WO2025007743A1 - Agonistes de sting et leurs utilisations - Google Patents

Agonistes de sting et leurs utilisations Download PDF

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Publication number
WO2025007743A1
WO2025007743A1 PCT/CN2024/099995 CN2024099995W WO2025007743A1 WO 2025007743 A1 WO2025007743 A1 WO 2025007743A1 CN 2024099995 W CN2024099995 W CN 2024099995W WO 2025007743 A1 WO2025007743 A1 WO 2025007743A1
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alkyl
compound
pharmaceutically acceptable
acceptable salt
heteroalkyl
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Yingdong Lu
Zichun ZHANG
Xiaohe SHI
Yu Shen
Jiani Yu
Mao Yin
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PrimeLink BioTherapeutics Shenzhen Co Ltd
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PrimeLink BioTherapeutics Shenzhen Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure generally relates to compounds or pharmaceutically acceptable salts thereof that may be useful as Stimulator of Interferon Genes (STING) agonists to active the STING pathway.
  • STING Stimulator of Interferon Genes
  • the present disclosure also relates to the synthesis process of such compounds and the use of such compounds for the treatment of diseases, such as cancers.
  • cGAS cyclic GMP-AMP synthase
  • STING Stimulator of Interferon Genes
  • IFN type I interferon
  • CDNs natural STING agonists
  • novel compounds that are capable of inducing the STING pathway.
  • the compounds of the present disclosure are useful in the activation of innate immune responses and the treatment of various diseases, including but not limited to cancer, viral infections, and autoimmune disorders.
  • the present disclosure provides a compound ofFormula (I) :
  • each A is independently selected from CH and N;
  • each of X 1 and X 3 is independently selected from the group consisting of a bond, -O-, -N (R a ) -, -S-, and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano or amino;
  • X 2 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b ;
  • L 1 is selected from the group consisting of a bond, -C (O) -, -S (O) -, -S (O) 2 -, and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b ;
  • L 2 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more groups independently selected from halogen, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, -N (R a ) 2 , or -OR b ;
  • L 3 is selected from the group consisting of hydrogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -C (O) SR b , -C (S) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) S (O) 2 R b , -S (O) 2 N (R a ) 2 , -OC (O) N (R a ) 2 , -N (R a ) C (O) OR b , -N (R a ) C (O) N (R a ) 2 , -N (R a ) C (O) OR b
  • L 4 is selected from the group consisting of heterocyclyl, heteroaryl, -C (O) N (R a ) S (O) -, -C (O) N (R a ) S (O) 2 -, -S (O) -, -S (O) 2 -and -C (O) N (R a ) -;
  • L 5 is selected from the group consisting of a bond, alkyl, -N (R a ) -alkyl-, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, and heterocyclylalkyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, and heterocyclylalkyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkyl, -N (R a ) 2 , or -OR b ;
  • L 6 is selected from the group consisting of hydrogen, cyano, -OR b , -SR, -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -C (O) SR b , -C (S) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) SO 2 -, -SO 2 N (R a ) 2 , -O-C (O) N (R a ) 2 , -N (R a ) C (O) OR b , -N (R a ) C (O) N (R a ) 2 , -N (R a ) S (O) 2 N (R a ) 2 , alky
  • each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) SO 2 -, -SO 2 N (R a ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl
  • each of R a and R b is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, wherein the alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl and heterocyclylalkyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino; and
  • n are each independently an integer selected from 0, 1, 2, 3 or 4.
  • the present disclosure provides a compound of Formula (IV) :
  • each A is independently selected from CH and N;
  • each of X 1 and X 3 is independently selected from the group consisting of a bond, -O-, -N (R a ) -, -S-, and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano or amino;
  • X 2 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b ;
  • L 1 is selected from the group consisting of a bond, -C (O) -, -S (O) -, -S (O) 2 -, and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b ;
  • L 2 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more groups independently selected from halogen, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, -N (R a ) 2 , or -OR b ;
  • L 3 is selected from the group consisting of hydrogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -C (O) SR b , -C (S) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) S (O) 2 R b , -S (O) 2 N (R a ) 2 , -OC (O) N (R a ) 2 , -N (R a ) C (O) OR b , -N (R a ) C (O) N (R a ) 2 , -N (R a ) C (O) OR b
  • L 7 is selected from the group consisting of a bond, -O-, -S-, -N (R a ) -, -C (O) -, -C (O) N (R a ) -, -N (R a ) C (O) -, -S (O) -, -S (O) 2 -, -N (R a ) S (O) 2 -, -S (O) 2 N (R a ) -, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, and heterocyclylalkyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,
  • L 8 is selected from the group consisting of a bond, alkyl, -N (R a ) -alkyl-, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cyclylalkyl, heterocyclylalkyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cyclylalkyl, heterocyclylalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , aryl, or -OR b ;
  • L 9 is selected from the group consisting of hydrogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -C (O) SR b , -C (S) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) S (O) 2 R b , -S (O) 2 N (R a ) 2 , -OC (O) N (R a ) 2 , -N (R a ) C (O) OR b , -N (R a ) C (O) N (R a ) 2 , -N (R a ) C (O) OR b
  • each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) SO 2 -, -SO 2 N (R a ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl
  • each of R a and R b is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, wherein the alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl and heterocyclylalkyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino; and
  • n is an integer selected from 0, 1, 2, 3, 4, 5, or 6, and
  • n is an integer selected from 0, 1, 2, 3 or 4.
  • the present disclosure provides a compoundor a pharmaceutically acceptable salt thereof, wherein the compound is selected from a group consisting of:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method ofinducing an immune response in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.
  • the present disclosure provides a method of inducing STING-dependent type I interferon production in a subject in need thereof, comprising administering to the subject an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure to the subject.
  • the present disclosure provides inducing STING-dependent cytokine production in a subject in need thereof, comprising administering to the subject an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure to the subject.
  • the present disclosure provides a method of treating a STING mediated disorder comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating STING mediated disorders.
  • the present disclosure provides a compound of present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for use in the treatment of STING mediated disorder.
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • a dash “-” at the front or end of a chemical group is used, a matter of convenience, to indicate a point of attachment for a substituent.
  • -OH is attached through the oxygen atom; chemical groups may be depicted with or without oneor more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom.
  • ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.
  • the term “compounds provided herein” , or “compounds disclosed herein” or “compounds of the present disclosure” refers to the compounds of Formula (I) , (II) , (III) and (IV) as well as the specific compounds disclosed herein.
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers, and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • alkyl refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms.
  • alkyl groups contain 1 to 10 carbon atoms.
  • alkyl groups contain 1 to 9 carbon atoms.
  • alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-10 alkyl examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • C 1-6 alkyl are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.
  • alkenyl refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms.
  • alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms.
  • alkenyl group include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.
  • alkynyl refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms.
  • alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms.
  • alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom.
  • C i-j alkoxy means that the alkyl moiety of the alkoxy group has i to j carbon atoms.
  • alkoxy groups contain 1 to 10 carbon atoms.
  • alkoxy groups contain 1 to 9 carbon atoms.
  • alkoxy groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy) , t-butoxy, neopentoxy, n-hexoxy, and the like.
  • amino refers to —NH 2 group. Amino groups may also be substituted with one or more groups such as alkyl, alkenyl, alkynyl, aryl, carbonyl or other amino groups.
  • aryl refers to a monocyclic or polycyclic ring system having a total of 5 to 20 ring members, which may be optionally substituted independently with one or more substituents described below, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members.
  • substituents include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more additional rings.
  • polycyclic ring system In the case of polycyclic ring system, only one of the rings needs to be aromatic (e.g., 2, 3-dihydroindole) , although all of the rings may be aromatic (e.g., quinoline) .
  • the second ring can also be fused or bridged.
  • polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • Aryl groups can be substituted at one or more ring positions with substituents as described below.
  • cyano refers to —CN.
  • cycloalkyl refers to a non-aromatic, saturated or partially unsaturated monocyclic or polycyclic ring system optionally substituted independently with one or more substituents described below, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms.
  • the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms.
  • Cycloalkyl groups may be saturated or partially unsaturated.
  • the cycloalkyl group may be a saturated cyclic alkyl group.
  • the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system.
  • the cycloalkyl group may be monocyclic or polycyclic. In the case of polycyclic ring system, the fused, spiro and bridged ring systems are included within the scope of this definition.
  • Examples of monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • polycyclic cycloalkyl group examples include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decanyl, bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, and the like.
  • cycloalkylalkyl refers to cycloalkyl-alkyl which is attached to the parent molecule through its alkyl group.
  • halogen refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • haloalkyl group include, but are not limited to, trifluoromethyl (-CF 3 ) , pentafluoroethyl (-C 2 F 5 ) , difluoromethyl (-CHF 2 ) , trichloromethyl (-CCl 3 ) , dichloromethyl (-CHCl 2 ) , pentachloroethyl (-C 2 Cl 5 ) , and the like.
  • heteroatom refers to nitrogen, oxygen, sulfur, phosphorus, and includes any oxidized form of nitrogen, sulfur or phosphorus, and any quaternized form of a basic nitrogen (including N-oxides) .
  • heteroalkyl refers to an alkyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkyl encompasses alkoxy and heteroalkoxy radicals.
  • heteroalkenyl refers to an alkenyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkenyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroalkynyl refers to an alkynyl, at least one of the carbon atoms of which is replaced with a heteroatom selected from N, O, or S.
  • the heteroalkynyl may be a carbon radical or heteroatom radical (i.e., the heteroatom may appear in the middle or at the end of the radical) , and may be optionally substituted independently with one or more substituents described herein.
  • heteroaryl refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms, wherein one or more ring atoms may be optionally substituted independently with one or more substituents.
  • the heteroaryl group can be monocyclic.
  • Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • the heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • polycyclic heteroaryl include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1, 3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl
  • heterocyclyl refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl may contains any oxidized form of carbon, nitrogen, sulfur or phoshporus, and any quaternized form of a basic nitrogen.
  • “Heterocyclyl” also includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring.
  • the heterocyclyl radical may be carbon linked or nitrogen linked where such is possible.
  • the heterocycle is carbon linked.
  • the heterocycle is nitrogen linked.
  • a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) .
  • a group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked) .
  • the term “3-to 12-membered heterocyclyl” refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, sulfur or phosphorus.
  • polycyclic ring system the fused, spiro and bridged ring systems are also included within the scope of this definition.
  • monocyclic heterocyclyl examples include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.
  • fused heterocyclyl examples include, but are not limited to, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, hexahydro-1H-pyrrolizinyl, imidazo [1, 2-a] pyridinyl, [1, 2, 4] triazolo [4, 3- a] pyridin
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, 2, 6-diazaspiro [3.3] heptanyl, 2, 5-diazaspiro [3.4] octanyl, 2, 6-diazaspiro [3.4] octanyl, 2, 7-diazaspiro [3.5] nonanyl, 5-oxa-2, 8-diazaspiro [3.5] nonanyl, 2, 7-diazaspiro [4.4] nonanyl, 1, 7-diazaspiro [3.5] nonanyl, 2, 8-diazaspiro [4.5] decanyl, 2, 8-diazaspiro [4.5] decanyl, and the like.
  • bridged heterocyclyl examples include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo [3.1.0] hexane, 3, 6-diazabicyclo [3.1.1] heptane, 2, 5-diazabicyclo [2.2.1] heptane, 8-aza-bicyclo [3.2.1] octane, 3-azabicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane, 3-azabicyclo [3.2.2] nonane, and the like.
  • heterocyclylalkyl refers to heterocyclyl-alkyl which is attached to the parent molecule through its alkyl group.
  • hydroxyl or “hydroxy” refers to —OH.
  • partially unsaturated refers to a radical that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • one or more item includes a single item selected from the list as well as mixtures of two or more items from the list.
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the said event or circumstance occurs and instances in which it does not.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the substituents may include, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted” , references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the present disclosure provides compounds of Formula (I) :
  • each A is independently selected from CH and N;
  • each of X 1 and X 3 is independently selected from the group consisting of a bond, -O-, -N (R a ) -, -S-, and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano or amino;
  • X 2 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b ;
  • L 1 is selected from the group consisting of a bond, -C (O) -, -S (O) -, -S (O) 2 -, and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b ;
  • L 2 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more groups independently selected from halogen, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, -N (R a ) 2 , or -OR b ;
  • L 3 is selected from the group consisting of hydrogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -C (O) SR b , -C (S) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , - N (R a ) S (O) 2 R b , -S (O) 2 N (R a ) 2 , -OC (O) N (R a ) 2 , -N (R a ) C (O) OR b , -N (R a ) C (O) N (R a ) 2 , -N (R a ) S (O) 2 N (R
  • L 4 is selected from the group consisting of heterocyclyl, heteroaryl, -C (O) N (R a ) S (O) -, -C (O) N (R a ) S (O) 2 -, -S (O) -, -S (O) 2 -and -C (O) N (R a ) -;
  • L 5 is selected from the group consisting of a bond, alkyl, -N (R a ) -alkyl-, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, and heterocyclylalkyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, and heterocyclylalkyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkyl, -N (R a ) 2 , or -OR b ;
  • L 6 is selected from the group consisting of hydrogen, cyano, -OR b , -SR, -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -C (O) SR b , -C (S) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) SO 2 -, -SO 2 N (R a ) 2 , -O-C (O) N (R a ) 2 , -N (R a ) C (O) OR b , -N (R a ) C (O) N (R a ) 2 , -N (R a ) S (O) 2 N (R a ) 2 , alky
  • each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) SO 2 -, -SO 2 N (R a ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl
  • each of R a and R b is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, wherein the alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl and heterocyclylalkyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino; and
  • n are each independently an integer selected from 0, 1, 2, 3 or 4.
  • each A is independently CH or N.
  • each A is independently CH or N.
  • each is independently
  • both are identical to each other.
  • L 1 to L 6 , X 1 to X 3 , R 1 and R 2 are as defined supra.
  • L 1 is -C (O) -.
  • L 2 is alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • L 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • L 2 is butyl. In centain embodiments, L 2 is
  • L 3 is -C (O) OR b .
  • R b is hydrogen or alkyl.
  • R b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R b is methyl.
  • L 1 is -C (O) -and L 2 is alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • L 1 is -C (O) -
  • L 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • L 1 is -C (O) -
  • L 2 is butyl, preferably
  • L 1 is -C (O) -
  • L 2 is alkyloptionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b
  • L 3 is -C (O) OR b .
  • L 1 is -C (O) -
  • L 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each of which is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b
  • L 3 is -C (O) OR b , wherein R b is hydrogen or alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) .
  • one of X 1 and X 3 is a bond, and the other is -O-.
  • both X 1 and X 3 are bond or -O-.
  • X 2 is alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • X 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • X 2 is propyl.
  • one of X 1 and X 3 is a bond, and the other is -O-, and X 2 is alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • alkyl such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl
  • both X 1 and X 3 are bond or -O-, and X 2 is alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • alkyl such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl
  • each of R 1 and R 2 is independently hydrogen, halogen or alkoxy. In certain embodiments, each of R 1 and R 2 is independently F, Cl, Br, I, C 1-6 alkoxy, C 1-5 alkoxy, C 1-4 alkoxy, C 1-3 alkoxy or C 1-2 alkoxy. In certain embodiments, each of R 1 and R 2 is independently F, Cl, methoxy, ethoxy, propoxy, butoxy or pentoxy.
  • each of R 1 andR 2 is independently F or methoxy.
  • m is 1 or 2.
  • n is 2.
  • m is 1 or 2
  • n is 2
  • each of R 1 andR 2 is independently F or methoxy.
  • L 1 to L 6 , X 1 to X 3 , R 1 , R 2 and R b are as defined supra.
  • R 1 is selected from hydrogen, halogen, alkyl, heteroalkyl or -OR b . In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is selected from F, Cl, Br and I. In certain embodiments, R 1 is F. In certain embodiments, R 1 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R 1 is heteroalkyl is C 1-6 heteroalkyl, C 1-5 heteroalkyl, C 1-4 heteroalkyl, C 1-3 heteroalkyl or C 1-2 heteroalkyl.
  • each of R 3 and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, or -OR b .
  • both R 3 and R 4 are hydrogen.
  • one of R 3 and R 4 is hydrogen, and the other is selected from alkyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, or -OR b , and R b is hydrogen or alkyl.
  • each of R 3 and R 4 is independently alkyl. In certain embodiment, each of R 3 and R 4 is independently C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiment, bothR 3 and R 4 are methyl.
  • each of R 3 and R 4 is independently C 1-6 heteroalkyl, C 1-5 heteroalkyl, C 1-4 heteroalkyl, C 1-3 heteroalkyl or C 1-2 heteroalkyl. In certain embodiments, each of R 3 and R 4 is independently C 3-13 cycloalkylalkyl, C 3-12 cycloalkylalkyl, C 3-11 cycloalkylalkyl, C 3-10 cycloalkylalkyl or C 3-9 cycloalkylalkyl.
  • each of R 3 and R 4 is independently heterocyclylalkyl.
  • R b is hydrogen. In some embodiments, R b is alkyl. In certain embodiments, R b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R b is methyl.
  • L 4 is heterocyclyl or heteroaryl. In certain embodiments, L 4 is heterocyclyl or heteroaryl containing one or more heteroatoms selected from N, O or S. In certain embodiments, L 4 is 3-12 membered heterocyclyl or heteroaryl, 3-11 membered heterocyclyl or heteroaryl, 3-10 membered heterocyclyl or heteroaryl, 3-9 membered heterocyclyl or heteroaryl, 3-8 membered heterocyclyl or heteroaryl, 3-7 membered heterocyclyl or heteroaryl, 3-6 membered heterocyclyl or heteroaryl, 3-5 membered heterocyclyl or heteroaryl or 5-6 membered heterocyclyl or heteroaryl.
  • the compoundprovided herein is presented by formula (IIIa) :
  • R b is hydrogen or alkyl; and Ring A is 5-to 6-membered heterocyclyl or heteroaryl.
  • Ring A is selected from the group consisting ofpyridinyl, pyrazinyl, oxazolyl, oxadiazolyl, thiazoyly, thiadiazolyl, and triazolyl.
  • Ring A is selected from the group consisting of:
  • R b is hydrogen. In some embodiments, R b is alkyl. In certain embodiments, R b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R b is methyl.
  • L 5 is a bond
  • L 5 is alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkyl, -N (R a ) 2 , or -OR b .
  • L 5 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkyl, -N (R a ) 2 , or -OR b .
  • R a is hydrogen or alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino. In certain embodiments, R a is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • L 5 is methyl
  • L 6 is -C (O) OR b . In certain embodiments, L 6 is -C (O) OR b , and R b is hydrogen. In certain embodiments, L 6 is -C (O) OR b and R b is alkyl. In certain embodiments, L 6 is -C (O) OR b and R b isC 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • L 5 is a bond
  • L 6 is -C (O) OR b .
  • L 5 is a bond
  • L 6 is -C (O) OH, -C (O) OCH 3 or -C (O) OCH 2 CH 3 .
  • L 4 is -C (O) N (R a ) S (O) -or -C (O) N (R a ) S (O) 2 -.
  • L 4 is -C (O) N (R a ) S (O) -or -C (O) N (R a ) S (O) 2 -
  • R a is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkylalkyl, or heterocyclylalkyl, wherein the alkyl, heteroalkyl, cycloalkylalkyl and heterocyclylalkyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino.
  • R a is hydrogen or alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino.
  • R a is hydrogen. In certain embodiments, R a is C 1-6 alkyl, C 1- 5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R a is methyl.
  • the compound provided herein is presented by the formula (IIIb) :
  • R b is hydrogen or alkyl; and R a is hydrogen or alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino.
  • R b is hydrogen. In some embodiments, R b is alkyl. In certain embodiments, R b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R b is methyl.
  • L 5 is a bond
  • L 6 is selected from alkyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl or -OR b .
  • L 6 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, L 6 is methyl.
  • L 6 is -OR b
  • R b is hydrogen or alkyl.
  • R b is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • L 6 is OH or methyl.
  • the compound provided herein is presented by the formula (IIIc) or (IIId) :
  • R b is hydrogen or alkyl
  • R b is hydrogen. In some embodiments, R b is alkyl. In certain embodiments, R b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R b is methyl.
  • L 5 is alkyl or -N (R a ) -alkyl-.
  • L 5 is alkyl. In certain embodiments, L 5 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, L 5 is methyl or ethyl.
  • L 5 is -N (R a ) -alkyl-. In certain embodiments, L 5 is-N (R a ) - (C 1- 6 alkyl) , -N (R a ) - (C 1-5 alkyl) , -N (R a ) - (C 1-4 alkyl) , -N (R a ) - (C 1-3 alkyl) or -N (R a ) - (C 1-2 alkyl) . In certain embodiments, R a is hydrogen or alkyl. In certain embodiments, R a is hydrogen. In certain embodiments, R a is methyl, ethyl, propyl, butyl, pentyl or hexyl.
  • L 5 is -NH-CH (CH 3 ) -.
  • L 6 is -C (O) OR b .
  • L 6 is -C (O) OR b
  • R b is hydrogen or alkyl.
  • R b is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • L 6 is -C (O) OH, -C (O) OCH 3 or -C (O) OCH 2 CH 3 .
  • L 5 is alkyl or -N (R a ) -alkyl-, and L 6 is -C (O) OR b .
  • L 5 is C 1-3 alkyl or -N (R a ) - (C 1-3 alkyl) -, and L 6 is -C (O) OR b .
  • L 5 is methyl, ethyl or -NH-CH (CH 3 ) -, and L 6 is -C (O) OH, -C (O) OCH 3 or -C (O) OCH 2 CH 3 .
  • L 4 is -C (O) N (R a ) -.
  • L 4 is -C (O) N (R a ) -
  • R a is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkylalkyl, or heterocyclylalkyl, wherein the alkyl, heteroalkyl, cycloalkylalkyl and heterocyclylalkyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino.
  • R a is hydrogen or alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino.
  • R a is hydrogen.
  • R a is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R a is methyl.
  • the compound provided herein is presented by the formula (IIIe) :
  • R b is hydrogen or alkyl
  • R a is hydrogen or alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino.
  • R b is hydrogen. In some embodiments, R b is alkyl. In certain embodiments, R b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R b is methyl.
  • L 5 is alkyl. In certain embodiments, L 5 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, L 5 is methyl or ethyl.
  • L 6 is -C (O) OR b .
  • L 6 is -C (O) OR b
  • R b is hydrogen or alkyl.
  • R b is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.
  • L 6 is -C (O) OH, -C (O) OMe or -C (O) OEt.
  • L 5 is alkyl, and L 6 is -C (O) OR b . In some embodiments, L 5 is C 1-3 alkyl, and L 6 is -C (O) OR b . In certain embodiments, L 5 is methyl, ethyl or propyl, and L 6 is -C (O) OH, -C (O) OCH 3 or -C (O) OCH 2 CH 3 .
  • each A is independently selected from CH and N;
  • each of X 1 and X 3 is independently selected from the group consisting of a bond, -O-, -N (R a ) -, -S-, and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano or amino;
  • X 2 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b ;
  • L 1 is selected from the group consisting of a bond, -C (O) -, -S (O) -, -S (O) 2 -, and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b ;
  • L 2 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more groups independently selected from halogen, cyano, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, -N (R a ) 2 , or -OR b ;
  • L 3 is selected from the group consisting of hydrogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -C (O) SR b , -C (S) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) S (O) 2 R b , -S (O) 2 N (R a ) 2 , -OC (O) N (R a ) 2 , -N (R a ) C (O) OR b , -N (R a ) C (O) N (R a ) 2 , -N (R a ) C (O) OR b
  • L 7 is selected from the group consisting of a bond, -O-, -S-, -N (R a ) -, -C (O) -, -C (O) N (R a ) -, -N (R a ) C (O) -, -S (O) -, -S (O) 2 -, -N (R a ) S (O) 2 -, -S (O) 2 N (R a ) -, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, and heterocyclylalkyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,
  • L 8 is selected from the group consisting of a bond, alkyl, -N (R a ) -alkyl-, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cyclylalkyl, heterocyclylalkyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cyclylalkyl, heterocyclylalkyl, aryl and heteroaryl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , aryl, or -OR b ;
  • L 9 is selected from the group consisting of hydrogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -C (O) SR b , -C (S) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) S (O) 2 R b , -S (O) 2 N (R a ) 2 , -OC (O) N (R a ) 2 , -N (R a ) C (O) OR b , -N (R a ) C (O) N (R a ) 2 , -N (R a ) C (O) OR b
  • each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, cyano, -OR b , -SR b , -S (O) R b , -S (O) 2 R b , -N (R a ) 2 , -C (O) OR b , -OC (O) R b , -C (O) N (R a ) 2 , -N (R a ) C (O) R b , -N (R a ) SO 2 -, -SO 2 N (R a ) 2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl
  • each of R a and R b is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl, and heterocyclylalkyl, wherein the alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkyl, cycloalkylalkyl and heterocyclylalkyl are each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, or amino; and
  • n is an integer selected from 0, 1, 2, 3, 4, 5, or 6, and
  • n is an integer selected from 0, 1, 2, 3 or 4.
  • L 1 to L 3 , L 7 to L 9 , X 1 to X 3 , R 1 and R 2 are as define supra.
  • L 1 is -C (O) -.
  • L 2 is alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • L 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • L 2 is butyl. In centain embodiments, L 2 is
  • L 3 is -C (O) OR b .
  • R b is hydrogen or alkyl.
  • R b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiments, R b is methyl.
  • L 1 is -C (O) -and L 2 is alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • L 1 is -C (O) -
  • L 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • L 1 is -C (O) -
  • L 2 is butyl, preferably
  • L 1 is -C (O) -
  • L 2 is alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b
  • L 3 is -C (O) OR b .
  • L 1 is -C (O) -
  • L 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each of which is optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b
  • L 3 is -C (O) OR b , wherein R b is hydrogen or alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) .
  • one of X 1 and X 3 is a bond, and the other is -O-.
  • both X 1 and X 3 are bond or -O-.
  • X 2 is alkyl optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • X 2 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • X 2 is propyl.
  • one of X 1 and X 3 is a bond, and the other is -O-, and X 2 is alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • alkyl such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl
  • both X 1 and X 3 are bond or -O-, and X 2 is alkyl (such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) optionally substituted with one or more groups independently selected from hydroxyl, halogen, cyano, -N (R a ) 2 , or -OR b .
  • alkyl such as C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl
  • each of R 1 and R 2 is independently hydrogen, halogen or alkoxy. In certain embodiments, each of R 1 and R 2 is independently F, Cl, Br, I, C 1-6 alkoxy, C 1-5 alkoxy, C 1-4 alkoxy, C 1-3 alkoxy or C 1-2 alkoxy. In certain embodiments, each of R 1 and R 2 is independently F, Cl, methoxy, ethoxy, propoxy, butoxy or pentoxy.
  • each of R 1 andR 2 is independently F or methoxy.
  • m is 1 or 2.
  • n is 2.
  • m is 1, n is 2, and each of R 1 and R 2 is independently F or methoxy.
  • R b is H or alkyl
  • each of R 3 and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, or -OR b .
  • both R 3 and R 4 are hydrogen.
  • one of R 3 and R 4 is hydrogen, and the other is selected from alkyl, heteroalkyl, cycloalkylalkyl, heterocyclylalkyl, or -OR b , and R b is hydrogen or alkyl.
  • each of R 3 and R 4 is independently alkyl. In certain embodiment, each of R 3 and R 4 is independently C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl. In certain embodiment, both R 3 and R 4 are methyl.
  • each of R 3 and R 4 is independently C 1-6 heteroalkyl, C 1-5 heteroalkyl, C 1-4 heteroalkyl, C 1-3 heteroalkyl or C 1-2 heteroalkyl. In certain embodiments, each of R 3 and R 4 is independently C 3-13 cycloalkylalkyl, C 3-12 cycloalkylalkyl, C 3-11 cycloalkylalkyl, C 3-10 cycloalkylalkyl or C 3-9 cycloalkylalkyl.
  • each of R 3 and R 4 is independently heterocyclylalkyl.
  • R b is hydrogen. In some embodiments, R b is alkyl. In certain embodiments, R b is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl. In certain embodiments, R b is methyl.
  • L 7 is selected from the group consisting of -C (O) -, -S (O) -, -S (O) 2 -, -N (R a ) S (O) 2 -, -S (O) 2 N (R a ) -, -C (O) N (R a ) -, and -N (R a ) C (O) -.
  • R a is hydrogen.
  • R a is alkyl.
  • R a is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.
  • R a is methyl, ethyl, propyl, butyl, pentyl or hexyl.
  • L 7 is selected from the group consisting of -C (O) -, -S (O) -, -S (O) 2 -, -C (O) NH-, -C (O) N (CH 3 ) -, -S (O) 2 NH-, and -S (O) 2 N (CH 3 ) -.
  • L 8 is alkyl optionally substituted with aryl. In certain embodiments, L 8 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with aryl. In certain embodiments, L 8 is methyl, ethyl, propyl, butyl, pentyl, or phenylethyl.
  • L 9 is -C (O) OR b . In certain embodiments, L 9 is -C (O) OR b , and R b is hydrogen. In certain embodiments, L 9 is -C (O) OR b and R b is alkyl. In certain embodiments, L 9 is -C (O) OR b and R b isC 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl.
  • L 8 is alkyl, and L 9 is -C (O) OR b .
  • L 8 is methyl, ethyl, propyl, butyl, pentyl, or phenylethyl and L 9 is -C (O) OH, -C (O) OCH 3 or -C (O) OCH 2 CH 3 .
  • prodrugs refers to compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
  • Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive. Preparation 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, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety.
  • metabolite e.g., active metabolite overlaps with prodrug as described above.
  • metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject.
  • metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodrug.
  • active metabolites are such pharmacologically active derivative compounds.
  • the prodrug compound is generally inactive or of lower activity than the metabolic product.
  • the parent compound may be either an active compound or may be an inactive prodrug.
  • Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem 40: 2011-2016; Shan et al., J Pharm Sci 86: 756-757; Bagshawe, 1995, DrugDev Res 34: 220-230; Wermuth, supra.
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as L-glycine, L-lysine, and L-arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present disclosure is intended to include all isotopic variations of the compounds provided herein.
  • different isotopic forms of hydrogen include protium ( 1 H) , deuterium ( 2 H) and tritium ( 3 H)
  • different isotopic forms of carbon includes 12 C and 13 C.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds or pharmaceutically acceptable salts thereof of present disclosure are meant to include their isotopic forms, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 I.
  • Compounds provided herein or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and 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, or in terms of relative configuration, as rel- (R) -or rel- (S) -.
  • the present disclosure includes 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 by conventional techniques, such as, chromatography and fractional crystallization.
  • Traditional 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
  • the embodiment includes, but is not limited to, the specific diastereomerically or enantiomerically enriched form. In situations that the chirality is not specified but is present, it is understood that the embodiment is intended to include either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound (s) .
  • the present disclosure provides a method of preparing the compounds provided herein.
  • the present disclosure provides a method of a compound provided herein, comprsing one or more steps as described herein.
  • the present disclosure provides a compound obtainable by, or obtained by a method for preparing a compound as described herein.
  • the present disclosure provides an intermediate as described herein, which is suitable for use in a method for preparing a compound as described herein.
  • the compounds provided herein can be prepared using any suitable organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
  • Reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with starting materials (reactants) , intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley &Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G. M. Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, an alkanoyl group, an alkoxycarbonyl group, an arylmethoxycarbonyl group, or an aroyl group.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, an alkanoyl group an aroyl group, or an arylmethyl group.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl, an ethyl group, or a benzyl group.
  • the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of the present disclosure into another compound of the present disclosure; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) .
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6)
  • compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present disclosure comprise a first compound provided herein or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula but said first compound and additional compounds are not the same molecules.
  • composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.
  • the pharmaceutical composition of the present disclosure comprises a therapeutically effective amount of one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present disclosure comprises a therapeutically effective amount of one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.
  • the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the term “pharmaceutical composition” refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical compositions include compositions suitable adapted for oral administration, rectal administration, topical administration, parenteral (including subcutaneous, intramuscular, and intravenous) administration, sublingual administration, ocular administration, transdermal administration or nasal administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient.
  • pharmaceutically acceptable excipient also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.
  • suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, dis
  • suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans.
  • a drug such as the compounds disclosed herein and, optionally, a chemotherapeutic agent
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.
  • compositions provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms
  • emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms.
  • emulsions and suspensions may be acceptable as liquid dosage forms
  • solutions, sprays, dry powders, and aerosols may be acceptable dosage form.
  • powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form.
  • pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.
  • compositions of the present disclosure may be in a form of formulation for oral administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations.
  • suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • preservatives such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) .
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • compositions of the present disclosure may be in a form of formulation for injection administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • compositions of the present disclosure may be in a form of formulation for inhalation administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • the pharmaceutical compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.
  • the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • the pharmaceutical compositions provided herein may be formulated for administration ocularly.
  • the pharmaceutical compostions provided herein may be in the form of ophthalmic formulation, such as eye ointments, powders, solutions and the like.
  • ophthalmic formulations are prepared at a comfortable pH with an appropriate buffer system.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure.
  • excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005) , which are incorporated herein by reference.
  • the dosage regimen for the compounds provided herein will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disorder.
  • the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.001-1000 mg/kg body weight/day, for example, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body weight/day, 1-50 mg/kg body weight/day, 1-45 mg/kg body weight/day, 1-40 mg/kg body weight/day, 1-35 mg/kg body weight/day, 1-30 mg/kg body weight/day, 1-25 mg/kg body weight/day of the
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporatedherein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form.
  • the amount of the compounds provided herein in the single dosage form will vary depending on the subject treated and particular mode of administration.
  • dosage forms suitable for administration may contain from about 1 mg to about 1000 mg of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.1-95%by weight based on the total weight of the composition.
  • the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Accordingly, the pharmaceutical formulations of the present disclosure may also be formulated for controlled release or for slow release.
  • a dose of the compounds provided herein or the pharamaceutical compositions provided herein is administered to a subject every day, every other day, every couple of days, every third day, once a week, twice a week, three times a week, or once every two weeks.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • a dose of the compounds provided herein or the pharamaceutical compositions provided herein is administered for 2 days, 3 days, 5 days, 7 days, 14 days, 21 days, 1 month, 2 months, 2.5 months, 3 months, 4 months, 5 months, 6 months or more.
  • compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • an article for distribution can include a container having deposited therein the compositions in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • the compounds provided herein or pharmaceutically acceptable salts thereof may be administered in combination with one or more additional therapeutically active agents.
  • the additional therapeutically active agents may have complementary activities to the compounds provided herein or pharmaceutically acceptable salts thereof such that they do not adversely affect each other. Such agents are suitably present in combination in amounts that are effective for the purpose intended.
  • the additional therapeutic agent or agents may be administered simultaneously or sequentially with the compounds provided herein. Sequential administration includes administration before or after the compounds provided herein. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the compounds provided herein. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the compounds provided herein.
  • the administration of an additional therapeutic agent with a compound provided herein may enable lower doses of the other therapeutic agents and/or administration at less frequent intervals.
  • the additional therapeutic agent is selected from the group consisting of STING agonist compounds, anti-viral compounds, antigens, adjuvants, CTLA-4, LAG-3 and PD-1 pathway antagonists, lipids, liposomes, peptides, anti-cancer and chemotherapeutic agents, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, or immunomodulatory agents including but not limited to anti-cancer vaccines.
  • STING agonist compounds STING agonist compounds
  • anti-viral compounds antigens
  • adjuvants CTLA-4, LAG-3 and PD-1 pathway antagonists
  • lipids liposomes
  • peptides anti-cancer and chemotherapeutic agents
  • checkpoint inhibitors vascular endothelial growth factor (VEGF) receptor inhibitors
  • topoisomerase II inhibitors smoothen inhibitor
  • the additional therapeutic agent is STING agonist compounds, including but not limited to cyclic di-nucleotide compounds, such as those disclosed, for example, in International Patent Application Publication Nos. WO2014093936, WO2014189805, WO2014189806, WO2015185565, W02016120305, WO2016096174, WO2016096577, WO2017027645, WO2017027646, WO2017075477, WO2017093933, and WO2018009466.
  • STING agonist compounds including but not limited to cyclic di-nucleotide compounds, such as those disclosed, for example, in International Patent Application Publication Nos. WO2014093936, WO2014189805, WO2014189806, WO2015185565, W02016120305, WO2016096174, WO2016096577, WO2017027645, WO2017027646, WO2017075477, WO2017093933, and WO2018009466.
  • the additional therapeutic agent is anti-viral compounds, including but not limited to hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors.
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • HCV hepatitis C virus
  • HCV hepatitis C virus
  • HCV polymerase inhibitors HCV NS4A inhibitors
  • HCV NS5A inhibitors HCV NS5b inhibitors
  • HCV NS5b inhibitors human immunodeficiency virus
  • the additional therapeutic agent is antigen and adjuvant, including but not limited to B7 costimulatory molecule, interleukin-2, interferon-y, GM-CSF, CTLA-4 antagonists, OX-40/0X-40 ligand, CD40/CD40 ligand, sargramostim, levamisol, vaccinia virus, Bacille Calmette-Guerin (BCG) , liposomes, alum, Freund’s complete or incomplete adjuvant, detoxified endotoxins, mineral oils, surface active substances such as lipolecithin, pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions.
  • BCG Bacille Calmette-Guerin
  • Adjuvants such as aluminum hydroxide or aluminum phosphate, can be added to increase the ability of the vaccine to trigger, enhance, or prolong an immune response.
  • Additional materials such as cytokines, chemokines, and bacterial nucleic acid sequences, like CpG, a toll-like receptor (TLR) 9 agonist as well as additional agonists for TLR 2, TLR 4, TLR 5, TLR 7, TLR 8, TLR9, including lipoprotein, LPS, monophosphoryllipid A, lipoteichoic acid, imiquimod, resiquimod, and in addition retinoic acid-inducible gene I (RIG-I) agonists such as poly I: C, used separately or in combination with the described compositions are also potential adjuvants.
  • Such antigens and anjuvants may be provided as a pharmaceutically acceptable salt, where appropriate.
  • the additional therapeutic agent is CTLA-4 and PD-1 pathway antagonists, including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, cemiplimab, atezolizumab, durvalumab, avelumab, AMP-224, and MDX-1106, .
  • the additional therapeutic agent is chemotherapeutic agents, including but not limited to abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2, 3, 4, 5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzene sulfonamide, bleomycin, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-Lproline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3’ , 4’ -didehydro-4’ deoxy-8’ -norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin
  • the additional therapeutic agent is VEGF receptor inhibitors include, but are not limited to, bevacizumab, axitinib Brivanib Alaninate, pasireotide, and sorafenib. Such inhibitors may be provided as a pharmaceutically acceptable salt, wherein appropriate.
  • the additional therapeutic agent is topoisomerase II inhibitors, including but not limited to, etoposide, and teniposide.
  • Such inhibitors may be provided as a pharmaceutically acceptable salt, wherein appropriate.
  • the additional therapeutic agent is alkylating agents, including but not limited to, 5-azacytidine, decitabine, temozolomide, dactinomycin, melphalan, altretamine, carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine, mechlorethamine, streptozocin, thiotepa.
  • alkylating agents may be provided as a pharmaceutically acceptable salt, wherein appropriate.
  • the additional therapeutic agent is anti-tumor antibiotics including but not limited to, doxorubicin, bleomycin, daunorubicin, daunorubicin liposomal, mitoxantrone, epirubicin, idarubicin, and mitomycin C.
  • anti-tumor antibiotics may be provided as a pharmaceutically acceptable salt, wherein appropriate.
  • the additional therapeutic agent is anti-metabolites, including but not limited to, claribine, 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, cytarabine liposomal, decitabine, hydroxyurea, fludarabine, floxuridine, cladribine, methotrexate, and pentostatin.
  • anti-metabolites may be provided as a pharmaceutically acceptable salt, wherein appropriate.
  • the additional therapeutic agent is retinoids, including but are not limited to, alitretinoin, tretinoin, Isotretinoin, and bexarotene.
  • retinoids including but are not limited to, alitretinoin, tretinoin, Isotretinoin, and bexarotene.
  • Such compounds may be provided as a pharmaceutically acceptable salt, wherein appropriate.
  • Compounds of the present disclosure and pharamaceutical composition comprising the same are capable of inducing STING pathway, and thus can be useful for inducing immune response, and inducing STING-dependent type I interferon production in a subject in need thereof, and for preventing or treating STING-mediated disorders.
  • the present disclosure provides a method of treating STING-mediated disorders, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein to a subject in need thereof.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Treating” can also mean prolonging survival as compared to expected survival if not receiving it. Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the term “preventing” , “prevention” or “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed, and the patient is temporarily or permanently protected against exacerbation or worsening of the disease, or the development of new symptoms associated with the disease.
  • the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for the treatment of a wide variety of STING-mediated disorders including cancer, viral infection, or autoimmune diseases, etc.
  • the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for treating cancers, including but not limited to brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary (i.e., cancers in which a metastasized cancer is found but the original cancer site is not known) .
  • the cancer is present in an adult patient.
  • the cancer is present in a pediatric patient.
  • the cancer is AIDS-related.
  • the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for treating viral infections including but not limited to human immunodeficiency virus infection, herpes simplex virus infection, hepatitis B virus infection, and hepatitis C virus infection.
  • the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for treating autoimmune diseases including but not limited to rheumatoid arthritis, graft versus host disease, dermatomyositis, systemic lupus erythromatosis (SLE) , scleroderma, multiple sclerosis, diabetes, organ rejection, inflammatory bowel disease, psoriasis, and other afflictions.
  • autoimmune diseases including but not limited to rheumatoid arthritis, graft versus host disease, dermatomyositis, systemic lupus erythromatosis (SLE) , scleroderma, multiple sclerosis, diabetes, organ rejection, inflammatory bowel disease, psoriasis, and other afflictions.
  • the administering is conducted via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and ocular administration.
  • the compounds of the present disclosure may be prepared by the methods known in the art.
  • the following illustrates the detailed preparation methods of the preferred compounds of the present disclosure. However, they are by no means limiting the preparation methods of the compounds of the present disclosure.
  • non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and/or by making routine modifications of reaction conditions.
  • persons skilled in the art will also understand that individual steps described herein or in the separate batches of a compound may be combined.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure, but rather is specified by the claims appended hereto.
  • aryl boronic acid 9-1 (65.0 mg, 0.163 mmol) in toluene/ethanol/H 2 O (2.0/0.4/2.0 mL) in a 10 mL flask was added 6-bromonicotinate (70.5 mg, 0.326 mmol) , followed by Na 2 CO 3 (27.5 mg, 0.326 mmol) and Pd (PPh 3 ) 4 (18.9 mg, 0.0163 mmol) under N 2 atmosphere. After refluxed (80 °C) for 18 hours, the reaction was cooled to room temperature, quenched with NH 4 Cl (10 mL) , and extracted with ethyl acetate (10mLx3) .
  • STING Reporter THP1 cell were resuspended in low-serum growth media (1640+2%FBS) at a density of 2x10 5 cells/mL, 50 ⁇ L of cells were seeded into each well of a 96-well white plates and incubated for 1 hour. Then the cells were treated with test compounds or DMSO, 50 ⁇ L of diluted compounds were added into plates and incubated for 24 hours.
  • 50 ⁇ L of bio-lite detection buffer added to each well and luminescence was read using Envision plate reader (Perkin Elmer) set with an integration time of 1 second. The results were shown in the table below:
  • Table 1 THP1 assay of the STING agnoists. 1 “A” means EC 50 ⁇ 100 nM, “B” 100 nM ⁇ EC 50 ⁇ 500 nM, “C” means EC 50 ⁇ 500 nM.

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Abstract

L'invention concerne des composés ou des sels pharmaceutiquement acceptables de ceux-ci qui sont utiles en tant qu'agonites de STING. L'invention concerne également des compositions pharmaceutiques comprenant de tels composés, ainsi que des procédés d'utilisation de tels composés ou compositions pour traiter un trouble à médiation par STING (par exemple, des cancers).
PCT/CN2024/099995 2023-07-04 2024-06-19 Agonistes de sting et leurs utilisations Pending WO2025007743A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110036001A (zh) * 2016-10-04 2019-07-19 默沙东公司 作为STING激动剂的苯并[b]噻吩化合物
CN111971277A (zh) * 2018-04-03 2020-11-20 默沙东公司 作为sting激动剂的苯并噻吩及相关化合物
CN113861161A (zh) * 2020-06-30 2021-12-31 上海海和药物研究开发股份有限公司 一种芳基并芳杂环衍生物及其制备方法和用途
WO2023239675A1 (fr) * 2022-06-06 2023-12-14 Sutro Biopharma, Inc. Composés agonistes de sting

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110036001A (zh) * 2016-10-04 2019-07-19 默沙东公司 作为STING激动剂的苯并[b]噻吩化合物
CN111971277A (zh) * 2018-04-03 2020-11-20 默沙东公司 作为sting激动剂的苯并噻吩及相关化合物
CN113861161A (zh) * 2020-06-30 2021-12-31 上海海和药物研究开发股份有限公司 一种芳基并芳杂环衍生物及其制备方法和用途
WO2023239675A1 (fr) * 2022-06-06 2023-12-14 Sutro Biopharma, Inc. Composés agonistes de sting

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