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R6 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; R7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R8 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R9 is independently halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR10, -N(R10)2, -C(O)R10, -C(O)OR10, -OC(O)R10, -C(O)N(R10)2, -NR10C(O)R10, -OC(O)N(R10)2, -NR10C(O)OR10, -S(O)0-2R10, -NR10S(O)1-2R10, -NR10C(O)N(R10)2, or -NR10S(O)1-2N(R10)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R10 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R11 is hydrogen, fluoro, chloro, cyano, -CF3, or aryl; wherein the aryl is independently optionally substituted with one to five halo; R12 is hydrogen, fluoro, chloro, cyano, -CF3, aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R13 is C1-6 alkyl, -C(O)OR8, or -C(O)N(R8)2; each R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -OC(O)NH-, -OC(O)N(C1-6 alkyl)-, -OC(O)N(C2-6 alkenyl)-, -OC(O)N(C2-6 alkynyl)-, -OC(O)N(C1-6 haloalkyl)-, -OC(O)N(C3-10 cycloalkyl)-, -OC(O)N(heterocyclyl)- , -OC(O)N(aryl)-, -OC(O)N(heteroaryl)-, -NHC(O)-, -N(C1-6 alkyl)C(O)-, -N(C2-6 alkenyl)C(O)-, -N(C2-6 alkynyl)C(O)-, -N(C1-6 haloalkyl)C(O)-, -N(C3-10 cycloalkyl)C(O)-, -N(heterocyclyl)C(O)-, -N(aryl)C(O)-, -N(heteroaryl)C(O)-, -NHC(O)O-, -N(C1-6 alkyl)C(O)O-, -N(C2-6 alkenyl)C(O)O-, -N(C2-6 alkynyl)C(O)O-, -N(C1-6 haloalkyl)C(O)O-, -N(C3-10 cycloalkyl)C(O)O-, -N(heterocyclyl)C(O)O- , -N(aryl)C(O)O-, -N(heteroaryl)C(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)NH-, -S(O)2NH-, -NHS(O)NH-, or -NHS(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b and L is further independently optionally substituted with one to six halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0085] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. [0086] In certain embodiments, each R9 is independently halo or C1-6 alkyl. [0087] Also provided is a compound of Formula A-IB:
Figure imgf000030_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R1, R4, R4’, R5, R6, n, and X are independently as defined herein. [0088] In certain embodiments, R4 and R4’ together with the atom to which they are attached form a C3-10 cycloalkyl or heterocyclyl; wherein each is independently optionally substituted with one to six Z1a. In certain embodiments, R4 and R4’ together with the atom to which they are attached form a C3-10 cycloalkyl. In certain embodiments, R4 and R4’ together with the atom to which they are attached form a C3-6 cycloalkyl. In certain embodiments, R4 and R4’ together with the atom to which they are attached form a cyclopropyl. [0089] Also provided is a compound of Formula A-IC:
Figure imgf000030_0002
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R1, R4, R5, R6, n, and X are independently as defined herein. [0090] Also provided is a compound of Formula A-II:
Figure imgf000030_0003
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R2, R3, R4, R5, R6, n, and X are independently as defined herein. [0091] Also provided is a compound of Formula A-IIA:
Figure imgf000030_0004
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R2, R11, R4, R5, R6, n, and X are independently as defined herein. [0092] In certain embodiments, R11 is hydrogen or fluoro. [0093] Also provided is a compound of Formula A-IIB:
Figure imgf000031_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R2, R12, R4, R5, R6, n, and X are independently as defined herein. [0094] In certain embodiments, R12 is fluoro, chloro, cyano, or -O-aryl optionally substituted with one to five halo. [0095] In certain embodiments, R12 is fluoro. [0096] In certain embodiments, R12 is -O-aryl optionally substituted with one to five halo. [0097] In certain embodiments, R12 is
Figure imgf000031_0003
[0098] Also provided is a compound of Formula A-IIC:
Figure imgf000031_0002
. or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R2, R13, R4, R5, R6, n, and X are independently as defined herein. [0099] In certain embodiments, R13 is -C(O)N(R8)2. [0100] In certain embodiments, R13 is -C(O)NHR8. [0101] In certain embodiments, R13 is
Figure imgf000031_0004
[0102] In certain embodiments, R2 is C1-6 alkyl substituted with -C(O)OC1-6 alkyl. [0103] In certain embodiments, R2 is C1-6 alkyl substituted with -C(O)OC2 alkyl. [0104] In certain embodiments, R2 is -CH2C(O)OC2 alkyl. [0105] In certain embodiments, the moiety
Figure imgf000032_0001
is:
Figure imgf000032_0002
, [0106] In certain embodiments, the moiety
Figure imgf000032_0003
is:
Figure imgf000033_0001
[0107] Also provided is a compound of Formula A-III:
Figure imgf000033_0002
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R4, R5, R6, n, and X are independently as defined herein. [0108] Also provided is a compound of Formula A-IIIA:
Figure imgf000033_0003
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R4, R5, R6, n, and X are independently as defined herein. [0109] Also provided is a compound of Formula A-IV:
Figure imgf000033_0004
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R7, R4, R5, R6, n, and X are independently as defined herein. [0110] Also provided is a compound of Formula A-IVA:
Figure imgf000034_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R7, R4, R5, R6, n, and X are independently as defined herein. [0111] Also provided is a compound of Formula A-IVB:
Figure imgf000034_0002
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R7, R4, R5, R6, n, and X are independently as defined herein. [0112] Also provided is a compound of Formula A-IVC:
Figure imgf000034_0003
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R7, R4, R5, R6, n, and X are independently as defined herein. [0113] In certain embodiments, R7 is hydrogen or C1-6 alkyl. [0114] In certain embodiments, R7 is ethyl. [0115] In certain embodiments, R5 is hydrogen, halo, or C1-6 alkyl. In certain embodiments, R5 is hydrogen. In certain embodiments, R5 is halo. In certain embodiments, R5 is C1-6 alkyl. In certain embodiments, R5 is C1-6 alkoxy. In certain embodiments, R5 is methyl. In certain embodiments, R5 is -O- CH3. [0116] In certain embodiments, R5 is hydrogen and X is O or S. [0117] Also provided is a compound of Formula A-V:
Figure imgf000035_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R1, R4, R5, R6, R9, m, and n are independently as defined herein. [0118] Also provided is a compound of Formula A-VA:
Figure imgf000035_0002
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R1, R4, R6, and n are independently as defined herein. [0119] In certain embodiments, R5 and X together with the atoms to which they are attached form a 5- membered heteroaryl. [0120] Also provided is a compound of Formula A-VI:
Figure imgf000035_0003
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each Z1a, R1, R4, R6, R9, m, and n are independently as defined herein. [0121] In certain embodiments, Z1a is halo or C1-6 alkyl. [0122] Also provided is a compound of Formula A-VIA:
Figure imgf000035_0004
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R1, R4, R6, R9, m, and n are independently as defined herein. [0123] Also provided is a compound of Formula A-VIB:
Figure imgf000036_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R1, R4, R6, and n are independently as defined herein. [0124] Also provided is a compound of Formula A-VII:
Figure imgf000036_0002
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R1, R4, R6, R9, m, and n are independently as defined herein. [0125] Also provided is a compound of Formula A-VIIA:
Figure imgf000036_0003
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein each R1, R4, R6, and n are independently as defined herein. [0126] In certain embodiments, R4 is C1-6 alkyl optionally substituted by phenyl. [0127] In certain embodiments, R4 is methyl, ethyl, isopropyl, or benzyl. [0128] In certain embodiments, n is 2. [0129] In certain embodiments, each R6 is independently halo or -N(R16)2. [0130] In certain embodiments, each R6 is independently chloro or -NH2. [0131] In certain embodiments, provided is a compound selected from Table A-1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Table A-1
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
[0132] For clarity, when a stereocenter is denoted with a “*”, it refers to a single unknown isomer (or unassigned) configuration. In certain embodiments, provided is a compound selected from Table A-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Table A-2
Figure imgf000057_0002
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0002
[0133] In certain embodiments, provided is a compound of Formula B-I:
Figure imgf000070_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; R1 is
Figure imgf000071_0001
R11 is hydrogen, fluoro, chloro, cyano, -CF3, or aryl; wherein the aryl is independently optionally substituted with one to five halo; R12 is hydrogen, fluoro, chloro, cyano, -CF3, aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R13 is C1-6 alkyl, -C(O)OR8, or -C(O)N(R8)2; R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; R4 is
Figure imgf000071_0002
wherein m is 0, 1, 2, 3, 4, or 5; or R3 and R4 together with the atoms to which they are attached form a ring selected from
Figure imgf000071_0003
wherein each is optionally substituted by oxo or a C3-6 spirocycle; R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R6 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R6 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R7 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR17, -N(R17)2, -C(O)R17, -C(O)OR17, -OC(O)R17, -C(O)N(R17)2, -NR17C(O)R17, -OC(O)N(R17)2, -NR17C(O)OR17, -S(O)0-2R17, -NR17S(O)1-2R17, -NR17C(O)N(R17)2, or -NR17S(O)1-2N(R17)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R5 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R8 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR10, -N(R10)2, -C(O)R10, -C(O)OR10, -OC(O)R10, -C(O)N(R10)2, -NR10C(O)R10, -OC(O)N(R10)2, -NR10C(O)OR10, -S(O)0-2R10, -NR10S(O)1-2R10, -NR10C(O)N(R10)2, or -NR10S(O)1-2N(R10)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R10 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -OC(O)NH-, -OC(O)N(C1-6 alkyl)-, -OC(O)N(C2-6 alkenyl)-, -OC(O)N(C2-6 alkynyl)-, -OC(O)N(C1-6 haloalkyl)-, -OC(O)N(C3-10 cycloalkyl)-, -OC(O)N(heterocyclyl)- , -OC(O)N(aryl)-, -OC(O)N(heteroaryl)-, -NHC(O)-, -N(C1-6 alkyl)C(O)-, -N(C2-6 alkenyl)C(O)-, -N(C2-6 alkynyl)C(O)-, -N(C1-6 haloalkyl)C(O)-, -N(C3-10 cycloalkyl)C(O)-, -N(heterocyclyl)C(O)-, -N(aryl)C(O)-, -N(heteroaryl)C(O)-, -NHC(O)O-, -N(C1-6 alkyl)C(O)O-, -N(C2-6 alkenyl)C(O)O-, -N(C2-6 alkynyl)C(O)O-, -N(C1-6 haloalkyl)C(O)O-, -N(C3-10 cycloalkyl)C(O)O-, -N(heterocyclyl)C(O)O- , -N(aryl)C(O)O-, -N(heteroaryl)C(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)NH-, -S(O)2NH-, -NHS(O)NH-, or -NHS(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b and L is further independently optionally substituted with one to six halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl. [0134] In certain embodiments, provided is a compound represented by Formula B-II:
Figure imgf000073_0001
wherein n, R2, R3, R4, R5, R6, and R11, are each independently as defined herein. [0135] In certain embodiments, R11 is hydrogen or fluoro. [0136] In certain embodiments, provided is a compound represented by Formula B-III:
Figure imgf000073_0002
wherein n, R2, R3, R4, R5, R6, and R12, are each independently as defined herein. [0137] In certain embodiments, R12 is fluoro, chloro, cyano, or -O-aryl optionally substituted with one to five halo. [0138] In certain embodiments, R12 is fluoro, chloro, or cyano. [0139] In certain embodiments, R12 is -O-aryl optionally substituted with one to five halo. [0140] In certain embodiments, R12 is
Figure imgf000073_0003
[0141] In certain embodiments, provided is a compound represented by Formula IV:
Figure imgf000074_0001
wherein n, R2, R3, R4, R5, R6, and R13, are each independently as defined herein. [0142] In certain embodiments, R13 is -C(O)OR8 or -C(O)N(R8)2. [0143] In certain embodiments, R13 is -C(O)OR8 or -C(O)NHR8. [0144] In certain embodiments, R13 is -C(O)OCH3 or
Figure imgf000074_0003
[0145] In certain embodiments, R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, and -C(O)OC1-6 alkyl. [0146] In certain embodiments, R2 is hydrogen or C1-6 alkyl substituted with -CH(OH)(CF3), -C(O)OH, or -C(O)OC2 alkyl. [0147] In certain embodiments, R2 is hydrogen, -CH2CH(OH)(CF3), -CH2C(O)OH, or -CH2C(O)OC2 alkyl. [0148] In certain embodiments, the moiety
Figure imgf000074_0004
is:
Figure imgf000074_0002
Figure imgf000075_0001
[0149] In certain embodiments, the moiety
Figure imgf000075_0002
is:
Figure imgf000075_0003
Figure imgf000076_0001
[0150] In certain embodiments, R3 is hydrogen. [0151] In certain embodiments, R3 is hydrogen and R4 is
Figure imgf000076_0002
, wherein m is 0 or 1. [0152] In certain embodiments, m is 0 or 1, and R7 is C1-6 haloalkyl. [0153] In certain embodiments, R3 and R4 together with the atoms to which they are attached form a ring selected from
Figure imgf000076_0004
wherein each is optionally substituted by oxo or a C3-6 spirocycle. [0154] In certain embodiments, R3 and R4 together with the atoms to which they are attached form a
Figure imgf000076_0003
. [0155] In certain embodiments, n is 2. [0156] In certain embodiments, each R6 is independently halo or -N(R16)2. [0157] In certain embodiments, each R6 is independently chloro or -NH2. [0158] In certain embodiments, R5 is C1-6 alkyl. [0159] In certain embodiments, R5 is tert-butyl. [0160] In certain embodiments, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Table B-1
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
[0161] In certain embodiments, provided is a compound selected from Table B-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Table B-2
Figure imgf000085_0002
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
3. Methods
[0162] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life and/or prolonging survival. In one embodiment, treating does not encompass preventing.
[0163] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
[0164] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
[0165] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.
[0166] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art. [0167] In certain embodiments, a compound disclosed herein can be used to treat or lessen a disease or condition mediated, at least in part, by caspase-1, by administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof. [0168] In certain embodiments, the disease or condition includes a chronic or acute form of a IL-1beta apoptosis-, IL-18-, or IFN-γ-mediated disease, or an inflammatory, autoimmune, destructive bone, proliferative, infectious, or degenerative disease. Exemplary diseases include, but are not limited to, chronic kidney disease, diabetic nephropathy, IgA nephropathy, uveitis, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, an excess dietary alcohol intake disease, necrotic diseases, a viral mediated disease, inflammatory peritonitis, osteoarthritis, pancreatitis (e.g., acute pancreatitis or chronic pancreatitis), asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, diabetes (e.g., juvenile diabetes, insulin-dependent diabetes mellitus (Type I)), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn’s disease, psoriasis, atopic dermatitis, scarring, graft vs. host disease, organ transplant rejection, osteoporosis, multiple myeloma-related bone disorder, leukemias and related disorders, myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi’s sarcoma, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Kennedy’s disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute or chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, coronary artery bypass graft, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV- or AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, various forms of liver disease, infectious hepatitis, hepatitis-B, hepatitis- C, hepatitis-G, yellow fever, dengue fever, Japanese encephalitis, lichenplanus, acute dermatomyositis, eczema, primary cirrhosis, Behcet’s disease, atopic skin disease, pure red cell aplasia, aplastic anemia, nephrotic syndrome, renal disease, renal tubulointerstitial fibrosis, neointimal hyperplasia (NH) in the arteries, polyaptic kidney disease, H. pylori-associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, or meningitis. [0169] In certain embodiments, the IL-1 or apoptosis mediated inflammatory disease which may be treated includes, but is not limited to osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, or adult respiratory distress syndrome. [0170] In certain embodiments, the IL-1 or apoptosis mediated autoimmune disease which may be treated includes, but is not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, insulin- dependent diabetes mellitus (Type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, Crohn’s disease, psoriasis, atopic dermatitis, or graft vs. host disease. [0171] In certain embodiments, the IL-1 or apoptosis mediated destructive bone disorders which may be treated include, but are not limited to, osteoporosis and multiple myeloma-related bone disorder. [0172] In certain embodiments, the IL-1 or apoptosis mediated proliferative diseases which may be treated include, but are not limited to, leukemias and related disorders, such as myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi’s sarcoma, and multiple myeloma. [0173] In certain embodiments, the IL-1 or apoptosis mediated infectious diseases which may be treated include, but are not limited to, sepsis, septic shock, or Shigellosis. [0174] In certain embodiments, the IL-1 or apoptosis mediated degenerative or necrotic diseases which may be treated include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, and myocardial ischemia. Preferably, the degenerative disease is Alzheimer’s disease. [0175] In certain embodiments, the IL-1 or apoptosis-mediated degenerative diseases which may be treated include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, or neurological damage due to stroke. [0176] Other diseases having an inflammatory or apoptotic component may be treated by the disclosed compounds. Such diseases may be systemic diseases or diseases with effects localized in the liver or other organs and may be caused by, for example, excess dietary alcohol intake or viruses, such as HBV, HCV, HGV, yellow fever virus, dengue fever virus, or Japanese encephalitis virus. [0177] In certain embodiments, the IL-18- or IFN-γ-mediated diseases which may be treated include, but are not limited to, inflammatory, infectious, autoimmune, proliferative, neurodegenerative and necrotic conditions. [0178] In certain embodiments, the IL-18- or IFN-γ-mediated inflammatory diseases which may be treated include, but are not limited to osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cerebral ischemia, myocardial ischemia and adult respiratory distress syndrome. [0179] In certain embodiments, the IL-18- or IFN-γ-mediated infectious diseases which may be treated include, but are not limited to infectious hepatitis, sepsis, septic shock and Shigellosis. [0180] In certain embodiments, the IL-18- or IFN-γ-mediated autoimmune diseases which may be treated include, but are not limited to glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, insulin-dependent diabetes mellitus (Type I), juvenile diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, myasthenia gravis, multiple sclerosis, psoriasis, lichenplanus, graft vs. host disease, acute dermatomyositis, eczema, primary cirrhosis, hepatitis, uveitis, Behcet’s disease, atopic skin disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis and nephrotic syndrome. [0181] In certain embodiments, provided is a method of treating diabetic nephropathy comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof. [0182] In certain embodiments, provided is a method of treating IgA nephropathy comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof. [0183] In certain embodiments, provided is a method of treating a renal disease comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof. [0184] In certain embodiments, provided is a method of treating chronic kidney disease (CKD), comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof. [0185] Chronic kidney disease (CKD) ultimately progresses to renal failure and the need for dialysis or renal transplantation. As such, also provided are methods for treating a patient in need of dialysis or renal transplantation comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof. [0186] Many factors are involved in the onset and progression of CKD. Renal tubulointerstitial fibrosis. characterized by ECM deposition, interstitial myofibroblast proliferation, and the infiltration of inflammatory mononuclear cells, is thought to play an important role in the pathogenesis of CKD. Therefore, preventing renal tubulointerstitial fibrosis remains a major target for clinicians. [0187] In certain embodiments, provided is a method of treating or preventing renal tubulointerstitial fibrosis, comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof. [0188] In certain embodiments, provided is a method of treating or preventing neointimal hyperplasia (NH) in the arteries, comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, to a subject in need thereof. [0189] One aspect of the present disclosure includes methods for treating a caspase-mediated disorder by administering a therapeutically effective amount of the disclosed compounds to a subject determined to be in need thereof. [0190] In certain embodiments, the compounds and compositions described herein may also be useful in treating complications associated with coronary artery bypass grafts and as a component of immunotherapy for the treatment of various forms of cancer. 4. Kits [0191] Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and suitable packaging. In certain embodiments, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein. [0192] Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe and intravenous bag. 5. Pharmaceutical Compositions and Modes of Administration [0193] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or prodrug thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.). [0194] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
[0195] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
[0196] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
[0197] Some examples of suitable excipients include, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
[0198] The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [0199] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [0200] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. [0201] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. 6. Dosing [0202] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. In some embodiments, a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. 7. Synthesis of the Compounds [0203] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. [0204] It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0205] Additionally, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J., Wiley- Interscience, and references cited therein. [0206] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0207] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). General Synthesis Method A-I [0208] The following reaction shown in Scheme I illustrates a general method which can be employed for the synthesis of compounds disclosed herein. In Scheme I, each R2, R3, R4, R4’, R5, R6, R7, R9, n, m, and X are independently as defined herein, LG is a leaving group (e.g., halo, such as bromo), and R50 is an alkyl group (e.g., ethyl). Scheme A-I
Figure imgf000103_0001
[0209] Referring to Scheme A-I, compound A-I-3 (e.g., compounds of Formula A-II where R2 is H) can be provided by contacting hydrazone compound A-I-1 with compound A-I-2 under standard amide coupling conditions. Coupling of compound A-I-3 with compound A-I-4 under standard nucleophilic substitution conditions provides compounds of Formula A-II. Compound A-I-1 can be prepared from the corresponding ester compounds A-I-5 using hydrazine hydrate under standard reaction conditions. [0210] Also referring to Scheme I, compounds of Formula A-IV can be prepared from the corresponding ester compounds A-I-5 by coupling with compound A-I-6 under standard metal catalyzed coupling conditions. Compounds of Formula A-III can then be provided by hydrolysing the compound of Formula A-IV, such as with an acid (e.g., HCl). [0211] Appropriate starting materials and reagents for the reactions shown in Scheme A-I can be purchased or prepared by methods known to one of skill in the art (e.g., see Examples below). For any compound shown in Scheme A-I, it should be understood that various derivatives can be provided by functional group interconversion at any step. In some embodiments, the various substituents of Formula A-I-1, A-I-2, A-I-3, A-I-4, or A-I-5 are as defined herein. However, derivatization of compounds A-I-1, A-I-2, A-I-3, A-I-4, or A-I-5 prior to reacting in any step, and/or further derivatization of the resulting reaction product, provides various compounds of Formula A-I. General Synthesis Method B-I [0212] The following reaction shown in Scheme B-I illustrates a general method which can be employed for the synthesis of compounds disclosed herein. In Scheme B-I, each n, R1, R2, R3, R4, R5, R6, m, and t are independently as defined herein, X is a leaving group (e.g., halo, such as bromo), and R50 is an alkyl group (e.g., ethyl). Scheme B-I
Figure imgf000104_0001
[0213] Referring to Scheme B-I, compound B-I-3 (e.g., compounds of Formula B-I where R2 is H) can be provided by contacting hydrazone compound B-I-1 with compound B-I-2 under standard amide coupling conditions. Coupling of compound B-I-3 with compound B-I-4 under standard nucleophilic substitution conditions provides compounds of Formula B-I. Compound B-I-1 can be prepared from the corresponding ester compounds B-I-5 using hydrazine hydrate under standard reaction conditions. [0214] Appropriate starting materials and reagents for the reactions shown in Scheme B-I can be purchased or prepared by methods known to one of skill in the art (e.g., see Examples below). For any compound shown in Scheme B-I, it should be understood that various derivatives can be provided by functional group interconversion at any step. In some embodiments, the various substituents of Formula B-I-1, B-I-2, B-I-3, B-I-4, or B-I-5 are as defined herein. However, derivatization of compounds B-I-1, B-I-2, B-I-3, B-I-4, or B-I-5 prior to reacting in any step, and/or further derivatization of the resulting reaction product, provides various compounds of Formula B-I. [0215] In the Schemes above, appropriate starting materials and reagents can be purchased or prepared by methods known to one of skill in the art. Upon each reaction completion, each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like. Other modifications to arrive at compounds of this disclosure are within the skill of the art. [0216] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. It should be appreciated that various isomers of Formula A-I or Formula B-Ican be separated as well. EXAMPLES [0217] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Example A-1 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000106_0001
Figure imgf000106_0002
[0218] Reagents and conditions: (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h, (g) Chiral resolution (see Examples A-2 and A-3). EXAMPLE A-1A 3-Chloro-N-(2-methoxypyridin-3-yl)-4-nitrobenzamide [0219] To a stirred solution of 3-chloro-4-nitrobenzoic acid (35 g, 174 mmol) in DMF (233 mL) was added N,N-Diisopropylethylamine (90.7 mL, 521 mmol), HATU (99 g, 260 mmol) and 2- methoxypyridin-3-amine (21.6 g, 174 mmol) sequentially over a period of 10-15 min. The reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (400 mL) and residue was extracted with ethyl acetate (200 mL × 2 times). The combined organic layer was washed with cold water (100 mL × 3 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-20%). Pure fractions were collected and concentrated to afford 3-chloro-N-(2-methoxypyridin-3-yl)-4-nitrobenzamide (50 g) as brown solid. EXAMPLE A-1B 3-Chloro-4-nitro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide [0220] To a stirred solution of Example A-1A (50 g, 163 mmol) dissolved in dioxane (300 mL) was added 4 M HCl in dioxane (150 mL) at 0 ⁰C. The reaction mixture was heated at 70 ⁰C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under vacuum, washed with diethyl ether and dried under vacuum to afford 3- chloro-4-nitro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide (45 g) as brown solid, which was used in the next step without further purification. EXAMPLE A-1C methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)propanoate [0221] To a stirred solution of Example A-1B (45 g, 153 mmol) dissolved in DMF (450 mL) was added cesium carbonate (125 g, 383 mmol) and methyl 2-bromopropanoate (17.2 mL, 153 mmol) at 0 ⁰C. The reaction mixture was heated at 60 ⁰C for 3 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (500 mL) and resulting residue was extracted with ethyl acetate (500 mL × 3 times). The combined organic layer was washed with cold water (500 mL × 10 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by flash column chromatography using 40-45% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford methyl 2-(3-(3- chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)propanoate (30 g) as yellowish black semi-solid which was used in the next step without further purification. EXAMPLE A-1D Methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanoate [0222] To a stirred solution of Example A-1C (30 g, 79 mmol) dissolved in ethanol (300 mL), water (150 mL) was added ammonium chloride (22.1 mL, 633 mmol) and Iron (20.6 g, 315 mmol). The reaction mixture was heated at 60 ⁰C for 14 hours. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite bed and residue was washed with methanol. Filtrate concentrated and worked up with dichloromethane (100 mL × 3 times), evaporated under reduced pressure to afford methyl 2-(3-(4-amino-3-chlorobenzamido)-2- oxopyridin-1(2H)-yl)propanoate (21 g) as a yellow colour solid which was used in the next step without further purification. EXAMPLE A-1E 2-(3-(4-Amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanoic acid [0223] To a stirred solution of Example A-1D (21 g, 60 mmol) dissolved in tetrahydrofuran (48 mL) and water (16 mL) was added lithium hydroxide monohydrate (7.56 g, 180 mmol) at rt. The reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was distilled and neutralized with 1N HCl (pH adjusted to 4-5) and the precipitate was filtered to afford the title compound (18 g) as a brown colour solid which was used in the next step without further purification. EXAMPLE A-1F 4-Amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo- 1,2-dihydropyridin-3-yl)benzamide (A-1) [0224] To a stirred solution of prop-2-en-1-yl N-[(3S)-2-ethoxy-5-oxooxolan-3-yl]carbamate (1.02 g, 4.47 mmol) in dichloromethane (3 mL) at 0 ⁰C was added 1,3-dimethyl-1,3-diazinane-2,4,6-trione (0.51 g, 3.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.067 g, 0.0596 mmol). The reaction mixture was allowed to stir for 15 minutes. Separately to a solution of Example A-1E (1 g, 2.98 mmol) in DMF (3 mL) was added followed by DIPEA (1.04 mL, 5.96 mmol), EDCl (0.69 g, 3.57 mmol), HOBt (0.46 g, 2.98 mmol). The solution was stirred at 0 °C for 10 minutes and the solution from the above reaction was added dropwise to it. The reaction mixture was stirred at rt for 4 h. The reaction progress was monitored by TLC and LCMS. The solvent of reaction mixture was dried under vacuum and the residue was diluted with water (5 mL) then extracted with ethyl acetate (5 × 10 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product. The compound was then purified by preparative HPLC Inertsil ODS C18 (250 × 20) mm; 5 µM column, 5 mM Ammonium acetate in water: acetonitrile as mobile phase (19 mL/min flow rate) and afforded the title compound (0.75 g) at Retention Time (RT) of 14.4 min. EXAMPLE A-2 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000109_0001
and EXAMPLE A-3 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000109_0002
[0225] Purification of the Example A-1F by chiral prep-HPLC using CHIRALPACK IC (250 mm × 20 mm × 5 µM) column and n-Hexane: IPA with 0.1% DEA (80:20) as mobile phase (19 mL/ min flow rate) and afforded the Example A-2 (0.125 g) at RT 5.26 min as the first eluting enantiomer and Example A-3 (0.175 g) at RT 15.13 min as the second eluting enantiomer.
EXAMPLE A-4 (3S)-3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-oxobutanoic acid
Figure imgf000110_0001
[0226] Reagents and conditions: (a) 5% aq. HCl, MeCN, rt, 16 h. [0227] To a stirred solution of Example A-2 (0.025 g, 0.054 mmol) in acetonitrile (2.5 mL) was added hydrogen chloride solution (1 mL, 5% in water) at 0 ⁰C. After overnight stirring, the reaction mixture was concentrated under vacuum to furnish the crude material, which was then purified by prep-HPLC using X Bridge C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) to afford the title compound (0.005 g) at RT of 11.61 min as a single unknown enantiomer.
EXAMPLE A-5 4-Amino-3-chloro-N-(1-(2-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-2-oxo-1-phenylethyl)- 2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000111_0001
Figure imgf000111_0002
[0228] Reagents and conditions: (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h. EXAMPLE A-5C Methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)-2-phenylacetate [0229] The title compound (0.8 g) was prepared using the procedure described in Example A-1C, using Example A-1B (1.5 g, 4.56 mmol) and methyl 2-bromo-2-phenylacetate in place of methyl 2- bromopropanoate. EXAMPLE A-5D Methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-2-phenylacetate [0230] The title compound (0.6 g) was prepared using the procedure described in Example A-1D, using Example A-5C (0.7 g, 1.58 mmol) in place of Example A-1C. EXAMPLE A-5E 2-(3-(4-Amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-2-phenylacetic acid [0231] The title compound (0.45 g) was prepared using the procedure described in Example A-1E, using Example A-5D (0.7 g, 1.70 mmol) in place of Example A-1D. EXAMPLE A-5F 4-Amino-3-chloro-N-(1-(2-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-2-oxo-1-phenylethyl)-2- oxo-1,2-dihydropyridin-3-yl)benzamide (A-5) [0232] The title compound (0.032 g) was prepared using the procedure described in Example A-1F, using Example A-5E (0.2 g, 0.50 mmol) in place of Example A-1E and purified by preparative HPLC Atlantis Prep C18 (19 × 100) mm; 5 µM column and water: acetonitrile as mobile phase (19 mL/ min flow rate) at RT 19.33 min. EXAMPLE A-6 4-Amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxo-3- phenylpropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000112_0001
Figure imgf000112_0002
[0233] Reagents and conditions: (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h. EXAMPLE A-6C Methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate [0234] The title compound (0.45 g) was prepared using the procedure described in Example A-1C, using Example A-1B (1.0 g, 3.41 mmol) and methyl 2-bromo-3-phenylpropanoate in place of methyl 2- bromopropanoate. EXAMPLE A-6D Methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate [0235] The title compound (0.4 g) was prepared using the procedure described in Example A-1D, using Example A-6C (0.45 g, 0.99 mmol) in place of Example A-1C. EXAMPLE A-6E 2-(3-(4-Amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid [0236] The title compound (0.3 g) was prepared using the procedure described in Example A-1E, using Example A-6D (0.4 g, 0.94 mmol) in place of Example A-1D. EXAMPLE A-6F 4-Amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxo-3-phenylpropan-2- yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-6) [0237] The title compound (0.03 g) was prepared using the procedure described in Example A-1F, using Example A-6E (0.15 g, 0.36 mmol) in place of Example A-1E and purified by preparative HPLC Inertsil ODS C18 (250 × 20) mm; 5 µM column, 5 mM Ammonium acetate in water: acetonitrile as mobile phase (19 ml/min flow rate) at RT 18.83 min.
EXAMPLE A-7 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxo-3- phenylpropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000114_0001
and EXAMPLE A-8 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxo-3- phenylpropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000114_0002
[0238] Purification of the Example A-6F by chiral prep-HPLC using CHIRALPACK IC (250 mm × 20 mm × 5 µM) column and Ethanol (100%) as mobile phase (20 mL/ min flow rate) afforded the title compound Example A-7 (0.006 g) at RT 10.24 min as a single unassigned enantiomer and title compound Example A-8 (0.01 g) at RT 11.61 min as a single unassigned enantiomer.
EXAMPLE A-9 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-3-methyl-1-oxobutan- 2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000115_0001
and EXAMPLE A-10 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-3-methyl-1-oxobutan- 2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000115_0002
Figure imgf000116_0001
[0239] Reagents and conditions: (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h, (g) Preparative separation. EXAMPLE A-9C Methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoate [0240] The title compound (1.7 g) was prepared using the procedure described in Example A-1C, using Example A-1B (2.0 g, 6.81 mmol) and methyl 2-bromo-3-methylbutanoate in place of methyl 2- bromopropanoate. EXAMPLE A-9D Methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoate [0241] The title compound (1.2 g) was prepared using the procedure described in Example A-1D, using methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoate (1.6 g, 3.92 mmol) in place of methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)propanoate. EXAMPLE A-9E 2-(3-(4-Amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoic acid [0242] The title compound (0.25 g) was prepared using the procedure described in Example A-1E, using methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoate (0.4 g, 1.06 mmol) in place of methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanoate. EXAMPLE A-9F 4-Amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-3-methyl-1-oxobutan-2-yl)- 2-oxo-1,2-dihydropyridin-3-yl)benzamide [0243] The title compound (0.11 g) was prepared using the procedure described in Example A-1F, using Example A-9E (0.23 g, 0.63 mmol) in place of Example A-1E. EXAMPLE A-9G 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-3-methyl-1-oxobutan-2-yl)- 2-oxo-1,2-dihydropyridin-3-yl)benzamide (Single Enantiomer- Example A-9) and 4-amino-3-chloro-N- (1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-3-methyl-1-oxobutan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)benzamide (Single Enantiomer- Example A-10) [0244] The crude product of Example A-9F was purified by preparative HPLC Inertsil ODS C18 (250 × 20) mm; 5 µM column, 5 mM Ammonium acetate in water: acetonitrile as mobile phase (19 mL/min flow rate) and afforded title compound Example A-9 (0.01 g) at RT 37.89 min and title compound Example A-10 (0.01 g) at RT 31.00 min. EXAMPLE A-11 2-(2-(4-Amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-N-((3S)-2-ethoxy- 5-oxotetrahydrofuran-3-yl)propanamide
Figure imgf000117_0001
Figure imgf000118_0001
[0245] Reagents and conditions: (a) DMF, 130 °C, 16 h, (b) H2, Pd/C, EtOH, (c) TsCl, NaH, THF, 0 °C, 12 h, (d) I2, LDA, THF, -78 °C, (e) Pd(dpffCl2).CH2Cl2, K2CO3, dioxane, H2O, 100 °C, 12 h, (f) 4 M HCl in dioxane, 70 °C, 12 h, (g) Cs2CO3, DMF, 60 °C, 8 h, (h) 20% NaOH, dioxane, 80 °C, 12 h, (i) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDC, HOBt, DIPEA, CH2Cl2/DMF, 16 h, (j) TFA, CH2Cl2, 0 °C, 1 h. EXAMPLE A-11A (E)-2-(2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethen-1-amine [0246] A solution of 2-methoxy-4-methyl-3-nitropyridine (5 g, 29.7 mmol) in DMF (7 mL, 90.4 mmol) and (dimethoxymethyl)dimethylamine (12.5 mL) was heated at 130 °C for 18 h, cooled, and poured onto cold water then filtered and dried to give (E)-2-(2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethen-1- amine (5.8 g). EXAMPLE A-11B 7-Methoxy-1H-pyrrolo[2,3-c]pyridine [0247] A solution of Example A-11A (4 g, 17.9 mmol) in ethanol (400 mL) containing 10% Pd/C (357 mg) was shaken under hydrogen at 15 psi for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mass was filtered through celite bed and concentrated to get crude. The residue was purified by silica gel flash column chromatography using EtOAc: heptane (25:75) as a eluent and afforded 7-methoxy-1H-pyrrolo[2,3-c]pyridine (1 g). EXAMPLE A-11C 7-Methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine [0248] To a stirred solution of Example A-11B (3.7 g, 25 mmol) in dry THF (40 mL) was cooled to 0 °C added sodium hydride (1.44 g, 37.5 mmol) and stirred for 30 min at same temperature, then cooled to 0 °C added benzenesulfonyl chloride (3.84 mL, 30 mmol) continued to stirred at room temperature for 16 h. The reaction mass cooled to 0 °C and quenched with water, diluted with ethyl acetate (50 mL) and cold water (50 mL). After separation, aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organics were washed with brine solution (50 mL), then dried over sodium sulphate, filtered and concentrated under vacuum. The residue was purified by silica gel flash column chromatography EtOAc: Heptane (25:75) afforded 7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (6.2 g). EXAMPLE A-11D 2-Iodo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine [0249] To a stirred solution of Example A-11C (3.1 g, 10.8 mmol) in dry THF (60 mL) was added lithium diisopropylamide (2.3 g, 21.5 mmol) at -78 °C and stirred for 30 min at -78 °C. To it iodine (5.46 g, 21.5 mmol) was added and the reaction mixture was then stirred at -78 °C for 5 h. The progress of the reaction was monitored by TLC and LC-MS. The reaction mass was quenched with ammonium chloride and washed with water, brine solution dried with sodium sulphate and concentrated to get crude product. The residue was purified by silica gel flash chromatography using EtOAc: heptane (25:75) as a eluent afforded 2-iodo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (4 g). EXAMPLE A-11E 2-Chloro-4-(7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridin-2-yl)aniline [0250] To a stirred solution of Example A-11D (2 g, 3.86 mmol) in dioxane (32 mL) was added 2- chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.08 g, 4.25 mmol) and potassium carbonate (1.6 g, 11.6 mmol) in water (8 mL) purged with nitrogen for 5 minutes. Then added [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.63 g, 0.77 mmol) and the reaction mixture was heated in a sealed tube at 100 °C for 16 h. The progress of the reaction was monitored by TLC and LC-MS. The reaction mass was diluted with ethyl acetate and washed with water, brine solution dried with sodium sulphate and concentrated under vacuum to get crude. The residue was purified by silica gel flash chromatography using EtOAc: Heptane (25:75) as eluent afforded 2-chloro-4-(7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridin-2-yl)aniline (1.2 g). EXAMPLE A-11F 2-(4-Amino-3-chlorophenyl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [0251] The title compound (1.5 g) was prepared using the procedure described in Example A-1B, using Example A-11E (1.5 g, 2.9 mmol). EXAMPLE A-11G Methyl 2-(2-(4-amino-3-chlorophenyl)-7-oxo-1-tosyl-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanoate [0252] The title compound (0.9 g) was prepared using the procedure described in Example A-1C, using Example A-11F (2 g, 5.0 mmol). EXAMPLE A-11H 2-(2-(4-Amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)propanoic acid [0253] To stirred a solution of Example A-11G (0.7 g, 1.44 mmol) in dioxane (10 mL) was added NaOH 20% in water (7 mL), the solution was stirred at 80 °C for 12 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mass was concentrated to remove solvent, and diluted with cold water (5 mL) aqueous phase was extracted with diethyl ether (2 × 10 mL), The aqueous layer was acidified with saturated citric acid in water (pH-6) followed by filtration afforded 2-(2-(4-amino-3- chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)propanoic acid (0.4 g) as pale yellow solid which was used in the next step without further purification. EXAMPLE A-11I tert-Butyl (3S)-3-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-4,4-diethoxybutanoate [0254] To a degassed solution (argon purging, 5 min) of tert-butyl (3S)-4,4-diethoxy-3-{[(prop-2-en-1- yloxy)carbonyl]amino}butanoate (0.12 g, 0.36 mmol) and 1,3-dimethyl-1,3-diazinane-2,4,6-trione (0.047 g, 0.30 mmol) in dichloromethane (5 mL) at room temperature was added tetrakis(triphenylphosphine)palladium(0) (0.005 g, 0.0045 mmol). The solution was stirred at room temperature for 15 min. At the same time, to the solution of Example A-11H (0.1 g, 0.30 mmol) in dichloromethane/ DMF (5 mL/ 5 mL) at 0 °C was added ({[3- (dimethylamino)propyl]imino}methylidene)(ethyl)amine (0.056 g, 0.36 mmol), DIPEA (0.16 mL, 0.90 mmol) and 1H-1,2,3-benzotriazol-1-ol hydrate (0.046 g, 0.30 mmol). The reaction mixture was stirred for 10 min and the solution from the above reaction was added dropwise to it. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After reaction completion, reaction mixture was diluted with dichloromethane (25 mL) and cold water (15 mL). After separation, aqueous phase was extracted with dichloromethane (2 × 20 mL). The combined organic phase was washed sequentially with aqueous saturated NaHCO3 (15 mL), 2% citric acid solution (10 mL) and brine solution (15 mL), then dried over sodium sulphate, filtered and concentrated under vacuum. The residue was purified by silica gel flash column chromatography using EtOAc: Heptane (40:60) as eluent afforded tert-butyl (3S)-3-{2-[2-(4-amino-3-chlorophenyl)-7-oxo- 1H,6H,7H-pyrrolo[2,3-c]pyridin-6-yl]propanamido}-4,4-diethoxybutanoate (0.08 g). EXAMPLE A-11J 2-(2-(4-Amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-N-((3S)-2-ethoxy-5- oxotetrahydrofuran-3-yl)propanamide (11) [0255] Under Argon, to a solution of Example A-11I (0.08 g, 0.14 mmol) in dichloromethane (4 mL) at 0 °C was added trifluoroacetic acid (0.11 mL, 1.43 mmol) . The reaction mixture was stirred at room temperature for 1 h. The formation of product was confirmed by TLC and LCMS. TLC monitoring (cyclohexane/EtOAc, 1/1) showed complete conversion. The reaction mixture was diluted with dichloromethane (10 ml) and neutralized with aqueous NaHCO3 (2%) at 0 °C and the aqueous layer extracted with dichloromethane (3 × 10 mL). The organic phase was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under vacuum at 30 °C. Purification of the crude by preparative HPLC using Sunfire C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) afforded 2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H- pyrrolo[2,3-c]pyridin-6-yl)-N-((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)propanamide (0.008 g) at RT 22.19 min. EXAMPLE A-12 Ethyl N-acryloyl-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)- yl)propanamido)glycinate
Figure imgf000122_0001
[0256] Reagents and conditions: (a) NH2NH2.H2O, EtOH, 80 °C, 16 h, (b) NMM, DMF, 0 °C-rt, 6 h, (c) NEt3, THF, 0 °C, 15 min. EXAMPLE A-12A 4-Amino-3-chloro-N-(1-(1-hydrazineyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide [0257] To a stirred solution of Example A-1D (1 g, 2.86 mmol) in ethanol (30 mL) was added hydrazine hydrate (5.2 mL, 114 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. Reaction was monitored by TLC. Reaction mixture was distilled and diluted with water (10 mL). The white precipitate formed was filtered and washed with water afforded 4-amino-3-chloro-N-(1-(1- hydrazineyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide (0.73 g). EXAMPLE A-12B Ethyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)glycinate [0258] To a stirred solution of Example A-12A (0.3 g, 0.858 mmol) in DMF (10.0 mL), 4- methylmorpholine (0.26 mL, 0.283 mmol), and ethyl 2-bromoacetate (0.19 mL, 0.858 mmol) were added dropwise at 0 °C and the mixture was allowed to stir for 6 h at room temperature. The progress of the reaction was monitored by TLC and LCMS. The solvent was removed under vacuum to get the crude product, which was purified using silica gel flash column chromatography using 70% ethyl acetate in n- hexane afforded ethyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)- yl)propanamido)glycinate (0.18 g). EXAMPLE A-12C Ethyl N-acryloyl-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)glycinate (12) [0259] To a solution of Example A-12B (0.12 g, 0.275 mmol) in THF (10 mL) was cooled to 0 °C added triethylamine (0.056 mL, 0.413 mmol), prop-2-enoyl chloride (0.018 mL, 0.22 mmol) under a nitrogen atmosphere, and the reaction mixture was continued at same temperature for 15 min. The progress of the reaction was monitored by TLC and LCMS. The reaction mass was concentrated to get crude. Purification of the crude product was performed by preparative HPLC using X Select CSH C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) and afforded ethyl N-acryloyl-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)glycinate (0.001 g) at RT 15.26 min. EXAMPLE A-13 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000123_0001
[0260] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 3 h. EXAMPLE A-13A Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate (A-13) [0261] To a solution of Example A-12B (0.3 g, 0.69 mmol) was added ethylbis(propan-2-yl)amine (0.36 mL, 2.06 mmol) in dimethylformamide (3.0 mL) was added HATU (0.31 g, 0.83 mmol) and under nitrogen atmosphere at 0 °C. Then sodium 2-fluoroacetate (0.14 g, 1.38 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude product, which was subjected to preparative HPLC purification using Inertsil ODS-3 (20 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) and afforded ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)- yl)propanamido)-N-(2-fluoroacetyl)glycinate (0.08 g) at RT 14.04 min. EXAMPLE A-14 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000124_0001
and EXAMPLE A-15 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000124_0002
[0262] Purification of Example A-13C by chiral prep-HPLC using CHIRALPACK IA (250 mm × 30 mm × 5 µM) column and ethanol and n-hexane (50:50) as mobile phase (40 mL/ min flow rate) afforded the title compound Example A-14 (0.02 g) at RT 8.78 min and title compound Example A-15 (0.02 g) at RT 20.39 min. EXAMPLE A-16 Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000125_0001
[0263] Reagents and conditions: (a) EDCl, DIPEA, HOBt, CH2Cl2, 0 °C-rt, 16 h. EXAMPLE A-16A Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate (A-16) [0264] To a stirred solution of 4-(benzylamino)-4-oxo-2-butenoic acid (0.21 g, 1.03 mmol) in dichloromethane (10 mL) ethylbis(propan-2-yl)amine (0.60 mL, 3.44 mmol) was added at 0 °C. To the above solution ({[3-(dimethylamino)propyl]imino}methylidene)(ethyl)amine hydrochloride (0.40 g, 2.06 mmol) and 1H-1,2,3-benzotriazol-1-ol hydrate (0.16 g, 1.03 mmol) was added at 0 °C. After 10 min, Example A-12B (0.3 g, 0.69 mmol) dissolved in dichloromethane and DMF (5 mL each) was added and stirring was continued at ambient temperature for 16 h. Reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with ice-cold water (2 × 15 mL). Organic phase was separated, dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography by eluting ethyl acetate and Hexane (45-50%) afforded product (0.25 g). Purification of the crude product was done using preparative HPLC with X Bridge C18 (19 × 250 mm); 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (18 mL/ min flow rate) and afforded ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2- oxopyridin-1(2H)-yl)propanamido)-N-(4-(benzylamino)-4-oxobut-2-enoyl)glycinate (0.1 g) at RT 18.15 min. EXAMPLE A-17 Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000126_0001
and EXAMPLE A-18 Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000126_0002
[0265] Purification of the Example A-16A (0.09 g, 0.14 mmol) was performed by chiral prep-HPLC using CHIRALPACK IC (250 mm × 30 mm × 5 µM) column and Ethanol and n-Hexane (40:60) as mobile phase (40 mL/ min flow rate) and afforded the title compound Example A-17 (0.032 g) at RT 14.87 min and title compound Example A-18 (0.017 g) at RT 19.33 min. EXAMPLE A-19 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycinate
Figure imgf000127_0001
EXAMPLE A-19A 2-(Perfluorophenoxy)acetyl chloride [0266] To a stirred solution of 2-(perfluorophenoxy)acetic acid (0.20 g, 0.97 mmol) in dioxane (3 mL) was added thionyl chloride (0.36 mL, 4.96 mmol) at room temperature. The reaction mixture was stirred at 75 °C for 90 min. After reaction completion, the reaction mixture was concentrated under argon atmosphere. The crude product was directly used in the next step without further purification. EXAMPLE A-19B Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycinate (A-19) [0267] To a stirred solution of Example A-12B (0.3 g, 0.69 mmol) in dichloromethane (4 mL) were added triethylamine (0.48 mL, 3.44 mmol) and Example A-19A (0.22 g, 0.83 mmol) at room temperature and the mixture was allowed to react for 16 h at room temperature. The progress of reaction was monitored by TLC and LCMS. Reaction mixture was diluted with dichloromethane (10 mL) and washed with water (10 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by flash column chromatography using methanol: dichloromethane system (0-3%) to get product (0.24 g). Purification of isolated product was further performed by preparative HPLC using Inertsil ODS C18 (20 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) and afforded ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycinate (0.06 g) at RT 18.8 min. EXAMPLE A-20 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycinate
Figure imgf000128_0001
and EXAMPLE A-21 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycinate
Figure imgf000128_0002
[0268] Purification of the Example A-19B (0.10 g, 0.15 mmol) was performed by chiral prep-HPLC using CHIRALPACK IC (250 mm × 30 mm × 5 µM) column and Ethanol and n-Hexane (40:60) as mobile phase (40 mL/ min flow rate) and afforded the title compound Example A-20 (0.025 g) at RT 11.42 min and title compound Example A-21 (0.036 g) at RT 14.45 min. EXAMPLE A-22 Ethyl N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(2-fluoroacetyl)glycinate
Figure imgf000129_0001
[0269] Reagents and conditions: (a) EDC, HOBt, NEt3, CH2Cl2, 0 °C-rt, 12 h, (b) HATU, DIPEA, DMF, 0 °C-rt, 3 h. EXAMPLE A-22A Ethyl (2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)glycinate [0270] To a stirred solution Example A-11H (0.3 g, 0.90 mmol) in dichloromethane (10 mL) at 0 °C triethylamine (0.50 mL, 3.62 mmol), EDC (0.21 g, 1.36 mmol), HOBt (0.21 g, 1.36 mmol) and ethyl 2- hydrazinylacetate hydrochloride (0.14 g, 0.90 mmol) were added and reaction mixture was stirred at rt for 12 h. Reaction mixture was quenched in cold water and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum to afford crude product, which was purified by flash column chromatography using methanol: dichloromethane system (0-10%) afforded ethyl (2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)glycinate (0.24 g). EXAMPLE A-22B Ethyl N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(2-fluoroacetyl)glycinate (A-22) [0271] The title compound (0.035 g) was prepared using the procedure described in Example A-13C, using Example A-22A (0.11 g, 0.26 mmol) in place of Example A-12B. Crude product was purified with preparative HPLC using X Bridge C18 (19 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 21.97 min. EXAMPLE A-23 Ethyl N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(2-fluoroacetyl)glycinate
Figure imgf000130_0001
and
EXAMPLE A-24 Ethyl N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(2-fluoroacetyl)glycinate
Figure imgf000131_0001
[0272] Purification of the Example A-22B (0.030 g, 0.059 mmol) by chiral prep-HPLC using CHIRALPACK IC (100 mm × 4.6 mm × 3 µM) column and n-hexane: ethanol (70:30) as mobile phase (30 mL/ min flow rate) afforded title compound Example A-23 (0.006 g) at RT 22.44 min and title compound Example A-24 (0.006 g) at RT 26.42 min. EXAMPLE A-25 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycinate
Figure imgf000131_0002
and EXAMPLE A-26 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycinate
Figure imgf000132_0001
Figure imgf000132_0002
[0273] Reagents and conditions: (a) SOCl2, dioxane, 80 °C, 90 min. (b) NEt3, CH2Cl2, rt, 16 h, (c) Chiral preparative HPLC separation. EXAMPLE A-25A 2-(2,3,5,6-Tetrafluorophenoxy)acetyl chloride [0274] The title compound (0.18 g) was prepared using the procedure described in Example A-19A, using 2-(2,3,5,6-tetrafluorophenoxy)acetic acid (0.16 g, 0.71 mmol) in place of 2- (perfluorophenoxy)acetyl chloride. EXAMPLE A-25B Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycinate [0275] The title compound was prepared using the procedure described in Example A-19B, using Example A-12B (0.5 g, 1.15 mmol) and Example A-25A in place of Example A-19A. Crude compound was purified with flash column chromatography using ethyl acetate: n-hexane system (0-40%) and afforded the title compound (0.17 g). EXAMPLE A-25 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycinate (A-25) and EXAMPLE A-26 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycinate (A-26) [0276] Purification of the Example A-25B (0.170 g, 0.26 mmol) by chiral prep-HPLC using CHIRALPACK IC (250 mm × 20 mm × 5 mic) column and n-Hexane: Ethanol (50:50) as mobile phase (19 mL/ min flow rate) afforded two isomers: Example A-25 (0.040 g) at RT 9.70 min and Example A- 26 (0.038 g) at RT 14.89 min. EXAMPLE A-27 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycinate
Figure imgf000133_0001
Figure imgf000134_0001
[0277] Reagents and conditions: (a) SOCl2, dioxane, 80 °C, 90 min. (b) NEt3, CH2Cl2, rt, 16 h. EXAMPLE A-27A 2-(2,6-Difluorophenoxy)acetyl chloride [0278] The title compound (0.26 g) was prepared using the procedure described in Example A-19A, using 2-(2,6-difluorophenoxy)acetic acid (0.24 g, 1.28 mmol) in place of 2-(perfluorophenoxy)acetyl chloride. EXAMPLE A-27B Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycinate (A-27) [0279] The title compound was prepared using the procedure described in Example A-19B, using Example A-12B (0.45 g, 1.03 mmol) and Example A-27A in place of Example A-19A. Crude product was purified with preparative HPLC using Inertsil ODH C18 (20 × 250) mm; 5 mic column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) and afforded the title compound (0.15 g) at RT 19.90 min. EXAMPLE A-28 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)butanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000135_0001
Figure imgf000135_0002
[0280] Reagents and conditions: (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) NH2NH2.H2O, EtOH, 80 °C, 16 h, (f) NMM, DMF, 0 °C-rt, 6 h, (g) HATU, DIPEA, DMF, 0 °C-rt, 3 h. EXAMPLE A-28C Methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)butanoate [0281] The title compound (3.0 g) was prepared using the procedure described in Example A-1C, using Example A-1B (4.5 g, 15.3 mmol) and methyl 2-bromobutanoate in place of methyl 2-bromopropanoate. EXAMPLE A-28D Methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)butanoate [0282] The title compound (3.8 g) was prepared using the procedure described in Example A-1D, using Example A-28C (4.8 g, 12.2 mmol) in place of Example A-1C. EXAMPLE A-28E 4-Amino-3-chloro-N-(1-(1-hydrazineyl-1-oxobutan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide [0283] The title compound (0.6 g) was prepared using the procedure described in Example A-12A, using Example A-28D (1.5 g, 4.12 mmol) in place of Example A-1D. EXAMPLE A-28F Ethyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)butanamido)glycinate [0284] The title compound (0.18 g) was prepared using the procedure described in Example A-12B, using Example A-28E (0.3 g, 0.83 mmol) in place of Example A-12A. EXAMPLE A-28G Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)butanamido)-N-(2- fluoroacetyl)glycinate (A-28) [0285] The title compound (0.012 g) was prepared using the procedure described in Example A-13C, using Example A-28F (0.18 g, 0.40 mmol) in place of Example A-12B. Crude compound was purified with preparative HPLC using Inertsil ODS C18 (20 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/min flow rate) at RT 16.66 min.
EXAMPLE A-29 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycinate
Figure imgf000137_0001
and EXAMPLE A-30 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycinate
Figure imgf000137_0002
[0286] The stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration). Purification of the Example A-27 by chiral prep-HPLC using CHIRALPACK IC (250 mm × 20 mm × 5 µM) column and n-Hexane: EtOH (50:50) as mobile phase (19 mL/ min flow rate) and afforded the Example A-29 (0.0479 g) at RT 3.58 min and Example A-30 (0.0471 g) at RT 5.67 min. EXAMPLE A-31 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000138_0001
[0287] Reagents and conditions: (a) NH2NH2.H2O, EtOH, 80 °C, 16 h, (b) NMM, DMF, 0 °C-rt, 6 h, (c) HATU, DIPEA, DMF, 0 °C-rt, 3 h. EXAMPLE A-31A 4-amino-3-chloro-N-(1-(1-hydrazineyl-3-methyl-1-oxobutan-2-yl)-2-oxo-1,2-dihydropyridin-3- yl)benzamide [0288] The title compound (1.2 g) was prepared using the procedure described in Example A-12A, using Example A-9D (1.9 g, 4.9 mmol) in place of Example A-1D. EXAMPLE A-31B ethyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate [0289] The title compound (1.0 g) was prepared using the procedure described in Example A-12B, using Example A-31A (1.2 g, 3.0 mmol) in place of Example A-12A. EXAMPLE A-31C ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-31) [0290] The title compound (1.1 g) was prepared using the procedure described in Example A-13A, using Example A-31B (1.0 g, 2.2 mmol) in place of Example A-12B. Crude product was purified with preparative HPLC using X Select C18 (19 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 19.40 min. EXAMPLE A-32 4-Amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000139_0001
Figure imgf000140_0001
[0291] Reagents and conditions: (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h. EXAMPLE A-32A 3-chloro-N-(2-methoxy-5-methylpyridin-3-yl)-4-nitrobenzamide [0292] The title compound (1.6 g) was prepared using the procedure described in Example A-1A, using 2-methoxy-5-methylpyridin-3-amine (1.0 g, 7.1 mmol) in place of 2-methoxypyridin-3-amine. EXAMPLE A-32B 3-chloro-N-(5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-nitrobenzamide [0293] The title compound (1.5 g) was prepared using the procedure described in Example A-1B, using Example A-32A (1.6 g, 4.8 mmol) in place of Example A-1A. EXAMPLE A-32C methyl 2-(3-(3-chloro-4-nitrobenzamido)-5-methyl-2-oxopyridin-1(2H)-yl)propanoate [0294] The title compound (1.5 g) was prepared using the procedure described in Example A-1C, using Example A-32B (1.5 g, 4.9 mmol) in place of Example A-1B. EXAMPLE A-32D methyl 2-(3-(4-amino-3-chlorobenzamido)-5-methyl-2-oxopyridin-1(2H)-yl)propanoate [0295] The title compound (1.2 g) was prepared using the procedure described in Example A-1D, using Example A-32C (1.5 g, 3.9 mmol) in place of Example A-1C. EXAMPLE A-32E 2-(3-(4-amino-3-chlorobenzamido)-5-methyl-2-oxopyridin-1(2H)-yl)propanoic acid [0296] The title compound (0.55 g) was prepared using the procedure described in Example A-1E, using Example A-32D (0.65 g, 1.8 mmol) in place of Example A-1D. EXAMPLE A-32F 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-32) [0297] The title compound (0.005 g) was prepared using the procedure described in Example A-1F, using Example A-32E (0.16 g, 0.45 mmol) in place of Example A-1E. Crude product was purified with preparative HPLC using X Bridge C18 (19 × 250) mm; 5 µM column and 1 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 15.73 min. EXAMPLE A-33 Ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4- (piperidin-1-yl)but-2-enoyl)glycinate
Figure imgf000141_0001
[0298] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 16 h. EXAMPLE A-33A ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4- (piperidin-1-yl)but-2-enoyl)glycinate (A-33) [0299] To a solution of 12B (0.2 g, 0.46 mmol) was added ethylbis(propan-2-yl)amine (0.4 mL, 2.29 mmol) in dimethylformamide (5.0 mL) was added HATU (0.26 g, 0.69 mmol) and under nitrogen atmosphere at 0 °C. Then (E)-4-oxo-4-(piperidin-1-yl)but-2-enoic acid (0.13 g, 0.69 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude product, which was subjected to preparative HPLC purification using X Bridge (19 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (18 mL/ min flow rate) afforded ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2- oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4-(piperidin-1-yl)but-2-enoyl)glycinate (0.029 g) at RT 17.06 min. EXAMPLE A-34 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycine
Figure imgf000142_0001
Figure imgf000143_0001
[0300] Reagents and conditions: (a) DMF, 0 °C-rt, 3 h, (b) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (c) TFA, DCM, 0 °C, 30 min. EXAMPLE A-34A tert-butyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)glycinate [0301] To a stirred solution of Example A-12A (1.0 g, 2.86 mmol) in DMF (10.0 mL), tert-butyl 2- bromoacetate (5.0 mL, 25.0 mmol) was added dropwise at 0 °C and the mixture was allowed to stir for 3 h at room temperature. The progress of the reaction was monitored by TLC and LCMS. The solvent was removed under vacuum to get the crude product, which was purified using silica gel flash column chromatography using 60% ethyl acetate in n-hexane afforded tert-butyl (2-(3-(4-amino-3- chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)glycinate (0.5 g). EXAMPLE A-34B tert-butyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- fluoroacetyl)glycinate [0302] The title compound (0.13 g) was prepared using the procedure described in Example A-13A, using Example A-34A (0.25 g, 0.54 mmol) in place of Example A-12B. EXAMPLE A-34C ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4- (piperidin-1-yl)but-2-enoyl)glycinate (A-34) [0303] To a stirred solution of Example A-34B (0.1 g, 0.19 mmol) in DCM (5 mL) at 0 °C TFA (0.14 mL, 1.91 mmol) was dropwise added over a period of 15 min. and the mixture was allowed to stir for 30 min at the same temperature. The progress of the reaction was monitored by TLC and LCMS. Upon reaction completion, reaction mixture was evaporated under reduced pressure to get the crude product, which was subjected to preparative HPLC purification using Inertsil C18 (19 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (15 mL/ min flow rate) to afford N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-fluoroacetyl)glycine (0.005 g) at RT 19.38 min. EXAMPLE A-35 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- chloroacetyl)glycinate
Figure imgf000144_0001
Figure imgf000144_0002
[0304] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 16 h. EXAMPLE A-35A Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- chloroacetyl)glycinate (A-35) [0305] To a solution of 12B (0.3 g, 0.69 mmol) in DMF (10 mL) was added ethylbis(propan-2-yl)amine (0.26 mL, 1.38 mmol) and HATU (0.39 g, 1.03 mmol) and under nitrogen atmosphere at 0 °C. Then 2- chloroacetic acid (0.19 g, 2.06 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to get the crude product, which was subjected to preparative HPLC purification using X Select (19 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (18 mL/ min flow rate) and afforded ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-chloroacetyl)glycinate (0.0082 g) at RT 16.81 min. EXAMPLE A-36 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine
Figure imgf000145_0001
[0306] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 12 h EXAMPLE A-36A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine (36) [0307] To a stirred solution of Example A-29 (0.0022 g, 0.036mmol) in DCE (2.0 mL) was added trimethyltin hydroxide (0.0033 g, 0.18 mmol) at rt. After overnight stirring at 80 °C, the reaction mixture was concentrated under vacuum to furnish the crude material, which was then purified by prep-HPLC using X Select C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) to afford the title compound (0.0027 g) at RT of 10.23 min.
EXAMPLE A-37 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine
Figure imgf000146_0001
[0308] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 12 h EXAMPLE A-37A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine (A-37) [0309] The title compound (0.0055 g) was prepared using the procedure described in Example A-36A, using Example A-30 (0.16 g, 0.45 mmol) in place of Example A-29. Crude was then purified by prep- HPLC using X Select C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) to afford the title compound (0.0055 g) at RT of 10.23 min.
EXAMPLE A-38 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,6- difluorophenoxy)acetyl)glycine
Figure imgf000147_0001
[0310] Reagents and conditions: (a) EDC.HCl, HOBt, DIPEA, CH2Cl2, DMF 0 °C-rt, 16 h. EXAMPLE A-38A ethyl (E)-N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(4-(benzylamino)-4-oxobut-2-enoyl)glycinate (A-38) [0311] To a stirred solution Example A-22A (0.1 g, 0.23 mmol) in dichloromethane (5 mL) and DMF (5 mL) at 0 °C DIPEA (0.20 mL, 1.16 mmol), EDC.HCl (0.13 g, 0.695 mmol), HOBt (0.05 g, 0.35 mmol) and (E)-4-(benzylamino)-4-oxobut-2-enoic acid (0.07 g, 0.35 mmol) were added and reaction mixture was stirred at rt for 16 h. Reaction mixture was quenched in cold water (15 mL) and extracted with dichloromethane (10 mL), washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum to afford crude product. It was then purified by prep-HPLC using X Select C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (18 mL/ min flow rate) to afford the title compound (0.01 g) at RT of 15.38 min. EXAMPLE A-39 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycine
Figure imgf000148_0001
and EXAMPLE A-40 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycine
Figure imgf000148_0002
Figure imgf000149_0001
[0312] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 4 h, (b) Chiral preparative HPLC separation. EXAMPLE A-39A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycine [0313] The title compound was prepared using the procedure described in Example A-37A, using Example A-25B (0.1 g, 0.16 mmol) in place of Example A-30. EXAMPLE A-39 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycine (A-39) and EXAMPLE A-40 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycine (A-40) [0314] Purification of the Example A-39A (0.025 g) by chiral prep-HPLC using CHIRALPACK IC (250 mm × 20 mm × 5 mic) column and n-Hexane: Ethanol (50:50) with 0.1% DEA as mobile phase (19 mL/ min flow rate) afforded two isomers: the title compound Example A-39 (0.0032 g) at RT 3.31 min and other compound Example A-40 (0.004 g) at RT 4.13 min. EXAMPLE A-41 (E)-N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6- yl)propanamido)-N-(4-(benzylamino)-4-oxobut-2-enoyl)glycine
Figure imgf000150_0001
Figure imgf000150_0002
[0315] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 12 h EXAMPLE A-41A (E)-N-(2-(2-(4-amino-3-chlorophenyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)propanamido)- N-(4-(benzylamino)-4-oxobut-2-enoyl)glycine (A-41) [0316] The title compound (0.0057 g) was prepared using the procedure described in Example A-36A, using Example A-38 (0.15 g, 0.24 mmol) in place of Example A-29. Crude was then purified by prep- HPLC using X Select C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (18 mL/ min flow rate) to afford the title compound (0.0055 g) at RT of 12.86 min.
EXAMPLE A-42 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000151_0001
and EXAMPLE A-43 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000151_0002
Figure imgf000152_0001
[0317] Reagents and conditions: (a) T3P, TEA, DCM, 0 °C-rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 6 h, (f) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h, (g) Chiral preparative HPLC separation. EXAMPLE A-42A 3-chloro-N-(5-fluoro-2-methoxypyridin-3-yl)-4-nitrobenzamide [0318] To a stirred solution of 3-chloro-4-nitrobenzoic acid (2.85 g, 14.1 mmol) in DCM (20 mL) at 0 °C was added triethylamine (5.91 mL, 42.4 mmol), T3P (6 mL, 18.4 mmol) and 5-fluoro-2- methoxypyridin-3-amine (2.01 g, 14.1 mmol). The reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (40 mL) and residue was extracted with DCM (20 mL × 2 times). The combined organic layer was washed with brine (15 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-20%). Pure fractions were collected and concentrated to afford 3-chloro-N-(5-fluoro-2-methoxypyridin-3-yl)-4-nitrobenzamide (3.5 g) as yellow solid. EXAMPLE A-42B 3-chloro-N-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-4-nitrobenzamide [0319] The title compound (3.1 g) was prepared using the procedure described in Example A-1B, using Example A-42A (3.5 g, 10.7 mmol) in place of Example A-1A. EXAMPLE A-42C methyl 2-(3-(3-chloro-4-nitrobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)propanoate [0320] The title compound (1.2 g) was prepared using the procedure described in Example A-1C, using Example A-42B (2.0 g, 6.2 mmol) in place of Example A-1B. EXAMPLE A-42D methyl 2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)propanoate [0321] The title compound (1.0 g) was prepared using the procedure described in Example A-1D, using Example A-42C (1.2 g, 3.0 mmol) in place of Example A-1C. EXAMPLE A-42E 2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)propanoic acid [0322] The title compound (0.9 g) was prepared using the procedure described in Example A-1E, using Example A-42D (1.0 g, 2.9 mmol) in place of Example A-1D. EXAMPLE A-42F 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide [0323] The title compound (0.05 g) was prepared using the procedure described in Example A-1F, using Example A-42E (0.075 g, 0.21 mmol) in place of Example A-1E. EXAMPLE A-42G 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-42) and 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-43) [0324] The crude product of Example A-42F was purified by preparative HPLC X Select CSH C18 (250 × 20) mm; 5 µM column, 5 mM Ammonium acetate in water: acetonitrile as mobile phase (19 mL/min flow rate) and afforded title compound Example A-42 (0.005 g) at RT 9.61 min and title compound Example A-43 (0.007 g) at RT 11.42 min. EXAMPLE A-44 (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycine
Figure imgf000154_0001
[0325] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 16 h, (b) TFA, DCM, 0 °C, 30 min. EXAMPLE A-44A tert-butyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycinate [0326] To a stirred solution of (E)-4-(benzylamino)-4-oxobut-2-enoic acid (0.2 g, 0.97 mmol) in DMF (15 mL) at 0 °C was added N,N-Diisopropylethylamine (0.3 mL, 1.94 mmol) and HATU (0.37 g, 0.97 mmol). After 15 min, Example A-34A (0.33 g, 0.647 mmol) was subsequently added to the reaction mixture. It was then stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (20 mL) and residue was extracted with ethyl acetate (20 mL × 2 times). The combined organic layer was washed with brine (10 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-30%). Pure fractions were collected and concentrated to afford 3-chloro-N-(2-methoxypyridin-3-yl)-4- nitrobenzamide (0.375 g) as orange solid. EXAMPLE A-44B (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-(benzylamino)-4- oxobut-2-enoyl)glycine (A-44) [0327] The title compound (0.16 g) was prepared using the procedure described in Example A-34C, using Example A-44A (0.25 g, 0.38 mmol) in place of Example A-34B. Crude product was purified with preparative HPLC using Sunfire C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 14.33 min. EXAMPLE A-45 Ethyl (2S,4R)-1-acryloyl-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)- yl)propanamido)pyrrolidine-2-carboxylate
Figure imgf000155_0001
Figure imgf000156_0001
[0328] Reagents and conditions: (a) PyBop, HOBt, DIPEA, MeCN, 0 °C-rt, 8 h, (b) HCl in dioxane, DCM, 0 °C, 2 h, (c) T3P, DIPEA, DCM, DMF, 0 °C-rt, 5 h, (d) Et3N, THF, H2O, 60 °C, 16 h EXAMPLE A-45A 1-(tert-butyl) 2-ethyl (2S,4R)-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)- yl)propanamido)pyrrolidine-1,2-dicarboxylate [0329] To a stirred solution of Example A-1E (1.3 g, 3.87 mmol) in MeCN (20 mL) at 0 °C was added PyBop (1.45 g, 3.87 mmol), HOBt (0.3 g, 1.94 mmol) and DIPEA (1.3 mL, 7.74 mmol). After 10 minutes 1-(tert-butyl) 2-ethyl (2S,4R)-4-aminopyrrolidine-1,2-dicarboxylate (1.3 g, 5.03 mmol) was added to the reaction mixture and it was stirred for 8 hours. Reaction progress was monitored with TLC and LCMS. After completion of the reaction, the reaction mixture was evaporated to dryness and diluted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL × 2 times) and brine (10 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-50%). Pure fractions were collected and concentrated to afford 3-chloro-N-(2-methoxypyridin-3-yl)-4- nitrobenzamide (1.8 g) as yellow solid. EXAMPLE A-45B ethyl (2S,4R)-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)pyrrolidine-2- carboxylate hydrochloride [0330] To a stirred solution of Example A-45A (1.5 g, 2.6 mmol) dissolved in dioxane (25 mL) was added 4 M HCl in dioxane (3 mL) at 0 ⁰C. The reaction mixture was stirred at 0 ⁰C for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under vacuum, washed with diethyl ether and dried under vacuum to afford 3-chloro-4- nitro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide (1 g) as brown solid, which was used in the next step without further purification. EXAMPLE A-45C ethyl (2S,4R)-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-1-(3- chloropropanoyl)pyrrolidine-2-carboxylate [0331] To a stirred solution of ethyl (2S,4R)-4-{2-[3-(4-amino-3-chlorobenzamido)-2-oxo-1,2- dihydropyridin-1-yl]propanamido}pyrrolidine-2-carboxylate hydrochloride (0.7 g, 1.37 mmol) and 3- chloropropanoic acid (0.45 g, 4.1 mmol) in DCM (10 mL) and DMF (5 mL) at 0 °C was added DIPEA (0.45 mL, 2.73 mmol) and T3P (1.5 mL, 4.1 mmol). The reaction mixture was stirred at rt for 5 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (40 mL) and residue was extracted with DCM (20 mL × 2 times). The combined organic layer was washed with brine (15 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-40%). Pure fractions were collected and concentrated to afford ethyl (2S,4R)-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-1-(3- chloropropanoyl)pyrrolidine-2-carboxylate (0.2 g) as yellow solid. EXAMPLE A-45D ethyl (2S,4R)-1-acryloyl-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)- yl)propanamido)pyrrolidine-2-carboxylate (A-45) [0332] To a stirred solution of Example A-45C (0.13 g, 0.23 mmol) in mixture of water (3.5 mL) and tetrahydrofuran (6.5 mL) was added triethylamine (0.1 mL, 0.7 mmol). Reaction mixture was stirred at 60 °C for 16 hours. The progress of the reaction was monitored with TLC and LCMS. Upon completion, reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL × 3 times). The organic layer was washed with brine (10 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified with preparative HPLC using Zorbax Eclipse C18 (21 × 150) mm; 5 µM column and 5% ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 9.65 min. to afford the title compound (0.013g) at RT of 9.65 min. EXAMPLE A-46 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-4- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000158_0001
and EXAMPLE A-47 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-4- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000158_0002
Figure imgf000159_0001
[0333] Reagents and conditions: (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 16 h, (g) Chiral preparative HPLC separation. EXAMPLE A-46A 3-chloro-N-(2-methoxy-4-methylpyridin-3-yl)-4-nitrobenzamide [0334] The title compound (6.0 g) was prepared using the procedure described in Example A-1A, using 2-methoxy-4-methylpyridin-3-amine (4.12 g, 14.9 mmol) in place of 2-methoxypyridin-3-amine. EXAMPLE A-46B 3-chloro-N-(4-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-nitrobenzamide [0335] The title compound (5.2 g) was prepared using the procedure described in Example A-1B, using Example A-46A (6.0 g, 18.6 mmol) in place of Example A-1A. EXAMPLE A-46C methyl 2-(3-(3-chloro-4-nitrobenzamido)-4-methyl-2-oxopyridin-1(2H)-yl)propanoate [0336] The title compound (2.0 g) was prepared using the procedure described in Example A-1C, using Example A-46B (3.0 g, 9.8 mmol) in place of Example A-1B. EXAMPLE A-46D methyl 2-(3-(4-amino-3-chlorobenzamido)-4-methyl-2-oxopyridin-1(2H)-yl)propanoate [0337] The title compound (1.7 g) was prepared using the procedure described in Example A-1D, using Example A-46C (2.0 g, 5.0 mmol) in place of Example A-1C. EXAMPLE A-46E 2-(3-(4-amino-3-chlorobenzamido)-4-methyl-2-oxopyridin-1(2H)-yl)propanoic acid [0338] The title compound (1.0 g) was prepared using the procedure described in Example A-1E, using Example A-46D (1.7 g, 4.68 mmol) in place of Example A-1D. EXAMPLE A-46F 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-4- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide [0339] The title compound (0.08 g) was prepared using the procedure described in Example A-1F, using Example A-46E (0.3 g, 0.86 mmol) in place of Example A-1E. EXAMPLE A-46G 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-4- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-46) and 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-4- methyl-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-47) [0340] The product of Example A-42F was purified by preparative chiral HPLC using Chiralpack IA (250 × 30) mm; 5 µM column and MTBE: EtOH with 0.1% DEA (70:30) as mobile phase (40 mL/ min flow rate) and afforded the Example A-46 (0.008 g) at RT 8.39 min and Example A-47 (0.015 g) at RT 10.48 min. EXAMPLE A-48 Ethyl (2S,4S)-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-1-((E)-4- (benzylamino)-4-oxobut-2-enoyl)pyrrolidine-2-carboxylate
Figure imgf000161_0001
[0341] Reagents and conditions: (a) T3P, DIPEA, DCM, DMF, 0 °C-rt, 5 h. EXAMPLE A-48A Ethyl (2S,4S)-4-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-1-((E)-4- (benzylamino)-4-oxobut-2-enoyl)pyrrolidine-2-carboxylate (A-48) [0342] The title compound was prepared using the procedure described in Example A-45C, using (E)-4- (benzylamino)-4-oxobut-2-enoic acid (0.4 g, 1.95 mmol) in place of 3-chloropropanoic acid. Crude was then purified by prep-HPLC using Inertsil ODS C18 (20 × 250) mm; 5 µM column and 5% ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) to afford the title compound (0.085 g) at RT of 16.83 min. EXAMPLE A-49 4-amino-3-chloro-N-(5-chloro-1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1- oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000162_0001
Figure imgf000162_0002
[0343] Reagents and conditions: (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) Pd(PPh3)4, DMBA, CH2Cl2, 15 min, (ii) EDCl, HOBt, DIPEA, DMF, 4 h. EXAMPLE A-49A 3-chloro-N-(5-chloro-2-methoxypyridin-3-yl)-4-nitrobenzamide [0344] The title compound (4.0 g) was prepared using the procedure described in Example A-1A, using 5-chloro-2-methoxypyridin-3-amine (1.97 g, 12.4 mmol) in place of 2-methoxypyridin-3-amine. EXAMPLE A-49B 3-chloro-N-(5-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-nitrobenzamide [0345] The title compound (3.7 g) was prepared using the procedure described in Example A-1B, using Example A-49A (4.0 g, 11.7 mmol) in place of Example A-1A. EXAMPLE A-49C methyl 2-(5-chloro-3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)propanoate [0346] The title compound (0.5 g) was prepared using the procedure described in Example A-1C, using Example A-49B (1.0 g, 3.05 mmol) in place of Example A-1B. EXAMPLE A-49D methyl 2-(3-(4-amino-3-chlorobenzamido)-5-chloro-2-oxopyridin-1(2H)-yl)propanoate [0347] The title compound (0.3 g) was prepared using the procedure described in Example A-1D, using Example A-49C (0.4 g, 0.96 mmol) in place of Example A-1C. EXAMPLE A-49E 2-(3-(4-amino-3-chlorobenzamido)-5-chloro-2-oxopyridin-1(2H)-yl)propanoic acid [0348] The title compound (0.2 g) was prepared using the procedure described in Example A-1E, using Example A-49D (0.3 g, 0.78 mmol) in place of Example A-1D. EXAMPLE A-49F 4-amino-3-chloro-N-(5-chloro-1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2- yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-49) [0349] The title compound (0.016 g) was prepared using the procedure described in Example A-1F, using Example A-49E (0.13 g, 0.35 mmol) in place of Example A-1E. Crude product was purified with preparative HPLC using X-Select C18 (19 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 16.82 min.
EXAMPLE A-50 (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4- (piperidin-1-yl)but-2-enoyl)glycine
Figure imgf000164_0001
[0350] Reagents and conditions: (a) Chiral preparative HPLC separation, (b) Me3SnOH, DCE, 80 °C, 12 h. EXAMPLE A-50A ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4- (piperidin-1-yl)but-2-enoyl)glycinate (A-50A) and EXAMPLE A-50B ethyl (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4- (piperidin-1-yl)but-2-enoyl)glycinate (A-50B) [0351] The stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration). Purification of the Example A-33A by chiral prep-HPLC using CHIRALPACK IA (250 mm × 20 mm × 5 µM) column and EtOH as mobile phase (10 mL/ min flow rate) and afforded the Example A-50A (0.04 g) at RT 14.83 min and Example A-50B (0.034 g) at RT 21.79 min. EXAMPLE A-50C (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4-(piperidin- 1-yl)but-2-enoyl)glycine (A-50) [0352] The title compound (0.004 g) was prepared using the procedure described in Example A-36A, using Example A-50A (0.02 g, 0.033 mmol) in place of Example A-29. EXAMPLE A-51 (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4- (piperidin-1-yl)but-2-enoyl)glycine
Figure imgf000165_0001
Figure imgf000165_0002
[0353] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 12 h. EXAMPLE A-51A (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4-oxo-4-(piperidin- 1-yl)but-2-enoyl)glycine (A-51) [0354] The title compound (0.016 g) was prepared using the procedure described in Example A-36A, using Example A-50B (0.03 g, 0.04 mmol) in place of Example A-29. EXAMPLE A-52 (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycine
Figure imgf000166_0001
and EXAMPLE A-53 (E)-N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(4- (benzylamino)-4-oxobut-2-enoyl)glycine
Figure imgf000166_0002
[0355] The stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration). Purification of the Example A-44B by chiral prep-HPLC using CHIRALPACK IC (250 mm × 20 mm × 5 µM) column and n-Hexane: EtOH (70:30) as mobile phase (20 mL/ min flow rate) and afforded the Example A-52 (0.018 g) at RT 8.39 min and Example A-53 (0.0135 g) at RT 11.08 min.
EXAMPLE A-54 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000167_0001
and EXAMPLE A-55 4-amino-3-chloro-N-(1-(1-(((3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000167_0002
[0356] The stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration). Purification of the Example A-43 by chiral prep-HPLC using CHIRALPACK IA (250 mm × 30 mm × 5 µM) column and n-Hexane: IPA (70:30) as mobile phase (40 mL/ min flow rate) and afforded the Example A-54 (0.025 g) at RT 7.249 min and Example A-55 (0.033 g) at RT 10.388 min. EXAMPLE A-56 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-2-methyl-1- oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000168_0001
Figure imgf000168_0002
[0357] Reagents and conditions: (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 16 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (e) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 4 h. EXAMPLE A-56A 4-amino-3-chloro-N-(2-methoxypyridin-3-yl)benzamide [0358] To a stirred solution of 4-amino-3-chlorobenzoic acid (20.0 g, 117.0 mmol) in DMF (200 mL) was added N,N-Diisopropylethylamine (60.9 mL, 350.0 mmol), HATU (67.0 g, 175.0 mmol) and 2- methoxypyridin-3-amine (17.4 g, 140.0 mmol) sequentially over a period of 10-15 min. The reaction mixture was heated at 60 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (300 mL) and residue was extracted with ethyl acetate (150 mL × 2 times). The combined organic layer was washed with cold water (100 mL × 3 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-40%). Pure fractions were collected and concentrated to afford 4-amino-3-chloro-N-(2-methoxypyridin-3- yl)benzamide (25 g) as yellow solid. EXAMPLE A-56B 4-amino-3-chloro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide [0359] The title compound (20.0 g) was prepared using the procedure described in Example A-1B, using Example A-56A (25.0 g, 90.0 mmol) in place of Example A-1A. EXAMPLE A-56C methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-2-methylpropanoate [0360] The title compound (0.5 g) was prepared using the procedure described in Example A-1C, using Example A-56B (1.0 g, 3.79 mmol) in place of Example A-1B. EXAMPLE A-56D 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-2-methylpropanoic acid [0361] The title compound (0.4 g) was prepared using the procedure described in Example A-1E, using Example A-56C (0.5 g, 1.45 mmol) in place of Example A-1D. EXAMPLE A-56E 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-2-methyl-1-oxopropan- 2-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-56) [0362] To a solution of benzyl ((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamate (0.25 g, 0.9 mmol) in ethyl acetate (10 mL) was added 20% Pd-C (0.025 g) was charged with hydrogen gas at 30 psi pressure in a parr shaker vessel. Reaction was continued for 16 hours. Upon completion, reaction mixture was filtered through a celite pad and the filtrate was evaporated to near dryness. Separately to a solution of Example A-56D (0.1 g, 0.28 mmol) in DMF (5 mL) was added EDC (0.08 g, 0.43 mmol), HOBt (0.046 g, 0.28 mmol). The solution was stirred at 0 °C for 10 minutes and the solution from the above reaction was added dropwise to it. The reaction mixture was stirred at rt for 4 h. The reaction progress was monitored by TLC and LCMS. The solvent of reaction mixture was dried under vacuum and the residue was diluted with water (5 mL) then extracted with ethyl acetate (5 × 10 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product. The compound was then purified by preparative HPLC X-Select CSH C18 (250 × 20) mm; 5 µM column, 5 mM Ammonium acetate in water: acetonitrile as mobile phase (19 mL/min flow rate) and afforded the title compound (0.03 g) at Retention Time (RT) of 13.27 min. EXAMPLE A-57 4-amino-3-chloro-N-(1-(2-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-2-oxoethyl)-2-oxo- 1,2-dihydropyridin-3-yl)benzamide
Figure imgf000170_0001
Figure imgf000170_0002
[0363] Reagents and conditions: (a) Cs2CO3, DMF, 60 ⁰C, 3 h, (b) LiOH, THF/H2O (3:1), rt, 16 h, (c) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 4 h. EXAMPLE A-57A methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)acetate [0364] The title compound (0.55 g) was prepared using the procedure described in Example A-1C, using Example A-56B (1.0 g, 3.79 mmol) in place of Example A-1B. EXAMPLE A-57B 2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)acetic acid [0365] The title compound (0.5 g) was prepared using the procedure described in Example A-1E, using Example A-57B (0.55 g, 1.64 mmol) in place of Example A-1D. EXAMPLE A-57C 4-amino-3-chloro-N-(1-(2-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-2-oxoethyl)-2-oxo-1,2- dihydropyridin-3-yl)benzamide (A-57) [0366] The title compound (0.025 g) was prepared using the procedure described in Example A-56E, using Example A-57B (0.1 g, 0.31 mmol) in place of Example A-56D. Crude product was purified with preparative HPLC using X-Select C18 (19 × 250) mm; 5 µM column and 5 mM ammonium acetate in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 15.25 min. EXAMPLE A-58 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000171_0001
and EXAMPLE A-59 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000171_0002
[0367] The stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration). Purification of the Example A-42 by chiral prep-HPLC using CHIRALPACK IA (250 mm × 30 mm × 5 µM) column and MTBE: ACN (80:20) as mobile phase (18 mL/ min flow rate) and afforded the Example A-58 (0.025 g) at RT 8.106 min and Example A-59 (0.052g) at RT 11.138 min. EXAMPLE A-60 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycine
Figure imgf000172_0001
Figure imgf000172_0002
[0368] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 12 h. EXAMPLE A-60A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycine (A-60) [0369] The title compound (0.012 g) was prepared using the procedure described in Example A-36A, using Example A-21 (0.05 g, 0.043 mmol) in place of Example A-29. Crude product was purified with preparative HPLC using X-Select C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 8.15 min.
EXAMPLE A-61 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycine
Figure imgf000173_0001
Figure imgf000173_0002
[0370] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 12 h. EXAMPLE A-61A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-N-(2- (perfluorophenoxy)acetyl)glycine (A-61) [0371] The title compound (0.01 g) was prepared using the procedure described in Example A-36A, using Example A-20 (0.07 g, 0.06 mmol) in place of Example A-29. Crude product was purified with preparative HPLC using Atlantis D C18 (19 × 100) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 7.33 min.
EXAMPLE A-62 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000174_0001
and EXAMPLE A-63 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000174_0002
[0372] The stereocenter denoted with a “*” refers to a single unknown isomer (or unassigned configuration). Purification of the Example A-31C by chiral prep-HPLC using CHIRALPACK IG (250 mm × 20 mm × 5 µM) column and n-Hexane: IPA (50:50) as mobile phase (20 mL/ min flow rate) and afforded the Example A-62 (0.36 g) at RT 3.88 min and Example A-63 (0.35 g) at RT 7.88 min.
EXAMPLE A-64 -(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-l(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoic acid
Figure imgf000175_0001
and EXAMPLE A-65 -(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-l(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoic acid
Figure imgf000175_0002
Figure imgf000176_0001
[0373] Reagents and conditions: (a) KF, DMF, rt, 16 h, (b) NaBH4, MeOH, THF, 0 ⁰C-rt, 3 h, (c) Pd-C, EtOAc, rt, 3 h, (d) EDC, HOBt, DCM, 0 °C-rt, 14 h, (e) IBX, EtOAc, 80 °C, 4 h, (f) TFA, DCM, 0 °C-rt, 2 h, (g) Chiral preparative HPLC separation. EXAMPLE A-64A tert-butyl (S)-3-(((benzyloxy)carbonyl)amino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoate [0374] To a stirred solution of tert-butyl (3S)-3-{[(benzyloxy)carbonyl]amino}-5-bromo-4- oxopentanoate (1.0 g, 2.74 mmol) and 2,3,5,6-tetrafluorophenol (0.46 g, 2.74 mmol) in DMF (25 mL) at room temperature under nitrogen was added potassium fluoride (0.46 g, 7.97 mmol). After stirring at room temperature for 16 hrs, the mixture was diluted with EtOAc (30 mL), washed successively with cold water (50 mL × 2 times) and saturated NaHCO3 (30 mL × 2 times). Organic layer was separated, dried over sodium sulphate and concentrated to afford the crude product. It was then purified by Combi flash chromatography using ethyl acetate/ Hexane (0-20%). Pure fractions were collected and concentrated to afford tert-butyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoate (0.92 g) as colorless viscous liquid. EXAMPLE A-64B tert-butyl (3S)-3-(((benzyloxy)carbonyl)amino)-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate [0375] To a stirred solution of Example A-64A (0.92 g, 1.89 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) at 0 °C was added sodium borohydride (0.36 g, 9.45 mmol). Reaction mixture was allowed to stir 3 h at rt while monitoring the progress with TLC and LCMS. After reaction completion, solvent was evaporated to dryness, diluted with ethyl acetate (20 mL) and washed with water (15 mL × 2 times). Organic layer was separated, dried over sodium sulphate and concentrated to afford tert-butyl (3S)-3-{[(benzyloxy)carbonyl]amino}-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate (0.9 g) as the crude material, which was taken for the next step without further purification. EXAMPLE A-64C tert-butyl 3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate [0376] To a stirred solution of Example A-64B (0.9 g, 1.84 mmol) in ethyl acetate (30 mL) was added Pd-C (10%, 0.36 g). The suspension was degassed under vacuum and flushed with hydrogen gas for couple of time. Finally, the mixture was stirred under hydrogen gas (15 psi) pressure at rt for 3 h. Upon completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under vacuum. Crude was co-evaporated with chloroform (10 mL × 2 times) to afford tert-butyl (3S)-3- amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate (0.54 g) as yellow oil which was taken to the next step without further purification. EXAMPLE A-64D tert-butyl 3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-hydroxy-5- (2,3,5,6-tetrafluorophenoxy)pentanoate [0377] To a solution of Example A-1E (0.5 g, 1.49 mmol) in DCM (10 mL) was added EDC (0.35 g, 2.24 mmol) and HOBt (0.34 g, 2.24 mmol). The solution was stirred at 0 °C for 10 minutes and then Example A-64C (0.53 g, 1.49 mmol) was added to it. The reaction mixture was stirred at rt for 14 h. The reaction progress was monitored by TLC and LCMS. The solvent of reaction mixture was dried under vacuum and the residue was diluted with water (20 mL) then extracted with ethyl acetate (3 times × 20 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 0-50% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford tert-butyl (3S)-3-(2-(3-(4-amino-3-chlorobenzamido)- 2-oxopyridin-1(2H)-yl)propanamido)-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate (0.4 g) as white solid. EXAMPLE A-64E tert-butyl 3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoate [0378] To a stirred solution of Example A-64D (0.4 g, 0.59 mmol) in ethyl acetate (20 mL) was added IBX (0.67 g, 2.38 mmol). The reaction mixture was stirred at 80 °C for 4 h while monitoring the progress with TLC and LCMS. Upon completion, reaction mixture was washed with water (2 times × 20 mL). Organic layer was separated, dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 20-50% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford tert-butyl (3S)-3-(2-(3-(4-amino-3-chlorobenzamido)- 2-oxopyridin-1(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoate (0.24 g) as white solid. EXAMPLE A-64F 3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoic acid [0379] The title compound (0.09 g) was prepared using the procedure described in Example A-34C, using Example A-64E (0.24 g, 0.36 mmol) in place of Example A-34B. EXAMPLE A-64G 3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoic acid (A-64) and 3-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)propanamido)-4-oxo-5-(2,3,5,6- tetrafluorophenoxy)pentanoic acid (A-65) [0380] The product of Example A-64F was purified by preparative chiral HPLC using Chiralpack IG (250 × 30) mm; 5 µM column and n-hexane: IPA (50:50) as mobile phase (19 mL/ min flow rate) and afforded the Example A-64 (0.022g) at RT 6.126 min and Example A-65 (0.019 g) at RT 9.124 min.
EXAMPLE A-66 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycine
Figure imgf000179_0001
Figure imgf000179_0002
[0381] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 4 h. EXAMPLE A-66A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycine (A-66) [0382] The title compound (0.006 g) was prepared using the procedure described in Example A-36A, using Example A-63 (0.03 g, 0.057 mmol) in place of Example A-29. Crude product was purified with preparative HPLC using Sunfire C18 (19 × 250) mm; 5 µM column and 1% formic acid in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 10.2 min.
EXAMPLE A-67 N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycine
Figure imgf000180_0001
Figure imgf000180_0002
[0383] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 4 h. EXAMPLE A-67A N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycine (A-67) [0384] The title compound (0.012 g) was prepared using the procedure described in Example A-36A, using Example A-62 (0.04 g, 0.076 mmol) in place of Example A-29. Crude product was purified with preparative HPLC using ODS C18 (20 × 250) mm; 5 µM column and 1% formic acid in water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 11.46 min.
EXAMPLE A-68 ethyl N-(2-(3-(4-acetamido-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N- (2-fluoroacetyl)glycinate
Figure imgf000181_0001
[0385] Reagents and conditions: (a) Toluene, 0 °C-rt, 12 h. EXAMPLE A-68A ethyl N-(2-(3-(4-acetamido-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-68) [0386] To a stirred solution of 63 (0.08 g, 0.15 mmol) in toluene at 0 °C was slowly added acyl chloride (0.05 mL, 0.75 mmol) and the reaction was continued for overnight. Progress of the reaction was monitored with TLC and LCMS. Upon completion, the solvent of reaction mixture was dried under vacuum and the residue was diluted with water (10 mL) then extracted with ethyl acetate (2 × 10 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product. The compound was then purified by Combi flash chromatography using ethyl acetate/ Hexane (0-50%). Pure fractions were collected and concentrated to afford the title compound as white solid (0.035 g). EXAMPLE A-69 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2- oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000182_0001
[0387] Reagents and conditions: (a) K2CO3, DMF, rt, 48 h, (b) LiOH, THF/H2O (3:1), rt, 16 h, (c) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 4 h. EXAMPLE A-69A methyl 1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate [0388] To a stirred solution of Example A-56B (2.0 g, 7.58 mmol) dissolved in DMF (30 mL) was added potassium carbonate (5.24 g, 37.9 mmol) and methyl 2,4-dibromobutanoate (2.74 mL, 11.4 mmol) at rt. The reaction mixture was stirred for 48 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (50 mL) and resulting residue was extracted with ethyl acetate (50 mL × 3 times). The combined organic layer was washed with brine (50 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by flash column chromatography using 30-35% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford methyl 1-(3-(4-amino-3- chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate (0.4 g). EXAMPLE A-69B 1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid [0389] The title compound (0.25 g) was prepared using the procedure described in Example A-1E, using Example A-69A (0.4 g, 1.11 mmol) in place of Example A-1D. EXAMPLE A-69C 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo- 1,2-dihydropyridin-3-yl)benzamide (A-69) [0390] The title compound (0.075 g) was prepared using the procedure described in Example A-56E, using Example A-69B (0.2 g, 0.58 mmol) in place of Example A-56D. Crude product was purified with preparative HPLC using X-Select CSH C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 12.947 min. EXAMPLE A-70 N-(2-(3-(4-acetamido-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycine
Figure imgf000183_0001
Figure imgf000183_0002
[0391] Reagents and conditions: (a) Me3SnOH, DCE, 80 °C, 4 h. EXAMPLE A-70A N-(2-(3-(4-acetamido-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycine (A-70) [0392] The title compound (0.020 g) was prepared using the procedure described in Example A-36A, using Example A-68 (0.025 g, 0.044 mmol) in place of Example A-29. Crude product was purified with preparative HPLC using X-Bridge C18 (19 × 250) mm; 5 µM column and 1% formic acid in water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 12.89 min. EXAMPLE A-71 Ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000184_0001
and EXAMPLE A-72 Ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000184_0002
Figure imgf000185_0001
[0393] Reagents and conditions: (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (e) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 16 h, (f) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (g) Chiral preparative HPLC separation. EXAMPLE A-71A N-(2-methoxy-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide [0394] The title compound (3.0 g) was prepared using the procedure described in Example A-56A, using 1H-indole-2-carboxylic acid (3.0 g, 18.6 mmol) in place of 4-amino-3-chlorobenzoic acid. EXAMPLE A-71B N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide [0395] The title compound (2.4 g) was prepared using the procedure described in Example A-1B, using Example A-71A (3.0 g, 10.2 mmol) in place of Example A-1A. EXAMPLE A-71C methyl 2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoate [0396] The title compound (0.9 g) was prepared using the procedure described in Example A-9C, using Example A-71B (2.0 g, 7.9 mmol) in place of Example A-1B. EXAMPLE A-71D 2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoic acid [0397] The title compound (0.25 g) was prepared using the procedure described in Example A-1E, using Example A-71C (0.3 g, 0.817 mmol) in place of Example A-1D. EXAMPLE A-71E ethyl (2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate [0398] To a solution of Example A-71D (0.25 g, 0.71 mmol) in DMF (5 mL) was added DIPEA (0.44 mL, 2.2 mmol), EDCl (0.24 g, 1.3 mmol), HOBt (0.2 g, 1.3 mmol). The solution was stirred at 0 °C for 10 minutes and then was added ethyl 2-hydrazinylacetate hydrochloride (0.2 mg, 1.27 mmol). The reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. The solvent of reaction mixture was dried under vacuum and the residue was diluted with water (15 mL) then extracted with ethyl acetate (3 × 10 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product. The compound was then purified by flash column chromatography using 40-60% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford ethyl (2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate (0.2 g). EXAMPLE A-71F ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate [0399] The title compound (0.09 g) was prepared using the procedure described in Example A-13A, using Example A-71E (0.2 g, 0.47 mmol) in place of Example A-12B. EXAMPLE A-71G ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-71) and ethyl N-(2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-72) [0400] The product of Example A-71F was purified by preparative chiral HPLC using Chiralpack IA (250 × 30) mm; 5 µM column and hexane: IPA (50:50) as mobile phase (40 mL/ min flow rate) and afforded the Example A-71 (0.015 g) at RT 11.282 min and Example A-72 (0.014 g) at RT 19.82 min. EXAMPLE A-73 (S)-3-((S)-2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)propanamido)-4- oxobutanoic acid
Figure imgf000187_0001
[0401] Reagents and conditions: (a) 5% aq. HCl, MeCN, rt, 16 h. EXAMPLE A-73A (3S)-3-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)propanamido)-4-oxobutanoic acid (A-73) [0402] The title compound (0.006 g) was prepared using the procedure described in Example A-4A, using Example A-58 (0.025 g, 0.05 mmol) in place of Example A-2. Crude product was purified with preparative HPLC using Sunfire C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 13.59 min. EXAMPLE A-74 N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-1H-indole-2-carboxamide
Figure imgf000188_0001
and EXAMPLE A-75 N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-1H-indole-2-carboxamide
Figure imgf000188_0002
Figure imgf000189_0001
[0403] Reagents and conditions: (a) K2CO3, DMF, 60 ⁰C, 16 h, (b) LiOH, THF/H2O (3:1), rt, 16 h, (c) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 4 h, (d) Chiral preparative HPLC separation. EXAMPLE A-74A methyl 2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)propanoate [0404] The title compound (0.85 g) was prepared using the procedure described in Example A-69A, using Example A-71B (1.0 g, 3.95 mmol) in place of Example A-56B and methyl 2-bromopropanoate (0.53 mL, 4.74 mmol). EXAMPLE A-74B 2-(3-(1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)propanoic acid [0405] The title compound (0.65 g) was prepared using the procedure described in Example A-1E, using Example A-74A (0.85 g, 2.5 mmol) in place of Example A-1D. EXAMPLE A-74C N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-1H-indole-2-carboxamide [0406] The title compound (0.148 g) was prepared using the procedure described in Example A-56E, using Example A-74B (0.41 g, 1.26 mmol) in place of Example A-56D. EXAMPLE A-74D N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-1H-indole-2-carboxamide (A-74) and N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-1H-indole-2-carboxamide (A-75) [0407] The product of Example A-74C was purified by preparative chiral HPLC using Chiralpack IG (250 × 30) mm; 5 µM column and MTBE: IPA (80:20) as mobile phase (40 mL/ min flow rate) and afforded the Example A-74 (0.05 g) at RT 8.182 min and Example A-75 (0.06 g) at RT 11.374 min. EXAMPLE A-76 Ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)- N-(2-fluoroacetyl)glycinate
Figure imgf000190_0001
and EXAMPLE A-77 Ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)- N-(2-fluoroacetyl)glycinate
Figure imgf000190_0002
Figure imgf000191_0001
[0408] Reagents and conditions: (a) HATU, DIPEA, DMF, rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) K2CO3, DMF, 60 ⁰C, 3 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (e) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 16 h, (f) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (g) Chiral preparative HPLC separation. EXAMPLE A-76A 7-chloro-N-(2-methoxypyridin-3-yl)-1H-indole-5-carboxamide [0409] The title compound (1.8 g) was prepared using the procedure described in Example A-56A, using 7-chloro-1H-indole-5-carboxylic acid (3.0 g, 15.3 mmol) in place of 4-amino-3-chlorobenzoic acid. EXAMPLE A-76B 7-chloro-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-5-carboxamide [0410] The title compound (1.8 g) was prepared using the procedure described in Example A-1B, using Example A-76A (2.0 g, 6.63 mmol) in place of Example A-1A. EXAMPLE A-76C methyl 2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoate [0411] The title compound (1.1 g) was prepared using the procedure described in Example A-69A, using Example A-76B (1.8 g, 6.2 mmol) in place of Example A-1B and methyl 2-bromo-3-methylbutanoate (1.11 mL, 7.65 mmol) EXAMPLE A-76D 2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanoic acid [0412] The title compound (0.8 g) was prepared using the procedure described in Example A-1E, using Example A-76C (1.0 g, 2.49 mmol) in place of Example A-1D. EXAMPLE A-76E ethyl (2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate [0413] The title compound (0.3 g) was prepared using the procedure described in Example A-71E, using Example A-76D (0.5 g, 1.29 mmol) in place of Example A-71D. EXAMPLE A-76F ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate [0414] The title compound (0.12 g) was prepared using the procedure described in Example A-13A, using Example A-76E (0.3 g, 0.61 mmol) in place of Example A-12B. EXAMPLE A-76G ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-76) and ethyl N-(2-(3-(7-chloro-1H-indole-5-carboxamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-77) [0415] The product of Example A-76F was purified by preparative chiral HPLC using Chiralpack IC (250 × 30) mm; 5 µM column and n-hexane: IPA (50:50) as mobile phase (40 mL/ min flow rate) and afforded the Example A-76 (0.034 g) at RT 12.662 min and Example A-77 (0.040 g) at RT 18.314 min. EXAMPLE A-78 Butyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000193_0001
and EXAMPLE A-79 Butyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate
Figure imgf000193_0002
[0416] Reagents and conditions: (a) DMF, rt, 3 h, (b) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (c) Chiral preparative HPLC separation. EXAMPLE A-78A butyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate [0417] To a stirred solution of Example A-31A (1.0 g, 2.65 mmol) in DMF (10 mL) was added butyl 2- bromoacetate (0.77 g, 3.97 mmol). Reaction was continued for 3 hours while monitoring the progress with TLC and LCMS. Upon completion reaction mixture was diluted with cold water (30 mL) then extracted with ethyl acetate (3 × 10 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product. The compound was then purified by flash column chromatography using 10-50% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford butyl (2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)glycinate (0.4 g). EXAMPLE A-78B butyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate [0418] The title compound (0.07 g) was prepared using the procedure described in Example A-13A, using Example A-78A (0.4 g, 0.81 mmol) in place of Example A-12B. EXAMPLE A-78C butyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-78) and butyl N-(2-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-79) [0419] The product of Example A-78B was purified by preparative chiral HPLC using Chiralpack IG (250 × 30) mm; 5 µM column and n-hexane: IPA (50:50) as mobile phase (19 mL/ min flow rate) and afforded the Example A-78 (0.005 g) at RT 8.089 min and Example A-79 (0.022 g) at RT 17.606 min.
EXAMPLE A-80 (S)-3-(1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxamido)-4- oxobutanoic acid
Figure imgf000195_0001
[0420] Reagents and conditions: (a) 5% aq. HCl, MeCN, rt, 16 h. EXAMPLE A-80A (S)-3-(1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxamido)-4- oxobutanoic acid (A-80) [0421] The title compound (0.004 g) was prepared using the procedure described in Example A-4A, using Example A-69C (0.020 g, 0.042 mmol) in place of Example A-2. Crude product was purified with preparative HPLC using X-Bridge C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 15.94 min. EXAMPLE A-81 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3- methylbutanamido)-N-(2-fluoroacetyl)glycinate
Figure imgf000196_0001
and EXAMPLE A-82 Ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3- methylbutanamido)-N-(2-fluoroacetyl)glycinate
Figure imgf000196_0002
Figure imgf000197_0001
[0422] Reagents and conditions: (a) K2CO3, DMF, 60 ⁰C, 3 h, (b) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (c) LiOH, THF/H2O (3:1), rt, 16 h, (d) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 16 h, (e) HATU, DIPEA, DMF, 0 °C-rt, 3 h, (f) Chiral preparative HPLC separation. EXAMPLE A-81A methyl 2-(3-(3-chloro-4-nitrobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanoate [0423] The title compound (2.5 g) was prepared using the procedure described in Example A-69A, using Example A-42B (5.0 g, 16.0 mmol) in place of Example A-1B and methyl 2-bromo-3-methylbutanoate (3.13 mL, 16.0 mmol) EXAMPLE A-81B methyl 2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanoate [0424] The title compound (2.2 g) was prepared using the procedure described in Example A-1D, using Example A-81A (2.5 g, 5.87 mmol) in place of Example A-1C. EXAMPLE A-81C 2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanoic acid [0425] The title compound (2.1 g) was prepared using the procedure described in Example A-1E, using Example A-81B (2.2 g, 5.56 mmol) in place of Example A-1D. EXAMPLE A-81D ethyl (2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3- methylbutanamido)glycinate [0426] The title compound (1.2 g) was prepared using the procedure described in Example A-71E, using Example A-81C (2.0 g, 5.24 mmol) in place of Example A-71D. EXAMPLE A-81E ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate [0427] The title compound (0.648 g) was prepared using the procedure described in Example A-13A, using Example A-81D (1.1 g, 2.28 mmol) in place of Example A-12B.
EXAMPLE A-81F ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-81) and ethyl N-(2-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanamido)-N-(2- fluoroacetyl)glycinate (A-82) [0428] The product of Example A-81E was purified by preparative chiral HPLC using Chiralpack IG (250 × 30) mm; 5 µM column and n-hexane: IPA (50:50) as mobile phase (40 mL/ min flow rate) and afforded the Example A-81 (0.23g) at RT 7.059 min and Example A-82 (0.28 g) at RT 10.593 min. EXAMPLE A-83 N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-5-fluoro-1H-indole-2-carboxamide
Figure imgf000199_0001
and EXAMPLE A-84 N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-5-fluoro-1H-indole-2-carboxamide
Figure imgf000199_0002
Figure imgf000200_0001
[0429] Reagents and conditions: (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (e) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) DCC, HOBt, DCM, 4 h, (f) Chiral preparative HPLC separation. EXAMPLE A-83A 5-fluoro-N-(2-methoxy-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide [0430] The title compound (3.0 g) was prepared using the procedure described in Example A-56A, using 5-fluoro-1H-indole-2-carboxylic acid (2.5 g, 14.0 mmol) in place of 4-amino-3-chlorobenzoic acid. EXAMPLE A-83B 5-fluoro-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide [0431] The title compound (2.7 g) was prepared using the procedure described in Example A-1B, using Example A-83A (2.9 g, 10.2 mmol) in place of Example A-1A. EXAMPLE A-83C methyl 2-(3-(5-fluoro-1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)propanoate [0432] The title compound (0.41 g) was prepared using the procedure described in Example A-1C, using Example A-83B (1.0 g, 3.69 mmol) in place of Example A-1B. EXAMPLE A-83D 2-(3-(5-fluoro-1H-indole-2-carboxamido)-2-oxopyridin-1(2H)-yl)propanoic acid [0433] The title compound (0.3 g) was prepared using the procedure described in Example A-1E, using Example A-83C (0.4 g, 1.12 mmol) in place of Example A-1D. EXAMPLE A-83E N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-5-fluoro-1H-indole-2-carboxamide [0434] To a solution of benzyl ((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamate (0.34 g, 1.22 mmol) in ethyl acetate (10 mL) was added 20% Pd-C (0.025 g) was charged with hydrogen gas at 30 psi pressure in a parr shaker vessel. Reaction was continued for 16 hours. Upon completion, reaction mixture was filtered through a celite pad and the filtrate was evaporated to near dryness. Separately to a solution of Example A-83D (0.28 g, 0.82 mmol) in DCM (10 mL) was added DCC (0.25 g, 1.22 mmol), HOBt (0.18 g, 1.22 mmol). The solution was stirred at 0 °C for 10 minutes and the solution from the above reaction was added dropwise to it. The reaction mixture was stirred at rt for 2 h. The reaction progress was monitored by TLC and LCMS. The solvent of reaction mixture was dried under vacuum and the residue was diluted with water (10 mL) then extracted with ethyl acetate (3 × 10 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 10-40% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 2-oxo-1,2-dihydropyridin-3-yl)-5-fluoro-1H-indole-2-carboxamide (0.11 g) as white solid. EXAMPLE A-83F N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-5-fluoro-1H-indole-2-carboxamide (A-83) and N-(1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2- dihydropyridin-3-yl)-5-fluoro-1H-indole-2-carboxamide (A-84) [0435] The product of Example A-83E was purified by preparative chiral HPLC using Chiralpack IA (250 × 30) mm; 5 µM column and n-hexane: IPA (50:50) as mobile phase (40 mL/ min flow rate) and afforded the Example A-83 (0.25g) at RT 11.923 min and Example A-84 (0.25 g) at RT 15.759 min. EXAMPLE A-85 4-amino-N-(5-bromo-1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2- yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-chlorobenzamide
Figure imgf000202_0001
and EXAMPLE A-86 4-amino-N-(5-bromo-1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2- yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-chlorobenzamide
Figure imgf000202_0002
Figure imgf000203_0001
[0436] Reagents and conditions: (a) T3P, TEA, DCM, 0 °C-rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) Cs2CO3, DMF, 60 ⁰C, 3 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EEDQ, DCM, 0 °C-rt, 4 h, (g) Chiral preparative HPLC separation. EXAMPLE A-85A N-(5-bromo-2-methoxypyridin-3-yl)-3-chloro-4-nitrobenzamide [0437] To a stirred solution of 3-chloro-4-nitrobenzoic acid (3.9 g, 19.0 mmol) in DCM (30 mL) at 0 °C was added triethylamine (4.0 mL, 28.86 mmol), T3P (11.5 mL, 19.3 mmol) and 5-bromo-2- methoxypyridin-3-amine (2.14 g, 10.65 mmol) sequentially over a period of 30 min. The reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (50 mL) and residue was extracted with DCM (30 mL × 2 times). The combined organic layer was washed with brine (25 mL × 3 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (0-20%). Pure fractions were collected and concentrated to afford N-(5-bromo-2-methoxypyridin-3-yl)-3-chloro-4-nitrobenzamide (2.5 g) as brown solid. EXAMPLE A-85B N-(5-bromo-2-oxo-1,2-dihydropyridin-3-yl)-3-chloro-4-nitrobenzamide [0438] The title compound (2.2 g) was prepared using the procedure described in Example A-1B, using Example A-85A (2.5 g, 6.5 mmol) in place of Example A-1A. EXAMPLE A-85C methyl 2-(5-bromo-3-(3-chloro-4-nitrobenzamido)-2-oxopyridin-1(2H)-yl)propanoate [0439] The title compound (1.0 g) was prepared using the procedure described in Example A-1C, using Example A-85B (2.0 g, 5..36 mmol) in place of Example A-1B. EXAMPLE A-85D methyl 2-(3-(4-amino-3-chlorobenzamido)-5-bromo-2-oxopyridin-1(2H)-yl)propanoate [0440] The title compound (0.72 g) was prepared using the procedure described in Example A-1D, using Example A-85C (0.9 g, 1.9 mmol) in place of Example A-1C. EXAMPLE A-85E 2-(3-(4-amino-3-chlorobenzamido)-5-bromo-2-oxopyridin-1(2H)-yl)propanoic acid [0441] The title compound (0.6 g) was prepared using the procedure described in Example A-1E, using Example A-85D (0.7 g, 1.63 mmol) in place of Example A-1D. EXAMPLE A-85F 4-amino-N-(5-bromo-1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-1,2-dihydropyridin-3-yl)-3-chlorobenzamide [0442] To a solution of benzyl ((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamate (1.2 g, 4.9 mmol) in ethyl acetate (18 mL) was added 20% Pd-C (0.12 g) was charged with hydrogen gas at 30 psi pressure in a parr shaker vessel. Reaction was continued for 16 hours. Upon completion, reaction mixture was filtered through a celite pad and the filtrate was evaporated to near dryness. Separately to a solution of Example A-85E (0.6 g, 1.45 mmol) in DMF (15 mL) was added ethyl 2-ethoxy-1,2- dihydroquinoline-1-carboxylate (0.72 g, 2.89 mmol). The solution was stirred at 0 °C for 10 minutes and the solution from the above reaction was added dropwise to it. The reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, reaction mixture was diluted with water (40 mL) then extracted with ethyl acetate (3 × 20 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 50-60% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford 4-amino-N-(5-bromo-1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)- 1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-3-chlorobenzamide (0.33 g) as white solid. EXAMPLE A-85G 4-amino-N-(5-bromo-1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-1,2-dihydropyridin-3-yl)-3-chlorobenzamide (A-85) and 4-amino-N-(5-bromo-1-(1-(((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-1,2-dihydropyridin-3-yl)-3-chlorobenzamide (A-86) [0443] The product of Example A-85F was purified by preparative chiral HPLC using Chiralpack IG (250 × 30) mm; 5 µM column and EtOH as mobile phase (25 mL/ min flow rate) and afforded the Example A-85 (0.023g) at RT 7.986 min and Example A-86 (0.045 g) at RT 13.164 min. EXAMPLE A-87 N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo-1,2- dihydropyridin-3-yl)-3-fluoro-4-methoxybenzamide
Figure imgf000205_0001
Figure imgf000206_0001
[0444] Reagents and conditions: (a) T3P, TEA, DCM, 0 °C-rt, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) K2CO3, DMF, rt, 16 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) DCC, HOBt, DCM, 0 °C-rt, 4 h. EXAMPLE A-87A 3-fluoro-4-methoxy-N-(2-methoxypyridin-3-yl)benzamide [0445] To a stirred solution of 3-fluoro-4-methoxybenzoic acid (6.0 g, 35.3 mmol) in DCM (60 mL) at 0 °C was added triethylamine (14.7 mL, 106.0 mmol), T3P (30.0 mL, 52.9 mmol) and 2-methoxypyridin- 3-amine (5.25 g, 42.3 mmol) sequentially over a period of 30 min. The reaction mixture was stirred at rt for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (100 mL) and residue was extracted with DCM (30 mL × 2 times). The combined organic layer was washed with brine (50 mL × 3 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (15-20%). Pure fractions were collected and concentrated to afford 3-fluoro-4-methoxy-N-(2-methoxypyridin-3-yl)benzamide (5.3 g). EXAMPLE A-87B 3-fluoro-4-methoxy-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide [0446] The title compound (4.7 g) was prepared using the procedure described in Example A-1B, using Example A-87A (5.0 g, 18.1 mmol) in place of Example A-1A. EXAMPLE A-87C methyl 1-(3-(3-fluoro-4-methoxybenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate [0447] The title compound (2.0 g) was prepared using the procedure described in Example A-69A, using Example A-87B (3.6 g, 13.7 mmol) in place of Example A-56B. EXAMPLE A-87D 1-(3-(3-fluoro-4-methoxybenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid [0448] The title compound (1.8 g) was prepared using the procedure described in Example A-1E, using Example A-87C (2.0 g, 5.55 mmol) in place of Example A-1D. EXAMPLE A-87E N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo-1,2- dihydropyridin-3-yl)-3-fluoro-4-methoxybenzamide (A-87) [0449] The title compound (0.18 g) was prepared using the procedure described in Example A-83E, using Example A-87D (0.35 g, 0.9 mmol) in place of Example A-83D and benzyl ((2S,3S)-2-ethoxy-5- oxotetrahydrofuran-3-yl)carbamate (0.3 g, 1.07 mmol) in place of benzyl ((2R,3S)-2-ethoxy-5- oxotetrahydrofuran-3-yl)carbamate. Crude product was purified with preparative HPLC using Sunfire C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (19 mL/ min flow rate) at RT 15.977 min. EXAMPLE A-88 4-amino-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo-1,2- dihydropyridin-3-yl)-3-fluorobenzamide
Figure imgf000207_0001
Figure imgf000208_0001
[0450] Reagents and conditions: (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) K2CO3, DMF, rt, 30 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 0 °C-rt, 4 h. EXAMPLE A-88A 4-amino-3-fluoro-N-(2-methoxypyridin-3-yl)benzamide [0451] The title compound (2.0 g) was prepared using the procedure described in Example A-56A, using 4-amino-3-fluorobenzoic acid (2.0 g, 12.9 mmol) in place of 4-amino-3-chlorobenzoic acid. EXAMPLE A-88B 4-amino-3-fluoro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide [0452] The title compound (1.7 g) was prepared using the procedure described in Example A-1B, using Example A-88A (2.0 g, 7.6 mmol) in place of Example A-1A. EXAMPLE A-88C methyl 1-(3-(4-amino-3-fluorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate [0453] The title compound (0.45 g) was prepared using the procedure described in Example A-69A, using Example A-88B (1.2 g, 4.85 mmol) in place of Example A-56B. EXAMPLE A-88D 1-(3-(4-amino-3-fluorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid [0454] The title compound (0.3 g) was prepared using the procedure described in Example A-1E, using Example A-88C (0.4 g, 1.16 mmol) in place of Example A-1D. EXAMPLE A-88E 4-amino-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo-1,2- dihydropyridin-3-yl)-3-fluorobenzamide (A-88) [0455] The title compound (0.043 g) was prepared using the procedure described in Example A-56E, using Example A-88D (0.25 g, 0.76 mmol) in place of Example A-56D. Crude product was purified with preparative chiral HPLC using Chiralpack IA (20 × 250) mm; 5 µM column and n-hexane: IPA (60:40) as mobile phase (19 mL/ min flow rate) at RT 14.018 min. EXAMPLE A-89 4-amino-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo-1,2- dihydropyridin-3-yl)-2,5-difluorobenzamide
Figure imgf000209_0001
Figure imgf000210_0001
[0456] Reagents and conditions: (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) K2CO3, DMF, rt, 30 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 0 °C-rt, 4 h. EXAMPLE A-89A 4-amino-2,5-difluoro-N-(2-methoxypyridin-3-yl)benzamide [0457] The title compound (2.5 g) was prepared using the procedure described in Example A-56A, using 4-amino-2,5-difluorobenzoic acid (3.0 g, 17.3 mmol) in place of 4-amino-3-chlorobenzoic acid. EXAMPLE A-89B 4-amino-2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide [0458] The title compound (2.0 g) was prepared using the procedure described in Example A-1B, using Example A-89A (2.5 g, 8.95 mmol) in place of Example A-1A. EXAMPLE A-89C methyl 1-(3-(4-amino-2,5-difluorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate [0459] The title compound (1.2 g) was prepared using the procedure described in Example A-69A, using Example A-89B (2.0 g, 7.545 mmol) in place of Example A-56B. EXAMPLE A-89D 1-(3-(4-amino-2,5-difluorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid [0460] The title compound (0.72 g) was prepared using the procedure described in Example A-1E, using Example A-89C (1.2 g, 3.3 mmol) in place of Example A-1D. EXAMPLE A-89E 4-amino-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo-1,2- dihydropyridin-3-yl)-2,5-difluorobenzamide (A-89) [0461] The title compound (0.06 g) was prepared using the procedure described in Example A-56E, using Example A-89D (0.3 g, 0.31 mmol) in place of Example A-56D. Crude product was purified with preparative chiral HPLC using Chiralpack IA (20 × 250) mm; 5 µM column and n-hexane: IPA (70:30) as mobile phase (19 mL/ min flow rate) at RT 19.629 min. EXAMPLE A-90 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000211_0001
and EXAMPLE A-91 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)- 2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000211_0002
Figure imgf000212_0001
[0462] Reagents and conditions: (a) (i) (COCl)2, DMF, DCM, 0 °C-rt, 1 h, (ii) TEA, THF, rt 1 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) K2CO3, DMF, rt, 4 h, (d) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (e) LiOH, THF/H2O (3:1), rt, 2 h, (f) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 0 °C-rt, 4 h, (g) Chiral preparative HPLC separation. EXAMPLE A-90A 3-chloro-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-nitrobenzamide [0463] To a stirred solution of 3-chloro-4-nitrobenzoic acid (5.45 g, 27.1 mmol) in DCM (20 mL) at 0 °C was slowly added oxalic dichloride (6.96 mL, 81.2 mmol) followed by the addition of DMF (1.0 mL, 13.0 mmol). Resulting mixture was allowed to stir for 1 h at rt. After reaction completion, solvent was evaporated under vacuum and diluted with THF (25 mL). Solution was again cooled to 0 °C and to it was added trimethylamine (12.8 mL, 81.2 mmol) and 2-methoxy-5-(trifluoromethyl)pyridin-3-amine (5.2 g, 27.1 mmol). This reaction mixture was allowed to stir for another 1 h at rt. The reaction progress was monitored by TLC and LCMS. Upon completion, reaction mixture was evaporated to dryness, diluted with water (50 mL) then extracted with ethyl acetate (3 times × 25 mL), combined organic layer dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 10-40% 3-chloro-N-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-4- nitrobenzamide (9.0 g) as white solid. EXAMPLE A-90B 3-chloro-4-nitro-N-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)benzamide [0464] The title compound (8.0 g) was prepared using the procedure described in Example A-1B, using Example A-90A (9.0 g, 24.0 mmol) in place of Example A-1A. EXAMPLE A-90C methyl 2-(3-(3-chloro-4-nitrobenzamido)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)propanoate [0465] To a stirred solution of Example A-90B (5.0 g, 13.8 mmol) dissolved in DMF (50 mL) was added potassium carbonate (9.6 g, 69.1 mmol) and methyl 2-bromopropanoate (2.31 mL, 20.7 mmol) at rt. The reaction mixture was stirred for 4 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (150 mL) and resulting residue was extracted with ethyl acetate (50 mL × 3 times). The combined organic layer was washed with brine (100 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by flash column chromatography using 20-40% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford methyl 2-(3-(3-chloro-4- nitrobenzamido)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)propanoate (5.0 g) as yellow solid. EXAMPLE A-90D methyl 2-(3-(4-amino-3-chlorobenzamido)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)propanoate [0466] The title compound (4.0 g) was prepared using the procedure described in Example A-1D, using Example A-90C (5.0 g, 11.2 mmol) in place of Example A-1C. EXAMPLE A-90E 2-(3-(4-amino-3-chlorobenzamido)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)propanoic acid [0467] The title compound (1.2 g) was prepared using the procedure described in Example A-1E, using Example A-90D (1.3 g, 3.11 mmol) in place of Example A-1D. EXAMPLE A-90F 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)benzamide [0468] The title compound (1.0 g) was prepared using the procedure described in Example A-56E, using Example A-90E (1.2 g, 2.97 mmol) in place of Example A-56D. EXAMPLE A-90G 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)benzamide (A-90) and 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)amino)-1-oxopropan-2-yl)-2- oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)benzamide (A-91) [0469] The product of Example A-90F was purified by preparative chiral HPLC using Chiralpack IG (250 × 30) mm; 5 µM column and n-hexane: EtOH (50:50) as mobile phase (40 mL/ min flow rate) and afforded the Example A-90 (0.482) at RT 5.459 min and Example A-91 (0.44 g) at RT 9.073 min. EXAMPLE A-92 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide
Figure imgf000214_0001
Figure imgf000215_0001
[0470] Reagents and conditions: (a) PPh3, DCM, 0 °C-rt, 16 h, (b) NaH, DMSO, 0 °C-rt, 3 h, (c) Iron, NH4Cl, EtOH/H2O (2:1), 60 ⁰C, 14 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) DCC, HOBt, DCM, 0 °C-rt, 4 h. EXAMPLE A-92A methyl 2-(3-(3-chloro-4-nitrobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)acrylate [0471] To a stirred solution of Example A-42B (8.0 g, 25.7 mmol) and triphenylphosphine (1.35 g, 5.13 mmol) in DCM (160 mL) at 0 °C was dropwise added a DCM solution (20 mL) of methyl prop-2-ynoate (2.28 mL, 25.7 mmol). The resulting reaction mixture was allowed to stir at rt for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, reaction mixture was evaporated to dryness, diluted with water (150 mL) then extracted with ethyl acetate (3 times × 50 mL), combined organic layer was dried over sodium sulphate and concentrated to afford the crude product, which was then purified by flash column chromatography using 0-30% to afford methyl 2-(3-(3-chloro-4- nitrobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)acrylate (5.0 g) as white solid. EXAMPLE A-92B methyl 1-(3-(3-chloro-4-nitrobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate [0472] Sodium hydride (0.51 g, 12.6 mmol) was portion wise added to a solution of trimethylsulfoxonium iodide (2.58 g, 12.6 mmol) in DMSO (15 mL) at 0 °C. Mixture was stirred for 1 h at rt and then again cooled to 0 °C and to it was added a solution of Example A-92A (5.0 g, 12.6 mmol) in DMSO (15 mL). The progress of the reaction was monitored by TLC and LCMS. After 2 h, upon completion of the reaction, it was quenched with cold water (150 mL) and resulting residue was extracted with ethyl acetate (40 mL × 3 times). The combined organic layer was washed with brine (100 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by flash column chromatography using 10-30% ethyl acetate/hexane. Pure fractions were collected and concentrated to afford methyl 1-(3-(3-chloro-4-nitrobenzamido)-5-fluoro-2- oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate (0.7 g) as white solid. EXAMPLE A-92C methyl 1-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate [0473] The title compound (0.3 g) was prepared using the procedure described in Example A-1D, using Example A-92B (0.7 g, 1.71 mmol) in place of Example A-1C. EXAMPLE A-92D 1-(3-(4-amino-3-chlorobenzamido)-5-fluoro-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid [0474] The title compound (0.2 g) was prepared using the procedure described in Example A-1E, using Example A-92C (0.3 g, 0.79 mmol) in place of Example A-1D. EXAMPLE A-92E 4-amino-3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-5- fluoro-2-oxo-1,2-dihydropyridin-3-yl)benzamide (A-92) [0475] The title compound (0.011 g) was prepared using the procedure described in Example A-87E, using Example A-92D (0.16 g, 0.44 mmol) in place of Example A-87D. Crude product was purified with preparative chiral HPLC using Chiralpack IC (20 × 250) mm; 5 µM column and n-hexane: IPA (50:50) as mobile phase (19 mL/ min flow rate) at RT 14.018 min. EXAMPLE A-93 3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo-1,2- dihydropyridin-3-yl)-4-(methylamino)benzamide
Figure imgf000217_0001
Figure imgf000217_0002
[0476] Reagents and conditions: (a) HATU, DIPEA, DMF, 60 °C, 16 h, (b) 4M HCl in dioxane, dioxane, 70 ⁰C, 16 h, (c) K2CO3, DMF, rt, 30 h, (d) LiOH, THF/H2O (3:1), rt, 16 h, (f) (i) H2, Pd-C, EtOAc, rt, 16 h, (ii) EDC, HOBt, DMF, 0 °C-rt, 4 h. EXAMPLE A-93A 3-chloro-N-(2-methoxypyridin-3-yl)-4-(methylamino)benzamide [0477] The title compound (2.9 g) was prepared using the procedure described in Example A-56A, using 3-chloro-4-(methylamino)benzoic acid (5.4 g, 29.1 mmol) in place of 4-amino-3-chlorobenzoic acid. EXAMPLE A-93B 3-chloro-4-(methylamino)-N-(2-oxo-1,2-dihydropyridin-3-yl)benzamide [0478] The title compound (2.4 g) was prepared using the procedure described in Example A-1B, using Example A-93A (2.7 g, 9.25 mmol) in place of Example A-1A. EXAMPLE A-93C methyl 1-(3-(3-chloro-4-(methylamino)benzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate [0479] The title compound (1.2 g) was prepared using the procedure described in Example A-69A, using Example A-93B (2.0 g, 7.2 mmol) in place of Example A-56B. EXAMPLE A-93D 1-(3-(3-chloro-4-(methylamino)benzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylic acid [0480] The title compound (0.6 g) was prepared using the procedure described in Example A-1E, using Example A-93C (0.9 g, 2.39 mmol) in place of Example A-1D. EXAMPLE A-93E 3-chloro-N-(1-(1-(((2S,3S)-2-ethoxy-5-oxotetrahydrofuran-3-yl)carbamoyl)cyclopropyl)-2-oxo-1,2- dihydropyridin-3-yl)-4-(methylamino)benzamide (A-93) [0481] The title compound (0.37 g) was prepared using the procedure described in Example A-56E, using Example A-93D (0.6 g, 1.66 mmol) in place of Example A-56D. Crude product was purified with preparative HPLC using X-Select CSH C18 (19 × 250) mm; 5 µM column and water and acetonitrile as mobile phase (18 mL/ min flow rate) at RT 16.542 min.
EXAMPLE A-94 Ethyl (S)-3-(1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1- carboxamido)-3-cyanopropanoate
Figure imgf000219_0001
[0482] Reagents and conditions: (a) (i) DBU, DMF, 0 °C-rt, 1 h, (ii) HATU, DIPEA, 0 °C-rt, 16 h EXAMPLE A-94A Ethyl (S)-3-(1-(3-(4-amino-3-chlorobenzamido)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxamido)-3- cyanopropanoate (A-94) [0483] To a stirred solution of ethyl (S)-3-cyano-3-[(9H-fluoren-9- yl)methoxycarbonylamino]propionate (0.027 g, 0.075 mmol) in DMF (1 mL) at 0 °C was added 1,8- diazabicyclo[5.4.0]undec-7-ene (0.016 mL, 0.12 mmol) and the reaction was continued for 1 h. Separately at 0 °C, to solution of Example A-69B (0.02 g, 0.12 mmol) in DMF (2 mL) was added N,N- Diisopropylethylamine (0.15 mL, 0.086 mmol), HATU (0.033 g, 0.086 mmol) and after 15 min, the above reaction mixture was added to it. This was then stirred for 16 h at rt. Reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with cold water (10 mL) and residue was extracted with ethyl acetate (10 mL × 2 times). The combined organic layer was washed with brine (10 mL × 2 times), dried over sodium sulfate and evaporated under reduced pressure to result in crude compound which was purified by Combi flash chromatography using ethyl acetate/ Hexane (20-50%). Pure fractions were collected and concentrated to afford the title compound (0.008 g). [0484] Data for select compounds is provided in the Table below:
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
EXAMPLE B-1 N-((2S)-1-((2-(2-acryloylhydrazineyl)-2-oxo-1-phenylethyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)-4- amino-3-chlorobenzamide
Figure imgf000235_0001
[0485] Reagents and conditions: (a) Isobutyl chloroformate, NMM, CH2C2, 0 °C-rt, 18 h; (b) LiOH, THF/H2O (5:1), rt, 8 h; (c) T3P, DIPEA, DMF, 0 °C-rt, 14 h; (d) Hydrazine hydrate, EtOH, 80 °C, 14 h; (e) T3P, DIPEA, DMF, 0 °C-RT, 18 h. EXAMPLE B-1A Methyl (S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoate [0486] To a stirred solution of 4-amino-3-chlorobenzoic acid (4.0 g, 23.3 mmol) in CH2CL2 (40 mL) at 0 °C was added NMM (10.3 mL, 93.3 mmol). Subsequently after 10 minutes, isobutyl chloroformate (5.4 mL, 46.6 mmol) was added. The reaction mixture was allowed to come to ambient temperature while stirring and finally (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (8.4, 46.6 mmol) was added to the reaction mixture. Reaction was continued until both the starting materials were consumed and upon completion the reaction mixture was diluted CH2CL2 (60 mL) and washed with water and brine (2×100 mL each). CH2CL2 layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material which was triturated and recrystallized from hexane to afford the title compound (3.2 g). EXAMPLE B-1B (S)-2-(4-Amino-3-chlorobenzamido)-3,3-dimethylbutanoic acid [0487] To a stirred solution of Example B-1A (3.2 g, 10.4 mmol) in THF (25 mL) and water (5 mL) was added lithium hydroxide (0.51 g, 20.8 mmol). The reaction mixture was stirred at an ambient temperature for overnight, concentrated to a minimum volume, and the residue was diluted with water (10 mL). The pH of the aqueous phase was adjusted to 1 by the addition of HCl (aq) (1.0 M) resulting in a thick precipitate that was collected by filtration and dried to afford the title compound (2.8 g). EXAMPLE B-1C Methyl (S)-2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetate [0488] To a stirred solution of Example B-1B (2.5 g, 9.8 mmol) at 0 °C in DMF (20 mL) was added propylphosphonic anhydride (50% wt solution in ethyl acetate) (5.2 mL, 19.6 mmol) and DIPEA (3.2 mL, 30.0 mmol). The reaction mixture was allowed to come to ambient temperature while stirring and finally methyl (S)-2-amino-2-phenylacetate hydrochloride (1.8 g, 9.8 mmol) was added to. After overnight stirring, the reaction mixture was diluted with ethyl acetate (50 mL) and washed consecutively with ice-cold water and brine (2×100 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (40% ethyl acetate in hexane) afforded the title compound (3.8 g). EXAMPLE B-1D 4-Amino-3-chloro-N-((2S)-1-((2-hydrazineyl-2-oxo-1-phenylethyl)amino)-3,3-dimethyl-1-oxobutan-2- yl)benzamide [0489] To a suspension of 1C (30 g, 54,6 mmol) in ethanol (240 mL) was added hydrazine hydrate (100 mL). The mixture was allowed to reflux for overnight. Upon reaction completion, ethanol was removed under vacuum and precipitated by cold water (300 mL). Thus obtained white precipitate was filtered, washed with water (3×100 mL) and dried to afford the title compound (26.4 g). EXAMPLE B-1D N-((2S)-1-((2-(2-acryloylhydrazineyl)-2-oxo-1-phenylethyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)-4- amino-3-chlorobenzamide (B-1) [0490] To a stirred solution of Example B-1D (0.15 g, 0.3 mmol) at 0 °C in DMF (5 mL) was added propylphosphonic anhydride (50% wt solution in ethyl acetate) (0.1 mL, 0.4 mmol) and DIPEA (0.18 mL, 1.0 mmol). The reaction mixture was allowed to come to ambient temperature while stirring and finally acrylic acid (0.02 mL, 0.3 mmol) was added to. After overnight stirring, the reaction mixture was diluted with ethyl acetate (15 mL) and washed consecutively with ice-cold water and brine (2×10 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by prep-HPLC using Sunfire C18 (19 X 250) mm; 5 µM column and water and MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.008 g) at RT 23.40 min. EXAMPLE B-2 Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- phenylacetamido)glycinate
Figure imgf000237_0001
[0491] Reagents and conditions: (a) Ethyl 2-bromoacetate, NMM, DMF, 0 °C-rt, 16 h; (b) acryloyl chloride, Et3N, THF, 0 °C-rt, 1 h. EXAMPLE B-2A Ethyl (2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)glycinate [0492] To a stirred solution of Example B-1D (3.0 g, 7.0 mmol) in DMF (30 mL) was added 4- methylmorpholine (2.3 mL, 20.0 mmol). Reaction mixture was cooled to 0 °C and ethyl 2-bromoacetate (3.0 mL, 20.0 mmol) was added slowly. After stirring the reaction mixture for overnight in an ambient temperature, it was diluted with ethyl acetate (50 mL) and washed consecutively with ice-cold water and brine (2×100 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (50- 90% ethyl acetate in hexane) afforded the title compound (2.5 g). EXAMPLE B-2B Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- phenylacetamido)glycinate (B-2) [0493] To a stirred solution of Example B-2A (0.5 g, 0.9 mmol) in THF (10 mL) at 0 °C was successively added triethyl amine (0.4 mL, 2.9 mmol) and acryloyl chloride (0.08 mL, 0.9 mmol). Reaction mixture was stirred and allowed to come to room temperature over a period of one hour. After this time, it was concentrated under reduced pressure to get the crude. Purification of the residue by prep- HPLC using XBridge C18 (19 X 250) mm; 5 µM column and water and MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.015 g) at RT 17.50 min. EXAMPLE B-3 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-cyanoacetyl)glycinate
Figure imgf000238_0001
[0494] Reagents and conditions: (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 18 h. [0495] To a solution of 2-cyanoacetic acid (0.12 g, 1.5 mmol) in DMF (10 mL) at 0 ⁰C was added EDCl (0.4 g, 2.1 mmol), HOBt (0.2 g, 1.5 mmol) and DIPEA (0.8 mL, 4.5 mmol). After 10 minutes Example B-2A (0.5 g, 1.0 mmol) was added to it. After overnight stirring, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with ice-cold water and brine (2×25 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by prep-HPLC using XSelect CSH C18 (4.6 X 250) mm; 5 µM column and water and MeCN as mobile phase (1 mL/ min flow rate) afforded the title compound (0.01 g) at RT 18.61 min. EXAMPLE B-4 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-cyanoacetyl)glycinate
Figure imgf000238_0002
[0496] During the preparative HPLC purification of Example B-3, the title compound (0.008 g) was isolated at RT 20.24 min. EXAMPLE B-5 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-fluoroacetyl)glycinate
Figure imgf000239_0001
[0497] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 4 h. [0498] To a mixture of Example B-2A (0.12 g, 0.2 mmol) and sodium 2-fluoroacetate (0.034 g, 0.3 mmol) in DMF (5 mL) at 0 °C was consecutively added HATU (0.1 g, 0.3 mmol) and DIPEA (0.1 mL, 0.7 mmol). Reaction mixture was stirred and allowed to come to room temperature over a period of four hours. Upon completion, it was diluted with ethyl acetate (15 mL) and washed with ice-cold water and brine (2×20 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by prep-HPLC using XBridge C18 (19 X 250) mm; 5 µM column and 0.1% ammonia in water and MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.02 g) at RT 18.44 min. EXAMPLE B-6 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-fluoroacetyl)glycinate
Figure imgf000239_0002
[0499] During the preparative HPLC purification of Example B-5, the title compound (0.018 g) was isolated at RT 19.73 min. EXAMPLE B-7 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- ((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000240_0001
Figure imgf000240_0002
[0500] Reagents and conditions: (a) (CO)2Cl2, CH2Cl2, 0 °C-rt, 4 h, (b) Et3N, CH2Cl2, rt, 2 h, (c) LiOH, THF/H2O (5:1), rt, 8 h; (d) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h. EXAMPLE B-7A Methyl (E)-4-chloro-4-oxobut-2-enoate [0501] To a stirred solution of (E)-4-methoxy-4-oxobut-2-enoic acid (10 g, 76.9 mmol) in dichloromethane (100 mL) was added oxalyl chloride (13.2 mL, 154.0 mmol) dropwise at 0 °C. then reaction was allowed to continue for 4 h. After this time a small fraction of the reaction mixture was quenched with methanol and TLC was checked, which showed the formation of a nonpolar ester spot. The whole reaction mixture was concentrated to dryness under nitrogen atmosphere to get methyl (E)-4- chloro-4-oxobut-2-enoate (11.0 g) in the crude form, which was directly used in the next step without further purification. EXAMPLE B-7B methyl (E)-4-(benzylamino)-4-oxobut-2-enoate [0502] To a stirred solution of 1-phenylmethanamine (5.1 mL, 46.7 mmol) in dichloromethane (100 mL) was added triethylamine (13.0 mL, 93 mmol) and the reaction mixture was stirred for 10 mins. After this time, Example B-7A (11.0 g, 74.7 mmol) was added to the reaction mixture and the reaction was continued for 2 hours at an ambient temperature. Upon completion, reaction mixture was diluted with DCM (100 mL) and washed with water (2×150 mL). Organic layer was separated, dried with sodium sulphate and concentrated in vacuo to get the crude, which was then purified by flash column chromatography using 40% ethyl acetate in hexane to get Methyl (E)-4-(benzylamino)-4-oxobut-2-enoate (9.2 g). EXAMPLE B-7C (E)-4-(benzylamino)-4-oxobut-2-enoic acid [0503] The title compound (7.0 g) was prepared using the procedure described in Example B-1B, using Example B-51B (9.2 g, 42.0 mmol) in place of Example B-1A. EXAMPLE B-7D Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- (benzylamino)-4-oxobut-2-enoyl)glycinate (B-7) [0504] To a stirred solution of Example B-7C (0.15 g, 0.7 mmol) in N,N dimethyl formamide (10 mL) at 0 °C was added EDCl (0.3 g, 1.5 mmol) and HOBt (0.1 g, 0.7 mmol). Subsequently after 10 minutes, DIPEA (0.4 mL, 2.4 mmol) and Example B-2A (0.25 g, 0.5 mmol) were added. Reaction was continued for overnight at an ambient temperature until both the starting materials were consumed and upon completion the reaction mixture was diluted ethyl acetate (50 mL) and washed with water and brine (2×100 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by prep-HPLC using Inertsil ODS C18 (250x20) mm; 5 µM column and 5mM ammonium acetate in water and MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.013 g) at RT 22.60 min. EXAMPLE B-8 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- ((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000242_0001
[0505] During the preparative HPLC purification of Example B-7D, the title compound (0.008 g) was isolated at RT 24.06 min. EXAMPLE B-9 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-(perfluorophenoxy)acetyl)glycinate
Figure imgf000242_0002
[0506] Reagents and conditions: (a) (i) SOCl2, dioxane, 105 °C, 1 h, (ii) Et3N, CH2Cl2, rt, 16 h. [0507] To a stirred solution of 2-(perfluorophenoxy)acetic acid (0.2 g, 0.8 mmol) in dioxane (8 mL) was added thionyl chloride (0.3 mL, 4.0 mmol) dropwise at 0 °C. then reaction was allowed to reflux for 1 h. The whole reaction mixture was concentrated to dryness under nitrogen atmosphere. Separately, to a stirred solution of Example B-2A (0.2 g, 0.4 mmol) in DCM (10 mL) was added triethyl amine (0.3 mL, 2.0 mmol) and after 15 minutes the crude 2-(perfluorophenoxy)acetyl chloride obtained from first reaction mixture was added to it. Reaction was allowed to stir for overnight and then it was evaporated to dryness to get the crude. Purification of the residue by prep-HPLC using XBridge C18 (19 X 250) mm; 5 µM column and 5mM ammonium acetate in water and MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.06 g) at RT 17.30 min. EXAMPLE B-10 Ethyl N-((S)-2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)- N-(2-(perfluorophenoxy)acetyl)glycinate
Figure imgf000243_0001
and EXAMPLE B-11 Ethyl N-((R)-2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)- N-(2-(perfluorophenoxy)acetyl)glycinate
Figure imgf000243_0002
[0508] Preparative HPLC purification of Example B-9 by using XSELECT C18 (19 mm X 250 mm X 5 µM) and 5mM ammonium acetate in water and MeCN as mobile phase (19 mL/ min flow rate) and afforded the title compound (10) (0.02 g) at RT 29.74 min and title compound (11) (0.01 g) at RT 31.49 min.
EXAMPLE B-12 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- (benzylamino)-4-oxobut-2-enoyl)glycine
Figure imgf000244_0001
[0509] Reagents and conditions: (a) t-Butyl bromoacetate, DMF, rt, 2 h; (b) EDCl, HOBt, DIPEA, CH2Cl2, 0 °C-rt, 14 h; (c) TFA, CH2Cl2, 0 °C-rt, 2 h. EXAMPLE B-12A tert-Butyl (2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- phenylacetamido)glycinate [0510] To a stirred solution of Example B-1D (10 g, 23.2 mmol) in N,N-dimethylformamide (50 mL) tert-butyl 2-bromoacetate (50 mL, 5 Vol ) was added dropwise at room temperature and reaction mixture was allowed to stir for 2 hours. Upon completion, reaction was quenched with cold water (150 mL) and extracted with ethyl acetate (2×100 mL). Organic layer was washed with brine, separated, dried over sodium sulphate and evaporated to dryness to get the crude. Purification of the residue by flash chromatography on silica gel (40-70% ethyl acetate in hexane) afforded the title compound (5.5 g). EXAMPLE B-12B tert-Butyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- ((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate [0511] To a stirred solution of Example B-7C ((0.17 g, 0.8 mmol) in dichloromethane (10 mL) at 0 °C was added EDCl (0.3 g, 1.6 mmol) and HOBt (0.13 g, 0.8 mmol). Subsequently after 10 minutes, DIPEA (0.5 mL, 2.75 mmol) and Example B-12A (0.3 g, 0.6 mmol) were added. Reaction was continued for overnight at an ambient temperature until both the starting materials were consumed and upon completion the reaction mixture was diluted DCM (20 mL) and washed with water and brine (2×50 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-50% ethyl acetate in hexane) afforded the title compound (0.25 g). EXAMPLE B-12C N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- (benzylamino)-4-oxobut-2-enoyl)glycine (B-12) [0512] To a stirred solution of Example B-12B (0.25 g, 0.3 mmol) in dichloromethane at 0 °C was dropwise added trifluoroacetic acid (2.5 mL, 32.7 mmol). Reaction mixture was stirred for couple of hours while the reaction temperature was allowed to come to room temperature. Upon completion, reaction mixture was evaporated to dryness to get the crude. Purification of the residue by prep-HPLC using ZORBAX C18 (21.2 X 150) mm; 5 µM column and water and MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.017 g) at RT 13.65 min. EXAMPLE B-13 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- (benzylamino)-4-oxobut-2-enoyl)glycine
Figure imgf000245_0001
[0513] During the preparative HPLC purification of Example B-12C, the title compound (0.02 g) was isolated at RT 14.12 min. EXAMPLE B-14 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-fluoroacetyl)glycinate
Figure imgf000246_0001
[0514] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 4 h; (b) TFA, CH2Cl2, 0 °C-rt, 2 h. EXAMPLE B-14A tert-Butyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacetyl)glycinate [0515] The title compound (0.1 g) was prepared using the procedure described in Example B-5, using Example B-12A (0.2 g, 0.4 mmol) in place of Example B-2A. EXAMPLE B-14B Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacetyl)glycinate (B-14) [0516] Following the procedure described in Example B-12C and using Example B-14A (0.1 g, 0.17 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using XBridge C18 (19 X 250) mm; 5 µM column and 5% ammonium acetate in water; MeCN as mobile phase (17 mL/ min flow rate) afforded the title compound (0.01 g) at RT 11.90 min. EXAMPLE B-15 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-fluoroacetyl)glycinate
Figure imgf000247_0001
[0517] During the preparative HPLC purification of Example B-14B, the title compound (0.01 g) was isolated at RT 12.95 min. EXAMPLE B-16 Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)glycinate
Figure imgf000247_0002
[0518] Reagents and conditions: (a) SOCl2, MeOH, 0 °C- rt, 16 h; (b) T3P, DIPEA, DMF, 0 °C-rt, 14 h; (c) Hydrazine hydrate, EtOH, 80 °C, 14 h; (d) Ethyl 2-bromoacetate, NMM, DMF, 0 °C-rt, 16 h; (e) acryloyl chloride, Et3N, THF, 0 °C-rt, 1 h. EXAMPLE B-16A Methyl 2-amino-2-(3-(trifluoromethyl)phenyl)acetate hydrochloride [0519] To a suspension of 2-amino-2-(3-(trifluoromethyl)phenyl)acetic acid (25.0 g, 114.0 mmol) in MeOH (250 mL) at 0 ⁰C was slowly added thionyl chloride (16.5 mL, 228.0 mmol). The reaction mixture was the allowed stir for overnight at an ambient temperature. Upon completion reaction mixture was concentrated to afford solid mass, which was then washed with diethyl ether to furnish the title compound (30.5 g). EXAMPLE B-16B Methyl 2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetate [0520] The title compound (15.0 g) was prepared using the procedure described in Example B-1C, using Example B-16A (10.1 g, 37.5 mmol) in place of methyl (S)-2-amino-2-phenylacetate hydrochloride. EXAMPLE B-16C 4-Amino-3-chloro-N-((2S)-1-((2-hydrazineyl-2-oxo-1-(3-(trifluoromethyl)phenyl)ethyl)amino)-3,3- dimethyl-1-oxobutan-2-yl)benzamide [0521] The title compound (13.4 g) was prepared using the procedure described in Example B-45A, using Example B-16B (25.0 g, 50.0 mmol) in place of Example B-1C. EXAMPLE B-16D Ethyl (2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)glycinate [0522] The title compound (7.4 g) was prepared using the procedure described in Example B-2A, using Example B-16C (13.0 g, 26.0 mmol) in place of Example B-45A. EXAMPLE B-16E Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)glycinate (B-16) [0523] Following the procedure described in Example B-2B and using Example B-16D (0.1 g, 0.16 mmol) in place of Example B-2A the crude product was obtained. Purification of the residue by prep- HPLC using XSelect C18 (19 X 250) mm; 5 µM column and 5mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.007 g) at RT 23.90 min. EXAMPLE B-17 Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- cyclopropylacetamido)glycinate
Figure imgf000249_0001
[0524] Reagents and conditions: (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h; (b) Hydrazine hydrate, EtOH, 80 °C, 14 h; (c) Ethyl 2-bromoacetate, NMM, DMF, 0 °C-rt, 16 h; (d) acryloyl chloride, Et3N, THF, 0 °C-rt, 1 h. EXAMPLE B-17A Methyl (S)-2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-cyclopropylacetate [0525] To a stirred solution of Example B-1B (1.0 g, 3.5 mmol) in N,N dimethyl formamide (15 mL) at 0 °C was added EDCl (1.0 g, 5.3 mmol) and HOBt (0.52 g, 3.86 mmol). Subsequently after 10 minutes, DIPEA (1.8 mL, 10.5 mmol) and methyl (S)-2-amino-2-cyclopropylacetate hydrochloride (0.58 g, 3.5 mmol) were added. Reaction was continued for overnight at an ambient temperature until both the starting materials were consumed and upon completion the reaction mixture was diluted ethyl acetate (50 mL) and washed with water and brine (2×100 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-60% ethyl acetate in hexane) afforded the title compound (0.9 g). EXAMPLE B-17B 4-Amino-3-chloro-N-((2S)-1-((1-cyclopropyl-2-hydrazineyl-2-oxoethyl)amino)-3,3-dimethyl-1-oxobutan- 2-yl)benzamide [0526] The title compound (1.2 g) was prepared using the procedure described in Example B-1D, using Example B-17A (2.0 g, 5.1 mmol) in place of Example B-1C. EXAMPLE B-17C Ethyl (2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- cyclopropylacetamido)glycinate [0527] The title compound (0.4 g) was prepared using the procedure described in Example B-2A, using Example B-17B (1.2 g, 2.5 mmol) in place of Example B-1D. EXAMPLE B-17D Ethyl N-acryloyl-N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- cyclopropylacetamido)glycinate (B-17) [0528] Following the procedure described in Example B-2B and using Example B-17C (0.2 g, 0.4 mmol) in place of Example B-2A the crude product was obtained. Purification of the residue by prep- HPLC using XSelect C18 (19 X 250) mm; 5 µM column and 5mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.01 g) at RT 12.86 min. EXAMPLE B-18 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- (perfluorophenoxy)acetyl)glycine
Figure imgf000250_0001
Figure imgf000251_0001
[0529] Reagents and conditions: (a) (i) SOCl2, dioxane, 105 °C, 1 h, (ii) Et3N, CH2Cl2, rt, 16 h; (b) TFA, CH2Cl2, 0 °C-rt, 2 h. EXAMPLE B-18A tert-Butyl (2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2- phenylacetamido)glycinate [0530] The title compound (0.09 g) was prepared using the procedure described in Example B-9, using Example B-12A (0.3 g, 0.5 mmol) in place of Example B-2A. EXAMPLE B-18B N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- (perfluorophenoxy)acetyl)glycine (B-18) [0531] Following the procedure described in Example B-12C and using Example B-18A (0.08 g, 0.1 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using SunFire C18 (19 X 250) mm; 5 µM column and water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.01 g) at RT 20.85 min.
EXAMPLE B-19 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-(2,3,5,6-tetrafluorophenoxy)acetyl)glycinate
Figure imgf000252_0001
[0532] Reagents and conditions: (a) (i) SOCl2, dioxane, 105 °C, 1 h, (ii) Et3N, CH2Cl2, rt, 16 h. [0533] Following the procedure described in Example B-9 and using 2-(2,3,5,6- tetrafluorophenoxy)acetic acid (0.2 g, 0.8 mmol) in place of 2-(perfluorophenoxy)acetic acid and crude product was obtained. Purification of the residue by prep-HPLC using SunFire C18 (19 X 250) mm; 5 µM column and water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.008 g) at RT 30.58 min. EXAMPLE B-20 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- (2-(2,3,5,6-tetrafluorophenoxy)acetyl)glycinate
Figure imgf000252_0002
[0534] During the preparative HPLC purification of Example B-19, the title compound (0.01 g) was isolated at RT 32.90 min. EXAMPLE B-21 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- (2,3,5,6-tetrafluorophenoxy)acetyl)glycine
Figure imgf000253_0001
[0535] Reagents and conditions: (a) (i) SOCl2, dioxane, 105 °C, 1 h, (ii) Et3N, CH2Cl2, rt, 16 h; (b) TFA, CH2Cl2, 0 °C-rt, 2 h. EXAMPLE B-21A tert-Butyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- (2,3,5,6-tetrafluorophenoxy)acetyl)glycinate [0536] The title compound (0.04 g) was prepared using the procedure described in Example B-9, using Example B-12A (0.1 g, 0.2 mmol) in place of Example B-2A. EXAMPLE B-21B N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2-(2,3,5,6- tetrafluorophenoxy)acetyl)glycine (B-21) [0537] Following the procedure described in Example B-12C and using Example B-21A (0.04 g, 0.05 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using SunFire C18 (19 X 250) mm; 5 µM column and 5 mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.005 g) at RT 26.81 min. EXAMPLE B-22 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacryloyl)glycine
Figure imgf000254_0001
[0538] Reagents and conditions: (a) BOP, DIPEA, DMF, 0 °C-rt, 14 h; (b) TFA, CH2Cl2, 0 °C-rt, 2 h. EXAMPLE B-22A tert-Butyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacryloyl)glycinate [0539] To a stirred solution of Example B-12A (0.35 g, 0.6 mmol) and 2-fluoroacrylic acid (0.09 g, 1.0 mmol) in DMF (10 mL) at 0 °C was subsequently added BOP (0.4 g, 1.0 mmol) and DIPEA (0.3 mL, 1.9 mmol). After overnight stirring, the reaction mixture was diluted with ethyl acetate (15 mL) and washed with ice-cold water and brine (2×10 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-50% ethyl acetate in hexane) afforded the title compound (0.15 g). EXAMPLE B-22B N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacryloyl)glycine (B-22) [0540] Following the procedure described in Example B-12C and using Example B-22A (0.15 g, 0.2 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using SunFire C18 (19 X 250) mm; 5 µM column and water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.008 g) at RT 17.25 min. EXAMPLE B-23 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- fluoroacryloyl)glycine
Figure imgf000255_0001
[0541] During the preparative HPLC purification of Example B-22B, the title compound (0.02 g) was isolated at RT 12.26 min. EXAMPLE B-24 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)- but-2-enoyl)glycine
Figure imgf000255_0002
Figure imgf000256_0001
[0542] Reagents and conditions: (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h; (b) TFA, CH2Cl2, 0 °C- rt, 2 h. EXAMPLE B-24A tert-Butyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- ((E)-but-2-enoyl)glycinate [0543] To a stirred solution of Example B-12A (0.2 g, 0.4 mmol) and (2E)-but-2-enoic acid (0.05 g, 0.6 mmol) in DMF (10 mL) at 0 °C was subsequently added EDCl (0.1 g, 0.7 mmol), HOBt (0.1 g, 0.7 mmol) and DIPEA (0.3 mL, 1.9 mmol). After overnight stirring, the reaction mixture was diluted with ethyl acetate (15 mL) and washed with ice-cold water and brine (2×10 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-50% ethyl acetate in hexane) afforded the title compound (0.05 g). EXAMPLE B-24B N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-but-2- enoyl)glycine (B-24) [0544] Following the procedure described in Example B-12C and using Example B-24A (0.05 g, 0.08 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using ZORBAX C18 (19 X 250) mm; 5 µM column and 5 mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.004 g) at RT 17.57 min. EXAMPLE B-25 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)- but-2-enoyl)glycine
Figure imgf000257_0001
[0545] During the preparative HPLC purification of Example B-24B, the title compound (0.015 g) was isolated at RT 19.70 min. EXAMPLE B-26 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- chloroacetyl)glycine
Figure imgf000257_0002
[0546] Reagents and conditions: (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h; (b) TFA, CH2Cl2, 0 °C- rt, 2 h. EXAMPLE B-26A tert-Butyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N- ((E)-but-2-enoyl)glycinate [0547] To a stirred solution of Example B-12A (0.2 g, 0.4 mmol) and 2-chloroacetic acid (0.05 g, 0.5 mmol) in DMF (10 mL) at 0 °C was subsequently added EDCl (0.1 g, 0.7 mmol), HOBt (0.03 g, 0.2 mmol) and DIPEA (0.3 mL, 1.9 mmol). After overnight stirring, the reaction mixture was diluted with ethyl acetate (15 mL) and washed with ice-cold water and brine (2×10 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-50% ethyl acetate in hexane) afforded the title compound (0.06 g). EXAMPLE B-26B N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-(2- chloroacetyl)glycine (B-26) [0548] Following the procedure described in Example B-12C and using Example B-26A (0.06 g, 0.08 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using SunFire C18 (19 X 250) mm; 5 µM column and water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.025 g) at RT 15.96 min. EXAMPLE B-28 N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- methoxy-4-oxobut-2-enoyl)glycine
Figure imgf000258_0001
Figure imgf000259_0001
[0549] Reagents and conditions: (a) T3P, DIPEA, CH2Cl2, 0 °C-rt, 2 h; (b) TFA, CH2Cl2, 0 °C-rt, 2 h. EXAMPLE B-28A Methyl (E)-4-((3S)-1-(4-amino-3-chlorophenyl)-3-(tert-butyl)-13,13-dimethyl-1,4,7,11-tetraoxo-6- phenyl-12-oxa-2,5,8,9-tetraazatetradecan-9-yl)-4-oxobut-2-enoate [0550] To a stirred solution of Example B-12A (0.2 g, 0.4 mmol) and (E)-4-methoxy-4-oxobut-2-enoic acid (0.05 g, 0.4 mmol) in DMF (10 mL) at 0 °C was added T3P (0.2 mL, 0.7 mmol) and DIPEA (0.3 mL, 1.6 mmol). Reaction mixture was allowed to stir for couple of hours while allowing to worm to room temperature gradually. Upon completion, reaction mixture was diluted with ethyl acetate and washed with water and brine (2×20 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material which was purified by flash chromatography on silica gel (0-40% ethyl acetate in hexane) afforded the title compound (0.13 g). EXAMPLE B-28B N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-phenylacetamido)-N-((E)-4- methoxy-4-oxobut-2-enoyl)glycine (B-28) [0551] Following the procedure described in Example B-12C and using Example B-28A (0.13 g, 0.2 mmol) in place of Example B-12B the crude product was obtained. Purification of the residue by prep- HPLC using SunFire C18 (19 X 250) mm; 5 µM column and water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.003 g) at RT 19.28 min. EXAMPLE B-29 N-((2S)-1-((2-(2-acryloyl-2-(3,3,3-trifluoro-2-hydroxypropyl)hydrazineyl)-2-oxo-1- phenylethyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)-4-amino-3-chlorobenzamide
Figure imgf000260_0001
[0552] Reagents and conditions: (a) NMM, DMF, 100 °C, 2 h; (b) NaBH4, THF, MeOH, 50 °C, 3 h; (c) EDC, HOBt, DMF, 0 °C-rt, 6 h. EXAMPLE B-29A 4-Amino-3-chloro-N-((2S)-3,3-dimethyl-1-oxo-1-((2-oxo-1-phenyl-2-(2-(3,3,3-trifluoro-2- oxopropyl)hydrazineyl)ethyl)amino)butan-2-yl)benzamide [0553] To a stirred solution of Example B-1D (0.5 g, 1.2 mmol) in DMF (15 mL) was added 4- methylmorpholine (0.2 mL, 1.2 mmol). Reaction mixture was cooled to 0 °C and 3-bromo-1,1,1- trifluoropropan-2-one (0.3 mg, 1.5 mmol) was added slowly. After stirring the reaction mixture for 2 hours at 100 °C, it was diluted with ethyl acetate (25 mL) and washed consecutively with ice-cold water and brine (2×50 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-50% ethyl acetate in hexane) afforded the title compound (0.23 g). EXAMPLE B-29B 4-Amino-3-chloro-N-((2S)-3,3-dimethyl-1-oxo-1-((2-oxo-1-phenyl-2-(2-(3,3,3-trifluoro-2- hydroxypropyl)hydrazineyl)ethyl)amino)butan-2-yl)benzamide [0554] To a stirred solution of Example B-29A (0.23 g, 0.4 mmol) in THF (10 mL) was added sodium borohydride (0.03 g, 0.8 mmol). Reaction mixture was heated to 40 °C and methanol (1 mL) was added. Reaction was continued at the same temperature for 3 hours and upon completion, it was quenched by adding water (15 mL) and extracted with ethyl acetate (2×20 mL). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-50% ethyl acetate in hexane) afforded the title compound (0.16 g). EXAMPLE B-29C N-((2S)-1-((2-(2-acryloyl-2-(3,3,3-trifluoro-2-hydroxypropyl)hydrazineyl)-2-oxo-1-phenylethyl)amino)- 3,3-dimethyl-1-oxobutan-2-yl)-4-amino-3-chlorobenzamide (B-29) [0555] To a solution of prop-2-enoic acid (0.013 g, 0.2 mmol) in DMF (5 mL) at 0 ⁰C was added EDC (0.04 g, 0.2 mmol) and HOBt (0.3 g, 0.16 mmol). After 10 minutes Example B-29B (0.1 g, 0.16 mmol) was added to it. After 6 hours of stirring, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with ice-cold water and brine (2×15 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by prep-HPLC using XSelect C18 (19 X 250) mm; 5 µM column and 5mM ammonium acetate in water and MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.005 g) at RT 25.01 min. EXAMPLE B-30 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-fluoroacetyl)glycinate
Figure imgf000261_0001
[0556] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 4 h. [0557] Following the procedure described in Example B-5 and using Example B-16D (0.3 g, 0.5 mmol) in place of Example B-2B the crude product was obtained. Purification of the residue by prep-HPLC using X-Select C18 (19 X 250) mm; 5 µM column and 5 mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.022 g) at RT 19.34 min. EXAMPLE B-31 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-fluoroacetyl)glycinate
Figure imgf000262_0001
[0558] During the preparative HPLC purification of Example B-30, the title compound (0.025 g) was isolated at RT 20.32 min. EXAMPLE B-32 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000262_0002
[0559] Reagents and conditions: (a) EDCl, HOBt, DIPEA, DMF, 0 °C-rt, 14 h. [0560] Following the procedure described in Example B-7D and using Example B-16D (0.3 g, 0.5 mmol) in place of Example B-2A the crude product was obtained. Purification of the residue by prep- HPLC using X-Select C18 (19 X 250) mm; 5 µM column and water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.03 g) at RT 19.43 min. EXAMPLE B-33 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000263_0001
[0561] During the preparative HPLC purification of Example B-32, the title compound (0.035 g) was isolated at RT 21.62 min. EXAMPLE B-34 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-(perfluorophenoxy)acetyl)glycinate
Figure imgf000263_0002
[0562] Reagents and conditions: (a) (i) SOCl2, dioxane, 105 °C, 1 h, (ii) Et3N, CH2Cl2, rt, 16 h. [0563] Following the procedure described in Example B-9 and using Example B-16D (0.3 g, 0.5 mmol) in place of Example B-2A the crude product was obtained. Purification of the residue by prep-HPLC using X-Select C18 (19 X 250) mm; 5 µM column and 5 mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.01 g) at RT 20.44 min. EXAMPLE B-35 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-(perfluorophenoxy)acetyl)glycinate
Figure imgf000264_0001
[0564] During the preparative HPLC purification of Example B-34, the title compound (0.04 g) was isolated at RT 22.61 min. EXAMPLE B-36 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-(2,3,5,6-tetrafluorophenoxy)acetyl)glycinate
Figure imgf000264_0002
[0565] Reagents and conditions: (a) (i) SOCl2, dioxane, 105 °C, 1 h, (ii) Et3N, CH2Cl2, rt, 16 h. [0566] Following the procedure described in Example B-9 and using Example B-16D (0.3 g, 0.5 mmol) in place of Example B-2A the crude product was obtained. Purification of the residue by prep-HPLC using X-Select C18 (19 X 250) mm; 5 µM column and 5 mM ammonium acetate in water; MeCN as mobile phase (19 mL/ min flow rate) afforded the title compound (0.01 g) at RT 16.70 min. EXAMPLE B-37 Ethyl N-(2-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanamido)-2-(3- (trifluoromethyl)phenyl)acetamido)-N-(2-(2,3,5,6-tetrafluorophenoxy)acetyl)glycinate
Figure imgf000265_0001
[0567] During the preparative HPLC purification of Example B-36, the title compound (0.01 g) was isolated at RT 17.22 min. EXAMPLE B-38 Ethyl N-(1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)- N-((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000265_0002
[0568] Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C-rt, 14 h; (b) LiOH, THF/H2O (5:1), rt, 8 h; (c) Ethyl 2-hydrazinylacetate hydrochloride, HATU, DIPEA, DMF, 0 °C-rt, 14 h; (d) T3P, DIPEA, DMF, 0 °C-rt, 14 h. EXAMPLE B-38A Methyl ((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)-L-prolinate [0569] To a stirred solution of Example B-1B (4.0 g, 14.0 mmol) in N,N dimethyl formamide (20 mL) at 0 °C was added HATU (7.0 g, 18.0 mmol) and DIPEA (7.3 mL, 42.0 mmol). Subsequently after 10 minutes, methyl L-prolinate hydrochloride (2.6 g, 15.0 mmol) was added. Reaction was continued overnight at an ambient temperature until both the starting materials were consumed and upon completion the reaction mixture was diluted ethyl acetate (40 mL) and washed with water and brine (2×100 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-40% ethyl acetate in hexane) afforded the title compound (5.0 g). EXAMPLE B-38B ((S)-2-(4-Amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)proline [0570] To a stirred solution of Example B-38A (5.0 g, 12.6 mmol) in THF (50 mL) and water (10 mL) was added lithium hydroxide (1.1 g, 42.0 mmol). The reaction mixture was stirred at an ambient temperature for overnight, concentrated to a minimum volume, and the residue was diluted with water (10 mL). The pH of the aqueous phase was adjusted to 1 by the addition of HCl (aq) (1.0 M) resulting in a thick precipitate that was collected by filtration and dried to afford the title compound (4.0 g). EXAMPLE B-38C Ethyl (1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)pyrrolidine-2- carboxamido)glycinate [0571] To a stirred solution of Example B-38B (0.5 g, 1.3 mmol) in N,N dimethyl formamide (10 mL) at 0 °C was added HATU (0.75 g, 2.0 mmol) and DIPEA (0.7 mL, 4.0 mmol). Subsequently after 10 minutes, ethyl 2-hydrazinylacetate hydrochloride (0.3 g, 2.0 mmol) was added. Reaction was continued overnight at an ambient temperature until both the starting materials were consumed and upon completion the reaction mixture was diluted ethyl acetate (40 mL) and washed with water and brine (2×100 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by flash chromatography on silica gel (0-60% ethyl acetate in hexane) afforded the title compound (0.4 g). EXAMPLE B-38D Ethyl N-(1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)-N- ((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate (B-38) [0572] To a solution of Example B-38C (0.3 g, 0.6 mmol) in DMF (10 mL) at 0 ⁰C was added propylphosphonic anhydride (50% wt solution in ethyl acetate) (0.8 mL, 1.2 mmol) and DIPEA (0.3 mL, 1.8 mmol). After 10 minutes, Example B-7C (0.25 g, 1.2 mmol) was added to the solution. After overnight stirring, the reaction mixture was diluted with ethyl acetate (30.0 mL) and washed with ice- cold water and brine (2×50 mL each). Organic layer was separated, dried over sodium sulfate and concentrated in vacuo to get the crude material. Purification of the residue by prep-HPLC using X Select CSH C18 (19 X 250) mm; 5 µM column and 5 mM ammonium acetate in water and MeCN as mobile phase (19 mL/min flow rate) afforded the title compound (0.03 g) at RT 18.72 min. EXAMPLE B-39 Ethyl N-(1-((S)-2-(4-amino-3-chlorobenzamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamido)- N-((E)-4-(benzylamino)-4-oxobut-2-enoyl)glycinate
Figure imgf000267_0001
[0573] During the preparative HPLC purification of Example B-38D, the title compound (0.11 g) was isolated at RT 18.72 min. [0574] Data for select compounds is provided in the Table below:
Figure imgf000267_0002
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
BIOLOGICAL EXAMPLES [0575] IL-1, IL-18 and NLRP3 inflammasome activity regulates pyroptosis and promotes fibrosis. The IL-1β and IL-18 cause inflammation and kidney fibrosis. Inhibition of IL-1β and reversal of pyroptosis will block or reverse phenotypic changes associated with CKD. Direct correlation between inflammasome activation, including caspase-1, IL-1β and IL-18 and severity of proteinuria was observed in kidney patients. Pyroptosis is an inflammatory form of programmed cell death driven by inflammatory caspase-1, caspase-4 and caspase-5 in humans following infection or cellular damage. Biological Example 1: Human IL-1β ELISA Assay [0576] IL-1β release assay measures the levels of IL-1β secreted from the LPS and nigericin induced THP-1 cells. These inducers activate inflammasome pathway in THP-1 cells. Upon inflammasome activation, pro-caspase-1 is converted to caspase-1 which further processes pro-IL-1β to its bioactive IL- 1β that is secreted out of the cells. [0577] THP-1 cells stimulated with the LPS (Lipopolysaccharides from Escherichia coli O111:B4) and nigericin (Catalogue number N7143) were treated with compounds at various concentration doses and the inhibition of IL-1β levels secreted into the media supernatant is measured by ELISA (Human IL 1β ELISA kit Cat no: 557953; BD Biosciences). 20,000 cells per well of THP-1 were seeded in 35 µL RPMI media in a 384-well white plate.5 µL of test compound was added and incubated for 1hour. 5 µL of LPS (300 ng/mL) was added to the cells according to the plate map and the plate was incubated for 1 hour at 37 °C. 5 µL of Nigericin was added all the wells except control and blank wells, and it was incubated for 2 hours at 37°C. 25 µL of supernatant was transferred to 384 well plate. The plate was stored at -80 °C until further use. The absorbance was read at 450 nm within 30 minutes of stopping reaction. Biological Example 2: Pyroptosis Assay [0578] Pyroptosis assay measures the degree of Pyroptosis that occurs upon stimulation of THP-1 cells with LPS and nigercin. Pyroptosis is an inflammatory form of program cell death that depends on the formation of plasma membrane pores by members of the gasdermin (GSDM) protein family, as a consequence of caspase-1 activation via inflammasomes. Pyroptosis occurs as the result of membranous pore formation and cytoplasmic swelling, and leakage of cytosolic contents. [0579] THP-1 cells stimulated with the LPS (Lipopolysaccharides from Escherichia coli O111:B4) and nigericin (Catalogue number N7143) are treated with compounds at various concentration doses and the inhibition of pyroptosis is measured by evaluation of levels of cellular ATP as an indirect measure of cell viability using Cell-Titer-gloTM reagent. [0580] 20,000 cells per well of THP-1 were seeded in 35 µL RPMI media in a 384-well white plate. 5 µL of compound was added and incubated for 1 hour. 5 µL of LPS (300 ng/mL) was added to the cells according to the plate map and the plate was incubated for 1 hour at 37 °C.5 µL of Nigericin was added all the wells except control and blank wells, and it was incubated for 2 hours at 37 °C. After incubation, plate was brought to room temperature for 5 minutes. 25 µL of CellTiter-Glo was added and the plate was incubated for 30 minutes on plate shaker covered with aluminium foil (protected from light). Luminescence was recorded on Tecan Spark. Assay buffer was thawed and aliquots of appropriate volumes was stored in -20 °C Freezer. [0581] Activity of the tested compounds in the assays above is provided in Table 3 as follows: +++ = IC50 < 10 µM; ++ = IC5010 to < 30 µM; + = IC50 ≥ 30 µM; +* = IC50 > 11 µM. Table 3
Figure imgf000274_0001
Figure imgf000274_0002
Figure imgf000275_0002
Figure imgf000275_0001
[0582] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0583] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.
[0584] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.
[0585] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

What is claimed is: 1. A compound of Formula A-I:
Figure imgf000277_0001
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2; R1 is
Figure imgf000277_0003
Figure imgf000277_0004
R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R2’ is hydrogen, cyano, or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R3 is
Figure imgf000277_0002
R4 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R4’ is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; or R4 and R4’ together with the atom to which they are attached form a C3-10 cycloalkyl or heterocyclyl; wherein each is independently optionally substituted with one to six Z1a; R5 is hydrogen, halo, C1-6 alkyl, or C1-6 alkoxy; X is O or S; or R5 and X together with the atoms to which they are attached form a 5-membered heteroaryl; wherein the 5-membered heteroaryl is independently optionally substituted with one to six Z1a; each R6 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R6 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; R7 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R8 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R8 together with the nitrogen atom to which they are attached form a heterocyclyl; which is optionally substituted with one to six Z1a; each R9 is independently halo, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR10, -N(R10)2, -C(O)R10, -C(O)OR10, -OC(O)R10, -C(O)N(R10)2, -NR10C(O)R10, -OC(O)N(R10)2, -NR10C(O)OR10, -S(O)0-2R10, -NR10S(O)1-2R10, -NR10C(O)N(R10)2, or -NR10S(O)1-2N(R10)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R10 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; R11 is hydrogen, fluoro, chloro, cyano, -CF3, or aryl; wherein the aryl is independently optionally substituted with one to five halo; R12 is hydrogen, fluoro, chloro, cyano, -CF3, aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R13 is C1-6 alkyl, -C(O)OR8, or -C(O)N(R8)2; each R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -OC(O)NH-, -OC(O)N(C1-6 alkyl)-, -OC(O)N(C2-6 alkenyl)-, -OC(O)N(C2-6 alkynyl)-, -OC(O)N(C1-6 haloalkyl)-, -OC(O)N(C3-10 cycloalkyl)-, -OC(O)N(heterocyclyl)- , -OC(O)N(aryl)-, -OC(O)N(heteroaryl)-, -NHC(O)-, -N(C1-6 alkyl)C(O)-, -N(C2-6 alkenyl)C(O)-, -N(C2-6 alkynyl)C(O)-, -N(C1-6 haloalkyl)C(O)-, -N(C3-10 cycloalkyl)C(O)-, -N(heterocyclyl)C(O)-, -N(aryl)C(O)-, -N(heteroaryl)C(O)-, -NHC(O)O-, -N(C1-6 alkyl)C(O)O-, -N(C2-6 alkenyl)C(O)O-, -N(C2-6 alkynyl)C(O)O-, -N(C1-6 haloalkyl)C(O)O-, -N(C3-10 cycloalkyl)C(O)O-, -N(heterocyclyl)C(O)O- , -N(aryl)C(O)O-, -N(heteroaryl)C(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)NH-, -S(O)2NH-, - NHS(O)NH-, or -NHS(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b and L is further independently optionally substituted with one to six halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
2. The compound of claim 1, wherein the compound is represented by Formula A-II:
Figure imgf000280_0001
.
3. The compound of claim 1 or 2, wherein the compound is represented by Formula A-IIA:
Figure imgf000280_0002
.
4. The compound of any one of claims 1-3, wherein R11 is hydrogen or fluoro.
5. The compound of claim 1 or 2, wherein the compound is represented by Formula A-IIB:
Figure imgf000280_0003
.
6. The compound of claim 1, 2, or 4, wherein R12 is fluoro, chloro, cyano, or -O-aryl optionally substituted with one to five halo.
7. The compound of claim 6, wherein R12 is fluoro.
8. The compound of claim 6, wherein R12 is -O-aryl optionally substituted with one to five halo.
9. The compound of claim 8, wherein R12 is
Figure imgf000280_0005
,
10. The compound of claim 1 or 2, wherein the compound is represented by Formula A-IIC:
Figure imgf000280_0004
.
11. The compound of claim 1 or 10, wherein R13 is -C(O)N(R8)2.
12. The compound of claim 1 or 10, wherein R13 is -C(O)NHR8.
13. The compound of claim 12, wherein R13 is
Figure imgf000281_0003
14. The compound of any preceding claim, wherein R2 is C1-6 alkyl substituted with -C(O)OC1- 6 alkyl.
15. The compound of any preceding claim, wherein R2 is C1-6 alkyl substituted with -C(O)OC2 alkyl.
16. The compound of any preceding claim, wherein R2 is -CH2C(O)OC2 alkyl.
17. The compound of claim 1 or 2, wherein the moiety
Figure imgf000281_0002
is:
Figure imgf000281_0001
18. The compound of claim 1, wherein the compound is represented by Formula A-III:
Figure imgf000282_0001
19. The compound of claim 1, wherein the compound is represented by Formula A-IIIA:
Figure imgf000282_0002
20. The compound of claim 1, wherein the compound is represented by Formula A-IV:
Figure imgf000282_0003
21. The compound of claim 1, wherein the compound is represented by Formula A-IVA:
Figure imgf000282_0004
22. The compound of claim 1, wherein the compound is represented by Formula A-IVB:
Figure imgf000282_0005
23. The compound of claim 1, wherein the compound is represented by Formula A-IVC:
Figure imgf000282_0006
24. The compound of any one of claims 1, or 21-23, wherein R7 is hydrogen or C1-6 alkyl.
25. The compound of any one of claims 1, or 21-23, wherein R7 is ethyl.
26. The compound of any preceding claim, wherein R5 is hydrogen and X is O or S.
27. The compound of any preceding claim, wherein the compound is represented by Formula A-VA:
Figure imgf000283_0001
.
28. The compound of any one of claims 1-25, wherein R5 and X together with the atoms to which they are attached form a 5-membered heteroaryl.
29. The compound of claim 28, wherein the compound is represented by Formula A-VIB:
Figure imgf000283_0002
.
30. The compound of any preceding claim, wherein R4 is C1-6 alkyl optionally substituted by phenyl.
31. The compound of any preceding claim, wherein R4 is methyl, ethyl, isopropyl, or benzyl.
32. The compound of any preceding claim, wherein n is 2.
33. The compound of any preceding claim, wherein each R6 is independently halo or -N(R16)2.
34. The compound of any preceding claim, wherein each R6 is independently chloro or -NH2.
35. A compound of Formula B-I:
Figure imgf000283_0003
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, 4, or 5; R1 is
Figure imgf000283_0004
R11 is hydrogen, fluoro, chloro, cyano, -CF3, or aryl; wherein the aryl is independently optionally substituted with one to five halo; R12 is hydrogen, fluoro, chloro, cyano, -CF3, aryl, or -O-aryl; wherein the aryl or -O-aryl is independently optionally substituted with one to five halo; R13 is C1-6 alkyl, -C(O)OR8, or -C(O)N(R8)2; R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, -C(O)OC1-6 alkyl, and tetrazolyl, wherein each -C(O)OC1-6 alkyl or tetrazolyl is independently optionally substituted with one to five Z1a; R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; R4 is
Figure imgf000284_0001
wherein m is 0, 1, 2, 3, 4, or 5; or R3 and R4 together with the atoms to which they are attached form a ring selected from
Figure imgf000284_0002
wherein each is optionally substituted by oxo or a C3-6 spirocycle; R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R6 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NR16C(O)R16, -OC(O)N(R16)2, -NR16C(O)OR16, -S(O)0-2R16, -NR16S(O)1-2R16, -NR16C(O)N(R16)2, or -NR16S(O)1-2N(R16)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R6 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R7 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR17, -N(R17)2, -C(O)R17, -C(O)OR17, -OC(O)R17, -C(O)N(R17)2, -NR17C(O)R17, -OC(O)N(R17)2, -NR17C(O)OR17, -S(O)0-2R17, -NR17S(O)1-2R17, -NR17C(O)N(R17)2, or -NR17S(O)1-2N(R17)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; or two R5 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R8 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, -NO2, -OR10, -N(R10)2, -C(O)R10, -C(O)OR10, -OC(O)R10, -C(O)N(R10)2, -NR10C(O)R10, -OC(O)N(R10)2, -NR10C(O)OR10, -S(O)0-2R10, -NR10S(O)1-2R10, -NR10C(O)N(R10)2, or -NR10S(O)1-2N(R10)2; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R10 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1b; each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with one to six Z1a; each Z1b is independently halo, cyano, -OH, -SH, -NH2, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N(C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C1-6 alkyl)-, -C(O)N(C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C3-10 cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -OC(O)NH-, -OC(O)N(C1-6 alkyl)-, -OC(O)N(C2-6 alkenyl)-, -OC(O)N(C2-6 alkynyl)-, -OC(O)N(C1-6 haloalkyl)-, -OC(O)N(C3-10 cycloalkyl)-, -OC(O)N(heterocyclyl)- , -OC(O)N(aryl)-, -OC(O)N(heteroaryl)-, -NHC(O)-, -N(C1-6 alkyl)C(O)-, -N(C2-6 alkenyl)C(O)-, -N(C2-6 alkynyl)C(O)-, -N(C1-6 haloalkyl)C(O)-, -N(C3-10 cycloalkyl)C(O)-, -N(heterocyclyl)C(O)-, -N(aryl)C(O)-, -N(heteroaryl)C(O)-, -NHC(O)O-, -N(C1-6 alkyl)C(O)O-, -N(C2-6 alkenyl)C(O)O-, -N(C2-6 alkynyl)C(O)O-, -N(C1-6 haloalkyl)C(O)O-, -N(C3-10 cycloalkyl)C(O)O-, -N(heterocyclyl)C(O)O- , -N(aryl)C(O)O-, -N(heteroaryl)C(O)O-, -NHC(O)NH-, -NHS(O)-, -S(O)NH-, -S(O)2NH-, - NHS(O)NH-, or -NHS(O)2NH-; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1b and L is further independently optionally substituted with one to six halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
36. The compound of claim 35, wherein the compound is represented by Formula B-II:
Figure imgf000286_0001
.
37. The compound of claim 35 or 36, wherein R11 is hydrogen or fluoro.
38. The compound of claim 35, wherein the compound is represented by Formula B-III:
Figure imgf000286_0002
.
39. The compound of claim 35 or 38, wherein R12 is fluoro, chloro, cyano, or -O-aryl optionally substituted with one to five halo.
40. The compound of claim 35 or 38, wherein R12 is fluoro, chloro, or cyano.
41. The compound of claim 35 or 38, wherein R12 is -O-aryl optionally substituted with one to five halo.
42. The compound of claim 41, wherein R12 is
Figure imgf000286_0004
43. The compound of claim 35, wherein the compound is represented by Formula B-IV:
Figure imgf000286_0003
.
44. The compound of claim 35 or 43, wherein R13 is -C(O)OR8 or -C(O)N(R8)2.
45. The compound of claim 35 or 43, wherein R13 is -C(O)OR8 or -C(O)NHR8.
46. The compound of claim 45, wherein R13 is -C(O)OCH3 or
Figure imgf000287_0002
47. The compound of any one of claims 35-46, wherein R2 is hydrogen or C1-6 alkyl substituted with one to six substituents independently selected from halo, hydroxy, -C(O)OH, and -C(O)OC1-6 alkyl.
48. The compound of any one of claims 35-47, wherein R2 is hydrogen or C1-6 alkyl substituted with -CH(OH)(CF3), -C(O)OH, or -C(O)OC2 alkyl.
49. The compound of any one of claims 35-48, wherein R2 is hydrogen, -CH2CH(OH)(CF3), -CH2C(O)OH, or -CH2C(O)OC2 alkyl.
50. The compound of any one of claims 35-49, wherein the moiety
Figure imgf000287_0003
is:
Figure imgf000287_0001
51. The compound of any one of claims 35-50, wherein R3 is hydrogen.
52. The compound of any one of claims 35-51, wherein R3 is hydrogen and R4 is
Figure imgf000288_0005
or
Figure imgf000288_0001
, wherein m is 0 or 1.
53. The compound of any one of claims 35-52, wherein m is 0 or 1, and R7 is C1-6 haloalkyl.
54. The compound of any one of claims 35-50, wherein R3 and R4 together with the atoms to which they are attached form a ring selected from
Figure imgf000288_0002
,
Figure imgf000288_0003
; wherein each is optionally substituted by oxo or a C3-6 spirocycle.
55. The compound of claim 54, wherein R3 and R4 together with the atoms to which they are attached form a
Figure imgf000288_0004
56. The compound of any one of claims 35-55, wherein n is 2. 57. The compound of any one of claims 35-56, wherein each R6 is independently halo or -N(R16)2. 58. The compound of any one of claims 35-57, wherein each R6 is independently chloro or -NH2. 59. The compound of any one of claims 35-58, wherein R5 is C1-6 alkyl. 60. The compound of any one of claims 35-59, wherein R5 is tert-butyl.61. A compound of Table A-1, Table A-2, Table B-1, or Table B-2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. 62. A pharmaceutical composition comprising a compound of any preceding claim, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof and a pharmaceutically acceptable excipient. 63. A method for treating a disease or condition mediated, at least in part, by caspase-1, the method comprising administering an effective amount of a compound of any one of claims 1-61, or the pharmaceutical composition of claim 62 to a subject in need thereof. 64. A method for treating a chronic or acute form of an IL-1-mediated, apoptosis-mediated, IL-18- mediated, IFN-γ-mediated disease, an inflammatory disease, an autoimmune disease, a destructive bone disease, a proliferative disease, an infectious disease, or a degenerative disease, comprising administering an effective amount of a compound of any one of claims 1-61, or the pharmaceutical composition of claim 62 to a subject in need thereof. 65. The method of claim 63, wherein the disease is chronic kidney disease, diabetic nephropathy, IgA nephropathy, uveitis, an excess dietary alcohol intake disease, a necrotic disease, a viral mediated disease, inflammatory peritonitis, osteoarthritis, pancreatitis (e.g., acute pancreatitis or chronic pancreatitis), asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, diabetes (e.g., juvenile diabetes, insulin-dependent diabetes mellitus (Type I)), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn’s disease, psoriasis, atopic dermatitis, scarring, graft vs. host disease, organ transplant rejection, osteoporosis, multiple myeloma-related bone disorder, leukemias and related disorders, myelodysplastic syndrome, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi’s sarcoma, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Kennedy’s disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute or chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, coronary artery bypass graft, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV- or AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, various forms of liver disease, infectious hepatitis, hepatitis-B, hepatitis- C, hepatitis-G, yellow fever, dengue fever, Japanese encephalitis, lichenplanus, acute dermatomyositis, eczema, primary cirrhosis, Behcet’s disease, atopic skin disease, pure red cell aplasia, aplastic anemia, nephrotic syndrome, renal disease, renal tubulointerstitial fibrosis, neointimal hyperplasia (NH) in the arteries, polyaptic kidney disease, H. pylori-associated gastric and duodenal ulcer disease, HIV infection, tuberculosis, or meningitis. 66. The method of claim 63, wherein the disease is chronic kidney disease. 67. Use of a compound of any one of claims 1-61, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for treating a disease or condition mediated, at least in part, by caspase-1. 68. Use of a compound of any one of claims 1-61, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for treating chronic kidney disease. 69. A compound of any one of claims 1-61, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in therapy. 70. A compound of any one of claims 1-61, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating chronic kidney disease.
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