WO2020132549A1 - Sting heterocycle agonists and uses thereof - Google Patents

Sting heterocycle agonists and uses thereof Download PDF

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WO2020132549A1
WO2020132549A1 PCT/US2019/068023 US2019068023W WO2020132549A1 WO 2020132549 A1 WO2020132549 A1 WO 2020132549A1 US 2019068023 W US2019068023 W US 2019068023W WO 2020132549 A1 WO2020132549 A1 WO 2020132549A1
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nitrogen
sulfur
oxygen
independently selected
heteroatoms independently
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PCT/US2019/068023
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French (fr)
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Silvana Marcel LEIT DE MORADEI
Donna L. Romero
Jennifer Knight
Anthony Clark
Pieter Bos
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Nimbus Titan, Inc.
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Publication of WO2020132549A1 publication Critical patent/WO2020132549A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems

Definitions

  • the present invention relates to compounds and methods useful for the modulation of STING-dependent type I interferon production.
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • Innate immunity is a rapid nonspecific immune response that fights against environmental insults including, but not limited to, pathogens such as bacteria or viruses.
  • Adaptive immunity is a slower but more specific immune response, which confers long-lasting or protective immunity to the host and involves differentiation and activation of naive T lymphocytes into CD4+ T helper cells and/or CD8+ cytotoxic T cells, to promote cellular and humoral immunity.
  • Antigen presentation cells of the innate immune system such as dendritic cells or macrophages, serve as a critical link between the innate and adaptive immune systems by phagocytosing and processing the foreign antigens and presenting them on the cell surface to the T cells, thereby activating T cell response.
  • STING (stimulator of interferon genes) is an endoplasmic reticulum adaptor that facilitates innate immune signaling (Ishikawa and Barber, Nature 2008, 455(7213):674-678).
  • STING comprises four putative transmembrane regions (Ouyang et ah, Immunity (2012) 36, 1073), predominantly resides in the endoplasmic reticulum and is able to activate NF-kB, STAT6, and IRF3 transcription pathways to induce expression of type I interferon (e.g., IFN-a and IFN-13) and exert a potent anti -viral state following expression (Ishikawa and Barber, Nature 2008, 455(7213):674-678; Chen et ak, Cell (2011) 147, 436- 446).
  • loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative stranded virus infection, including vesicular stomatitis virus. (Ishikawa and Barber, Nature. 2008, 455(7213):674-678).
  • Compounds provided by this invention are also useful for the study of STING and associated proteins in biological and pathological phenomena; the study of STING occurring in bodily tissues; and the comparative evaluation of new STING agonists or other regulators of STING in vitro or in vivo.
  • STING ligands Compounds of the present invention, and compositions thereof, are useful as STING ligands.
  • the terms“agonist,”“binder,”“modulator,” and“ligand” are used interchangeably and describe a compound that binds to, modulates, activates, is a ligand for, or agonist of STING.
  • the present invention provides a compound of formula I:
  • Z is Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocycl
  • L is a covalent bond or a Ci- 4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’) 2 -, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0) 2 -,
  • each R’ is independently hydrogen or Ci-4 aliphatic; or
  • R’ two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having
  • two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 is selected from H; Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 1 is halogen, -CN, -NO2, -OR,
  • R 2 is selected from H, Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 2 is halogen, -CN, -N0 2 , -OR,
  • R 3 is selected from H, Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 3 is halogen, -CN, -N0 2 , -OR,
  • R 4 is selected from H; Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 4 is halogen, -CN, -N0 2 , -OR,
  • R 5 is -H, Ci- 6 aliphatic which is substituted with q instances of R c , or -L’-Q; or
  • R 4 and R 5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of R c ;
  • L’ is a covalent bond or a Ci-is bivalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one to four methylene units of the chain are optionally and independently
  • each instance of -Cy’- is independently an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Q is hydrogen or a CRBN binding moiety
  • each instance of R 6 is independently oxo, halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -S(0)NR 2 , -C(0)R, -C(0)0R, -C(0)NR 2 , -C(0)N(R)0R,
  • R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen
  • R 6 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each instance of R c is independently oxo, halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -S(0)NR 2 , -C(0)R, -C(0)0R, -C(0)NR 2 , -C(0)N(R)0R,
  • R c is independently an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from
  • each of n and q is independently 0, 1, 2, 3, or 4;
  • each of x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • aliphatic or“aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,”“cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or“carbocycle” or“cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a“bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a“bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
  • lower alkyl refers to a Ci-4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a Ci-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3 ,4-di hydro-2//-pyrrol yl ), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • Ci-s (or Ci- 6 ) saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An“alkylene chain” is a polymethylene group, i.e., -(CH2) n- , wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in“aralkyl,”“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • the term“aryl” may be used interchangeably with the term“aryl ring.”
  • “aryl” refers to an aromatic ring system which includes, but 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 non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and“heteroar-,” used alone or as part of a larger moiety e.g., “heteroaralkyl,” or“heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and“heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
  • a heteroaryl group may be mono- or bicyclic.
  • the term“heteroaryl” may be used interchangeably with the terms“heteroaryl ring,”“heteroaryl group,” or“heteroaromatic,” any of which terms include rings that are optionally substituted.
  • the term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms“heterocycle,”“heterocyclyl,”“heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro- 2H pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • the term“partially unsaturated” refers to a ring moiety that includes at least one double or triple bond.
  • the term“partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain“optionally substituted” moieties.
  • the term“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.
  • 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.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • the term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o- 2 R*, -(haloR*), -(CH 2 ) O-2 OH, -(CH 2 ) O-2 OR ⁇ , -(CH 2 ) O-2 CH(OR*) 2 ; -0(haloR*), -CN, -N 3 , -(CH 2 ) 0-
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: -0(CR * 2 ) 2- 3O-, wherein each independent occurrence of Rf is selected from hydrogen, Ci- 6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, R*, -(haloR*), -OH, -OR*, -0(haloR*), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO2, wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 PI1, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ ,
  • each R' is independently hydrogen, Ci- 6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R' are independently halogen, - R*, -(haloR* ), -OH, -OR*, -0(haloR*), -CN, -C(0)OH, -C(0)OR*, -NH 2 , NHR*, -NR* 2 , or -NO2, wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 PI1, -0(CH 2 )o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci ⁇ alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. For example, it will be appreciated by those skilled in the art that the compounds of this invention may exist in tautomeric
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention
  • an agonist or activator has an EC50 and/or effective concentration of less than about 50 mM, less than about 1 mM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • a compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents.
  • a detectable moiety may be attached to a provided compound via a suitable substituent.
  • suitable substituent refers to a moiety that is capable of covalent attachment to a detectable moiety.
  • moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few.
  • moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain.
  • such moieties may be attached via click chemistry.
  • such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst.
  • Methods of using click chemistry are known in the art and include those described by Rostovtsev et al ., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al, Bioconjugate Chem., 2006, 17, 52-57.
  • the term“detectable moiety” is used interchangeably with the term "label” and relates to any moiety capable of being detected, e.g., primary labels and secondary labels.
  • Primary labels such as radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications.
  • Detectable moieties also include luminescent and phosphorescent groups.
  • secondary label refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal.
  • the secondary intermediate may include streptavidin-enzyme conjugates.
  • antigen labels secondary intermediates may include antibody-enzyme conjugates.
  • fluorescent label refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength.
  • fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy
  • mass-tag refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques.
  • mass-tags include electrophore release tags such as N-[3-[4’-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2, 3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives.
  • mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition.
  • nucleotides dideoxynucleotides
  • oligonucleotides of varying length and base composition oligopeptides, oligosaccharides
  • other synthetic polymers of varying length and monomer composition.
  • a large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.
  • measurable affinity and“measurably activate,” as used herein, means a measurable change in STING activity between a sample comprising a compound of the present invention, or composition thereof, and STING, and an equivalent sample comprising STING, in the absence of said compound, or composition thereof.
  • the present invention provides a compound of formula I:
  • Z is Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocycl
  • L is a covalent bond or a Ci- 4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’) 2 -, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0) 2 -,
  • each R’ is independently hydrogen or Ci-4 aliphatic; or
  • R’ two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having
  • two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 1 is selected from H; Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 1 is halogen, -CN, -NO2, -OR,
  • R 2 is selected from H, Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 2 is halogen, -CN, -NO2, -OR,
  • R 3 is selected from H, Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 3 is halogen, -CN, -N0 2 , -OR,
  • R 4 is selected from H; Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 4 is halogen, -CN, -N0 2 , -OR,
  • R 5 is -H, Ci- 6 aliphatic which is substituted with q instances of R c , or -L’-Q; or
  • R 4 and R 5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of R c ;
  • L’ is a covalent bond or a Ci-15 bivalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one to four methylene units of the chain are optionally and independently replaced
  • each instance of -Cy’- is independently an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Q is hydrogen or a CRBN binding moiety
  • each instance of R 6 is independently oxo, halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -S(0)NR 2 , -C(0)R, -C(0)0R, -C(0)NR 2 , -C(0)N(R)0R,
  • R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen
  • R 6 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each instance of R c is independently oxo, halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R,
  • R c is independently an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from
  • each of n and q is independently 0, 1, 2, 3, or 4;
  • each of x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • Z is Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bi
  • Z is Ci- 6 aliphatic; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R 6 .
  • Z is Ci-4 aliphatic; a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R 6 .
  • Z is -OR.
  • Z is selected from -Me, -Et, -Pr, -iPr, -Bu, -sBu, -iBu, straight chain or branched pentyl, straight chain or branched hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolin
  • Z is selected from -Me, -Et, -Pr, -CH 2 OCH 3 , -CH(Et) 2 , -OMe, -O/Bu,
  • Z is -Me. In some embodiments, Z is -Et. In some embodiments, Z is -Pr. In some embodiments, Z is -CH 2 OCH 3. In some embodiments, Z is - CH(Et) 2. In some embodiments, Z is -OMe. In some embodiments, Z is -O/Bu.
  • Z is
  • Z is
  • Z is
  • Z is ? V-l
  • Z is n(R 6 )
  • Z is
  • Z is
  • Z is .
  • Z is -Me, -Et, -Pr, -CH2OCH3, -CH(Et)2, -OMe, -O-/-B11,
  • Z is selected from those depicted in Table 1, below.
  • L is a covalent bond or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’)2-, -N(R)-, -N(R)C(0)-, -C(0)N(R)- , -N(R)S(0) 2 -, -S(0) 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -S(0)- or -S(0) 2 -.
  • L is a covalent bond
  • L is a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’) 2 -, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0) 2 -
  • L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R>, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -0-, -C(O)-, -OC(O)- , -C(0)0-, -S-, -S(O)-, or— S(0) 2 -.
  • L is a Ci- 4 bivalent unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’) 2 -, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0) 2 -
  • L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -C(R’) 2 -, -N(R)-, - N(R)C(0)-, -C(0)N(R)-, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -S(O)-, or— S(0) 2 -.
  • L is a Ci-4 bivalent unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -C(R>, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -0-, -C(0)-, -OC(O)- , -C(0)0-, -S-, -S(O)-, or -S(0) 2 -.
  • L is a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain. In some embodiments, L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain. In some embodiments, L is a Ci-4 bivalent unsaturated, straight or branched hydrocarbon chain.
  • L is a covalent bond, -C(R’) 2 -, -N(R)-, or -0-. In some embodiments, L is a covalent bond or -N(R)-. In some embodiments, L is -C(R’) 2 -, -N(R)-, or - 0-. In some embodiments, L is a covalent bond, -CH 2 -, -N(H)-, or -0-. In some embodiments, L is -CH 2 -, -N(H)-, or -0-.
  • L is -CH 2 -.
  • L is selected from those depicted in Table 1, below.
  • each R’ is independently hydrogen or Ci-4 aliphatic; or two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 3-7 membered saturated or partially unsaturated carbocyclylene ring; or two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R’ is hydrogen. In some embodiments, R’ is Ci-4 aliphatic. In some embodiments, two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 3-7 membered saturated or partially unsaturated carbocyclylene ring. In some embodiments, two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R’ is selected from those depicted in Table 1, below.
  • each R is independently hydrogen, or an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated s
  • two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is selected from those depicted in Table 1, below.
  • R 1 is selected from H; Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 1 is halogen, -CN, -NO2, -OR,
  • R 1 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; phenyl which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 1 is halogen, -CN, -NO2, -OR,
  • R 1 is H.
  • R 1 is Ci- 6 aliphatic which is substituted with q instances of R c ; phenyl which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 1 is halogen, -CN, -N0 2 , -OR,
  • R 1 is Ci- 6 aliphatic which is substituted with q instances of R c .
  • R 1 is phenyl which is substituted with q instances of R c .
  • R 1 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c .
  • R 1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c .
  • R 1 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R C .
  • R 1 is halogen, -CN, -NO2, -OR,
  • R 1 is halogen, -OR, -NR 2 , -C(0)R, -C(0)OR, - C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, or -N(R)C(0)NR 2 .
  • R 1 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 1 is halogen, -OR,
  • R 1 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; or R 1 is halogen, OR, -C(0)R, -C(0)OR.
  • R 1 is H.
  • R 1 is selected from those depicted in Table 1, below.
  • R 2 is selected from H, Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 2 is halogen, -CN, -N0 2 , -OR,
  • R 2 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; phenyl which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 2 is halogen, -CN, -NO2, -OR,
  • R 2 is H.
  • R 2 is Ci- 6 aliphatic which is substituted with q instances of R c ; phenyl which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 2 is halogen, -CN, -N0 2 , -OR,
  • R 2 is Ci- 6 aliphatic which is substituted with q instances of R c .
  • R 2 is phenyl which is substituted with q instances of R c .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c .
  • R 2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c .
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c .
  • R 2 is halogen, -CN, -N0 2 , -OR, SR, -NR 2 , -S(0) 2 R, -S(0)(NR)R, -S(0) 2 NR 2 , -S(0)R, -S(0)NR 2 , -C(0)R, -C(0)0R, - C(0)NR 2 , -C(0)N(R)0R, -0C(0)R, -0C(0)NR 2 , -N(R)C(0)R, -N(R)C(0)0R, -N(R)C(0)NR 2 , - N(R)C(NR)NR 2 , -N(R)S(0) 2 NR 2 , -N(R)S(0) 2 R, or -P(0)R 2 .
  • R 2 is halogen, -OR, -NR 2 , -C(0)R, -C(0)0R, - C(0)NR 2 , -C(0)N(R)0R, -0C(0)R, -0C(0)NR 2 , -N(R)C(0)R, -N(R)C(0)0R, or -N(R)C(0)NR 2 .
  • R 2 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; or R 2 is halogen, -
  • R 2 is H, -OR, -C(0)OR, -C(0)NR 2, -OC(0)R, or -N(R)C(0)R.
  • R 2 is -H, or -C(0)NH 2 .
  • R 2 is selected from those depicted in Table 1, below.
  • R 3 is selected from H, Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 3 is halogen, -CN, -N0 2 , -OR,
  • R 3 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; phenyl which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 3 is halogen, -CN, -N0 2 , -OR, SR, -NR 2 , -S(0) 2 R, -S(0)(NR)R, -S(0) 2 NR 2 , -S(0)R, -S(0)NR
  • R 3 is H.
  • R 3 is Ci- 6 aliphatic which is substituted with q instances of R c ; phenyl which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 3 is halogen, -CN, -N0 2 , -OR,
  • R 3 is Ci- 6 aliphatic which is substituted with q instances of R c .
  • R 3 is phenyl which is substituted with q instances of R c .
  • R 3 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c .
  • R 3 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c .
  • R 3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c .
  • R 3 is halogen, -CN, -N0 2 , -OR,
  • R 3 is halogen, -OR, -NR 2 , -C(0)R, -C(0)OR, - C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)NR 2 .
  • R 3 is -H, Ci- 6 aliphatic which is substituted with q instances of R c ; or R 3 is halogen, -
  • R 3 is -H, -OR, -C(0)OR, -C(0)NR 2, -OC(0)R, or -N(R)C(0)R.
  • R 3 is -H or -C(0)NH 2 .
  • R 3 is selected from those depicted in Table 1, below.
  • R 4 is selected from H; Ci- 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of R c ; or R 4 is halogen, -CN, -N0 2 , -OR,
  • R 4 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; phenyl which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 4 is halogen, -CN, -N0 2 , -OR,
  • R 4 is H.
  • R 4 is Ci- 6 aliphatic which is substituted with q instances of R c ; phenyl which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 1 is halogen, -CN, -NO2, -OR,
  • R 4 is Ci- 6 aliphatic which is substituted with q instances of R c .
  • R 4 is phenyl which is substituted with q instances of R c .
  • R 4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c .
  • R 4 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c .
  • R 4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c .
  • R 4 is halogen, -CN, -N0 2 , -OR,
  • R 4 is halogen, -OR, -NR 2 , -C(0)R, -C(0)OR, - C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, or -N(R)C(0)NR 2 .
  • R 4 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of R c ; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of R c ; or R 4 is halogen, -OR, SR, -NR 2 , -S(0) 2 R, -S(0)(NR)R, -S(0) 2 NR 2 , -S(0)R, -S(0)NR 2 , -C(0)R, -C(0)OR, -C(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(0) 2 NR 2 , or
  • R 4 is H, Ci- 6 aliphatic which is substituted with q instances of R c ; or R 4 is halogen, -OR, -C(0)R, -C(0)OR.
  • R 4 is -H, -Me, -OH, -OMe, -C(0)OH,
  • R 4 is selected from those depicted in Table 1, below.
  • R 5 is -H, Ci- 6 aliphatic which is substituted with q instances of R c , or -L’-Q.
  • R 5 is -H.
  • R 5 is Ci- 6 aliphatic which is substituted with q instances of R c .
  • R 5 is Ci-4 aliphatic which is substituted with q instances of R c .
  • R 5 is -L’-Q.
  • R 5 is -H, -Pr,
  • R 5 is selected from those depicted in Table 1, below.
  • R 4 and R 5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of R c .
  • R 4 and R 5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with n instances of R c .
  • R 4 and R 5 taken together is selected from those depicted in Table 1, below.
  • L’ is a covalent bond or a Ci-is bivalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one to four methylene units of the
  • L’ is selected from those depicted in Table 1, below.
  • each instance of -Cy’- is independently an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy’- is an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • -Cy’- is selected from those depicted in Table 1, below.
  • Q is hydrogen or a CRBN binding moiety.
  • Q is hydrogen. In some embodiments, Q is a CRBN binding moiety.
  • Q is selected from those depicted in Table 1, below.
  • each instance of R 6 is independently oxo, halogen, -CN,
  • R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membere
  • each instance of R 6 is independently oxo, halogen, -CN, - N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R,
  • R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen,
  • R 6 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • each instance of R 6 is independently halogen, -CN, -N0 2 , - OR, -NR 2 , -S(0) 2 R,
  • R 6 is independently an optionally substituted Ci- 6 aliphatic.
  • each instance of R 6 is independently halogen, -OR, -NR 2 , or optionally substituted Ci- 6 aliphatic In certain embodiments, each instance of R 6 is independently -Cl, -Me, -Et, -OMe, or -CF .
  • each R 6 is independently is selected from those depicted in Table 1, below.
  • each instance of R c is independently oxo, halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -S(0)NR 2 , -C(0)R, -C(0)OR, -
  • each hydrogen bound to carbon can be optionally and independently replaced by deuterium.
  • a hydrogen bound to carbon is replaced by deuterium.
  • n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
  • n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 3. In some embodiments, n is 2 or 3. In some embodiments, n is 2 or 4. In some embodiments, n is 1, 2, or 4. In some embodiments, n is 1, 3, or 4. In some embodiments, n is 2, 3, or 4.
  • n is selected from those depicted in Table 1, below.
  • q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.
  • q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In some embodiments, q is 2 or 4. In some embodiments, q is 1, 2, or 4. In some embodiments, q is 1, 3, or 4. In some embodiments, q is 2, 3, or 4.
  • q is selected from those depicted in Table 1, below.
  • each of x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10.
  • x is selected from those depicted in Table 1, below.
  • the present invention provides a compound of formula II:
  • the present invention provides a compound of formula III:
  • the present invention provides a compound of formula IV wherein L is a covalent bond, thereby forming a compound of formula IV:
  • the present invention provides a compound of formula V wherein L is a covalent bond, thereby forming a compound of formula V:
  • the present invention provides a compound of formula VI wherein L is a covalent bond, thereby forming a compound of formula VI:
  • compositions are provided.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to modulate STING, or a mutant thereof, - dependent type I interferon production in a biological sample or in a patient.
  • the amount of compound in compositions of this invention is such that is effective to measurably modulate STING, or a mutant thereof, -dependent type I interferon production in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • the term“patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a non toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene
  • A“pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite or residue thereof.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • the invention provides a method of inducing an immune response in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
  • the invention provides a method of inducing a STING- dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
  • the invention provides a method of inducing a STING- dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method of treating cell proliferation disorders, including cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma.
  • the invention provides a method of treating a cell proliferation disorder in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, to the subject.
  • the cell proliferation disorder is cancer.
  • the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
  • the cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • the cancer is selected from 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; in additional embodiments, the cancer is present in a pediatric patient.
  • the cancer is AIDS-related.
  • the cancer is selected from brain and spinal cancers.
  • the cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (olfactory blastomas).
  • the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma), oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, and anaplastic aplastic
  • the cancer is selected from cancers of the head and neck, including nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), and cancers of the eye or ocular cancers.
  • the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.
  • the cancer is selected from leukemia and cancers of the blood.
  • the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)- associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas.
  • Leukemias referenced herein may be acute or chronic.
  • the cancer is selected from skin cancers.
  • the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers.
  • the cancer is selected from cancers of the reproductive system.
  • the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, prostate cancers, penile cancers, and testicular cancers.
  • the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors.
  • the breast cancer may be male breast cancer or female breast cancer.
  • the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas.
  • the cancer is an ovarian cancer selected from the group consisting of epithelial cancers.
  • the cancer is selected from cancers of the gastrointestinal system.
  • the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers), gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer.
  • the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas.
  • the cancer is selected from liver and bile duct cancers.
  • the cancer is liver cancer (hepatocellular carcinoma).
  • the cancer is bile duct cancer (cholangiocarcinoma); in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.
  • the cancer is selected from kidney and bladder cancers.
  • the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers.
  • the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas.
  • the cancer is selected from bone cancers.
  • the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma.
  • the cancer is selected from lung cancers.
  • the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.
  • the cancer is selected from malignant mesothelioma.
  • the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.
  • the cancer is selected from sarcomas.
  • the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.
  • the cancer is selected from lymphomas.
  • the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., Reed- Stemberg cells), non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphomas, and primary central nervous system lymphomas.
  • Hodgkin lymphoma e.g., Reed- Stemberg cells
  • non-Hodgkin lymphoma e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma
  • cutaneous T-cell lymphomas e.g., T-cell lymphomas
  • primary central nervous system lymphomas e.g., cutaneous T-cell lymphomas
  • the cancer is selected from glandular cancers.
  • the cancer is selected from the group consisting of adrenocortical cancer, pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.
  • the cancer is selected from thyroid cancers.
  • the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.
  • the cancer is selected from germ cell tumors.
  • the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors.
  • the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.
  • the cancer is selected from heart tumors.
  • the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.
  • the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases.
  • the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma.
  • the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors).
  • gestational trophoblastic neoplasia e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as“appropriate for the disease, or condition, being treated.”
  • a provided combination, or composition thereof is administered in combination with another therapeutic agent.
  • combination therapies of the present invention are administered in combination with a monoclonal antibody or an siRNA therapeutic.
  • Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term“combination,”“combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents.
  • the therapeutic agent may be administered together with a compound of formula I, or may be administered prior to or following administration of a compound of formula I. Suitable therapeutic agents are described in further detail below.
  • a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent.
  • a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.
  • the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents.
  • additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrex
  • NSAIDS non
  • the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methyl prednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofm (Ridaura®), D-pen
  • NSAIDS non-ster
  • the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.
  • NSAIDS non-steroidal anti inflammatory drugs
  • the present invention provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcin
  • NSAIDS non-ster
  • the present invention provides a method of treating Crohn’s disesase, ulcerative colitis, or inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxaci
  • the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (
  • the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone,
  • beta-2 agonists such as
  • the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
  • the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
  • additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor,
  • the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and a Hedgehog (Hh) signaling pathway inhibitor.
  • the hematological malignancy is DLBCL (Ramirez et al“Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).
  • the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.
  • rituximab Renuxan®
  • Cytoxan® cyclophosphamide
  • doxorubicin Hydrodaunorubicin®
  • vincristine Oncovin®
  • prednisone a hedgehog signaling inhibitor
  • the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’ s disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto’s thyroiditis, Ord’s thyroiditis, Graves’ disease, autoimmune thyroiditis, Sjogren’s syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonus-
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.
  • the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immuno
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • cutaneous lupus erythematosus systemic lupus erythematosus
  • rheumatoid arthritis polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the disorder is a proliferative disorder, lupus, or lupus nephritis.
  • the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin’s disease, small-cell lung cancer, non-small- cell lung cancer, myelodysplastic syndrome, lymphoma, a hematological neoplasm, or solid tumor.
  • the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • the expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, pol yvi nyl pyrroli di none, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of activating STING, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of irreversibly inhibiting STING, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Activation of STING (or a mutant thereof) activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • Another embodiment of the present invention relates to a method of activating STING in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of activating STING, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of reversibly or irreversibly inhibiting one or more of STING, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the present invention provides a method for treating a disorder mediated by STING, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof.
  • a disorder mediated by STING or a mutant thereof
  • Such disorders are described in detail herein.
  • additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as“appropriate for the disease, or condition, being treated.”
  • a compound of the current invention may also be used to advantage in combination with other therapeutic compounds.
  • the other therapeutic compounds are antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti neoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiprolifer
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane is marketed under the trade name AromasinTM.
  • Formestane is marketed under the trade name LentaronTM.
  • Fadrozole is marketed under the trade name AfemaTM.
  • Anastrozole is marketed under the trade name ArimidexTM.
  • Letrozole is marketed under the trade names FemaraTM or FemarTM.
  • Aminoglutethimide is marketed under the trade name OrimetenTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen is marketed under the trade name NolvadexTM.
  • Raloxifene hydrochloride is marketed under the trade name EvistaTM.
  • Fulvestrant can be administered under the trade name FaslodexTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an anti estrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CasodexTM).
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name ZoladexTM.
  • topoisom erase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CamptosarTM.
  • Topotecan is marketed under the trade name HycamptinTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CaelyxTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name EtopophosTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name AcriblastinTM or AdriamycinTM.
  • Epirubicin is marketed under the trade name FarmorubicinTM.
  • Idarubicin is marketed under the trade name ZavedosTM.
  • Mitoxantrone is marketed under the trade name Novantron.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • Paclitaxel is marketed under the trade name TaxolTM.
  • Docetaxel is marketed under the trade name TaxotereTM.
  • Vinblastine sulfate is marketed under the trade name Vinblastin R.PTM.
  • Vincristine sulfate is marketed under the trade name FarmistinTM.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CyclostinTM. Ifosfamide is marketed under the trade name HoloxanTM.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • SAHA suberoylanilide hydroxamic acid
  • antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine is marketed under the trade name XelodaTM.
  • Gemcitabine is marketed under the trade name GemzarTM.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CarboplatTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark EloxatinTM.
  • the term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor- receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (I
  • BCR-Abl kinase and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD 180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAR, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or members of the cyclin- dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds
  • c-Met receptor compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF
  • PI3K inhibitor includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to RI3Ka, RI3Kg, RBKd, RI3Kb, PI3K-C2a, PI3K-C2p, PI3K- C2y, Vps34, pi 10-a, pi 10-b, pi 10-g, pi 10-d, p85-a, r85-b, r55-g, pl50, plOl, and p87.
  • PI3K inhibitors useful in this invention include but are not limited to ATE1-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
  • the term“BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
  • the term“SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see W02008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see W02004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax.
  • the Bcl-2 inhibitor is a small molecule therapeutic.
  • the Bcl-2 inhibitor is a small molecule therapeutic.
  • BTK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in W02008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
  • PI3K inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in W02004019973, W02004089925, W02007016176, US8138347, W02002088112, W02007084786,
  • W02007129161, W02006122806, W02005113554, and W02007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in W02009114512, W02008109943, W02007053452, W02000142246, and W02007070514, the entirety of which are incorporated herein by reference.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (ThalomidTM) and TNP-470.
  • proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- g- or d- tocopherol or a- g- or d-tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CelebrexTM), rofecoxib (VioxxTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • Cox- 2 inhibitors such as celecoxib (CelebrexTM), rofecoxib (VioxxTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid is marketed under the trade name DidronelTM.
  • Clodronic acid is marketed under the trade name BonefosTM.
  • Tiludronic acid is marketed under the trade name SkelidTM.
  • Pamidronic acid is marketed under the trade name ArediaTM.
  • Alendronic acid is marketed under the trade name FosamaxTM.
  • Ibandronic acid is marketed under the trade name BondranatTM.
  • Risedronic acid is marketed under the trade name ActonelTM.
  • Zoledronic acid is marketed under the trade name ZometaTM.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras
  • a "famesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (ZamestraTM).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VelcadeTM) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, I-b-D-arabinofuransyl cytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DMl, erbitux, bevacizumab (AvastinTM), rituximab (Rituxan ® ), PR064553 (anti-CD40) and 2C4 Antibody.
  • trastuzumab HerceptinTM
  • Trastuzumab-DMl erbitux
  • bevacizumab AvastinTM
  • rituximab Rasteran ®
  • PR064553 anti-CD40
  • compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • the present invention provides a method of treating AML associated with an ITD and/or D835Y mutation, comprising administering a compound of the present invention together with a one or more FLT3 inhibitors.
  • the FLT3 inhibitors are selected from quizartinib (AC220), a staurosporine derivative ( e.g .
  • the FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.
  • anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • Compounds which target, decrease or inhibit activity of histone deacetyl ase (HD AC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases.
  • HD AC histone deacetyl ase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl) ⁇ 2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • the term "ionizing radiation” referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Heilman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate
  • AngiostatinTM EndostatinTM
  • anthranilic acid amides ZD4190; ZD6474; SU5416; SU6668
  • bevacizumab or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab
  • VEGF aptamer such as Macugon
  • FLT-4 inhibitors, FLT-3 inhibitors VEGFR-2 IgGI antibody
  • Angiozyme RI 4610)
  • Bevacizumab AvastinTM
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
  • Examples of photodynamic therapy include treatment with compounds, such as VisudyneTM and porfimer sodium.
  • Angiostatic steroids refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • angiogenesis such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • a compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-l 1294A (Napp), BAY19-8004 (Bayer), SCH- 351591 (Schering- Plough), Arofylline (Almirall Prodesfarma), PD 189659 / PD 168787 (Parke-
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.
  • chemokine receptors e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH- 55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H- benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4- aminium chloride (TAK-770).
  • TAK-770 antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H- benzo-cyclohepten-8-yl]carbony
  • a compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • a compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • a compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • Those additional agents may be administered separately from an inventive compound- containing composition, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term“combination,”“combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.
  • compositions which comprise an additional therapeutic agent that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 pg/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the compounds of this invention, or pharmaceutical compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • the crude product (120 mg) was purified by Prep-HPLC with the following conditions: column: X bridge Prep OBD C18 column, 30x 150mm 5um; mobile phase A: water (10MMOL/L NH 4 HCO 3 +0.1%NH 3 -H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 36% B to 50% B in 7 min; detector, UV 254/220 nm; rt: 5.92 min. This resulted in 100 mg (69.30%) of 1-1 as a white solid.
  • the crude product (5 mL) was purified by Prep-HPLC with the following conditions: column: X bridge Cl 8 OBD Prep column, lOOA, 5 pm, 19 mm X 250 mm; mobile phase A:water(10MMOL/L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 35% B to 45% B in 8 min; detector, UV 254/220 nm; rt: 7.10 min.
  • the mixture was evaporated, and the residue was purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, ACN and (AcOH in water), 10% to 50% gradient in 10 min; detector, UV 254 nm.
  • the crude product (19.1mg) was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column 30* 150, 5um; Mobile Phase A: Water (l%HOAc), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 50% B in 7 min; 254;220 nm; Rt: 5.57 min). This resulted in 3.9 mg (2.18%) of 1-80 as an off-white solid.
  • the product was obtained.
  • the residue was applied onto Prep-TLC with ethyl acetate/petroleum ether (2: 1). This resulted in 3.2 mg (2.45%) of 1-9 as a white solid.
  • the residue was applied onto Prep-TLC with ethyl acetate/petroleum ether (2: 1). This resulted in 7.1 mg (5.27%) of 1-10 as a white solid.
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18silical gel; mobile phase, FA in water, 10% to 50% gradient in 10 min; detector, UV 254 nm.
  • the crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column : Xbridge prep C18 5um 19* 150mm ; Mobile phase A: Waters(0.1%NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 20 ml/min; Gradient: 32 %B to 42 %B in 8 min; 254&220nm; t: 7.30 min). This resulted in 16.1 mg (7.67%) of 1-77 as a white solid.
  • the crude product (74 mg) was purified by Prep-HPLC with the following conditions (Column : Xbridge prep Cl 8 5um 19* 150mm ; Mobile phase A: Waters(0.1%FA), Mobile phase B: ACN; Flow rate: 20 ml/min; Gradient: 8 %B to 20 %B in 8 min; 254&220nm; t: 7.68 min).
  • the crude product was purified by Prep-HPLC with the following conditions: column: Cl 8, 30* 100mm, 5 um; mobile phase A: water/lOmmol/L NHdTCCh, mobile phase B: ACN flow rate: 25mL/min; gradient: 25%B to 55%B in 8min, hold 1.0 min; Detector 254nm&220nm; rt: 7.35min. This resulted in 14.9 mg (10.81%) of 1-11 as a white solid. (ES, m/z) ⁇ .
  • the resulting solution was irradiated with microwave radiation for 1 h at 140°C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3x5 mL of ethyl acetate. The resulting mixture was washed with 1 x5 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated.
  • the crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, silica gel; mobile phase, CFLCN/FLC O: ! increasing to CH3CN/H2OM : 1 within 20 min; Detector, UV 254nm. This resulted in 2.5 mg (2%) of 1-69 as a white solid.
  • the crude product was purified by Prep-SFC with the following conditions (Prep SFCIOO): Column, Lux 5u Cellulose-4, 2.12*25cm, 5um; mobile phase, CO2 (g) and EtOH (2mM NFL- MeOH) (50%) within 3.472 min; Detector, 254 nm. This resulted in 24.9 mg (16.45%) of 1-67 as a white solid.
  • the resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated.
  • the resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated.
  • Example 36 Synthesis of /V-(5-carbamoyl-l-propyl-l//-benzo[ ⁇ /
  • the resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated.
  • the resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated.
  • the crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 Column, 19*250mm, 5um; mobile phase, Water (l%HOAc) and MeOH-(60% PhaseB up to 80% in 7 min); Detector, UV 254 nm. This resulted in 33.2 mg (21.27%) of 1-50 as a off-white solid.
  • the resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated.
  • the solution was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep OBD; mobile phase, Water (lOmmol/L NHzdTCCL) and ACN (26% Phase B up to 36% in 10 min); Detector UV: 254 nm. This resulted in 29.6 mg (14.78%) of 1-21 as a white solid.
  • Table 2 below provides 3 ⁇ 4 NMR and MS data for additional exemplary compounds which were prepared using similar synthetic methodology and routes as Examples 1-59.
  • Results of exemplary compounds tested in the SPR assay are provided in Table 3, below.
  • Compounds that provided a KD of ⁇ 5 mM in the SPR assay are designated“A”; compounds that provided a KD of >5 mM and ⁇ 10 mM are designated“B”; and compounds that provided a KD of >10 mM are designated“C”.
  • HEK293T cells (ATCC CRL-3216) were stably co-transfected with plasmids expressing full length human STING (NM_198282 with the Histidine at position 232 mutated to an Arginine) (Genewiz) and the enzyme firefly luciferase driven by the interferon stimulated response element promoter (pISRE-luc2p) (Promega). Transfections were prepared using a cell suspension with Fugene ® 6 following the manufacturer’s instructions (3 : 1 Fugene® 6 :DNA). Stable clones were selected in media containing puromycin and hygromycin.
  • Percent activity was determined using the following equation: (Tope - Low)* 100/(Top R - Low) where Tope is the top luminescence value of compound; Low is luminescence value of low control and Top R is the top luminescence value of the reference compound.
  • Results of exemplary compounds tested in the 293T-luc2p-h232R agonist assay are provided in Table 4, below.
  • Compounds that provided an ECso of ⁇ 5 mM in the assay are designated“A”; compounds that provided a EC50 of >5 mM and ⁇ 30 pM are designated“B”; and compounds that provided a EC50 of >30 pM are designated“C”.
  • Example 63 293T-luc2p-mouse STING Agonist Assay.
  • HEK293T cells (ATCC CRL-3216) were stably co-transfected with plasmids expressing full length mouse STING (NM_028261) and the enzyme firefly luciferase driven by the interferon stimulated response element promoter (pISRE-luc2p) (Promega). Transfections were prepared using a cell suspension with Fugene ® 6 following the manufacturer’s instructions (3:1 Fugene® 6 :DNA). Stable clones were selected in media containing puromycin and hygromycin. 25 microliters of cell suspension containing 20,000 cells was dispensed into a 384 well plate containing 125 nanoliters of a compound.
  • Percent activity was determined using the following equation: (Tope - Low)* 100/(Top R - Low) where Tope is the top luminescence value of compound; Low is luminescence valueDof low control and Top R is the top luminescence value of the reference compound.
  • Results of exemplary compounds tested in the 293T-luc2p-mouse STING agonist assay are provided in Table 5, below.
  • Compounds that provided an ECso of ⁇ 5 mM in the assay are designated“A”; compounds that provided a ECso of >5 mM and ⁇ 30 mM are designated“B”; and compounds that provided a ECso of >30 mM are designated“C”.
  • Example 64 Human STING SPA Binding Assay
  • a radioligand binding assay was used to measure interactions of compound binding to STING protein by competition with [ 3 H]2’,3’-cGAMP.
  • Test compound is pre-incubated with 0.2ug/well His-tagged human STING (NM_198282) protein spanning residues 149-341 for 10 minutes at room temperature in a Perkin-Elmer Isoplate.
  • 150nM of the [ 3 H]2’,3’-cGAMP probe along with lOOug/well PVT Cu-His-tag SPA beads are then added to the plate and the reaction mixture is incubated at room temperature for another 45 minutes. Following incubation, the plates are placed in counting cassettes and counted on a Microbeta microplate counter for radiometric detection.
  • Compound binding IC50 is calculated using non-linear regression of the dose-response curve.
  • Results of exemplary compounds tested in the human STING SPA binding assay are provided in Table 6, below.
  • Compounds that provided an IC50 of ⁇ 10 mM in the assay are designated“A”; compounds that provided a IC50 of >10 mM and ⁇ 50 mM are designated“B”; compounds that provided a IC50 of >50 mM and ⁇ 100 mM are designated“B”; and compounds that provided a IC50 of >100 mM are designated“D”.
  • Example 65 Mouse STING SPA Binding Assay
  • a radioligand binding assay was used to measure interactions of compound binding to mouse STING protein by competition with [ 3 H]2’,3’-cGAMP.
  • Test compound is pre-incubated with 0.04ug/well His-tagged mouse STING (NM_028261) protein spanning residues 149-341 for 10 minutes at room temperature in a Perkin-Elmer Isoplate.
  • 20nM of the [ 3 H]2’,3’-cGAMP probe along with 20ug/well PVT Cu-His-tag SPA beads are then added to the plate and the reaction mixture is incubated at room temperature for another 45 minutes.
  • the plates are placed in counting cassettes and counted on a Microbeta microplate counter for radiometric detection.
  • Compound binding IC50 is calculated using non-linear regression of the dose-response curve.
  • Results of exemplary compounds tested in the mouse STING SPA binding assay are provided in Table 7, below.
  • Compounds that provided an IC50 of ⁇ 10 mM in the assay are designated“A”; compounds that provided a IC50 of >10 mM and ⁇ 50 mM are designated“B”; compounds that provided a IC50 of >50 mM and ⁇ 100 mM are designated“B”; and compounds that provided a IC50 of >100 mM are designated“D”.

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Abstract

The present invention provides compounds, compositions thereof, and methods of using the same for the modulation of STING, and the treatment of STING-mediated disorders.

Description

STING HETEROCYCLE AGONISTS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to United States provisional patent application serial number 62/783,489, filed December 21, 2018, the entirety of which is incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to compounds and methods useful for the modulation of STING-dependent type I interferon production. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
BACKGROUND OF THE INVENTION
[0003] Innate immunity is a rapid nonspecific immune response that fights against environmental insults including, but not limited to, pathogens such as bacteria or viruses. Adaptive immunity is a slower but more specific immune response, which confers long-lasting or protective immunity to the host and involves differentiation and activation of naive T lymphocytes into CD4+ T helper cells and/or CD8+ cytotoxic T cells, to promote cellular and humoral immunity. Antigen presentation cells of the innate immune system, such as dendritic cells or macrophages, serve as a critical link between the innate and adaptive immune systems by phagocytosing and processing the foreign antigens and presenting them on the cell surface to the T cells, thereby activating T cell response.
[0004] STING (stimulator of interferon genes) is an endoplasmic reticulum adaptor that facilitates innate immune signaling (Ishikawa and Barber, Nature 2008, 455(7213):674-678).
It was reported that STING comprises four putative transmembrane regions (Ouyang et ah, Immunity (2012) 36, 1073), predominantly resides in the endoplasmic reticulum and is able to activate NF-kB, STAT6, and IRF3 transcription pathways to induce expression of type I interferon (e.g., IFN-a and IFN-13) and exert a potent anti -viral state following expression (Ishikawa and Barber, Nature 2008, 455(7213):674-678; Chen et ak, Cell (2011) 147, 436- 446). In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative stranded virus infection, including vesicular stomatitis virus. (Ishikawa and Barber, Nature. 2008, 455(7213):674-678).
[0005] There remains a need for new therapeutics that are effective as STING agonists for the treatment of diseases, in particular cancer.
SUMMARY OF THE INVENTION
[0006] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as STING agonists. Such compounds have the general formula I:
Figure imgf000003_0001
I
or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
[0007] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with STING. Such diseases, disorders, or conditions include those described herein.
[0008] Compounds provided by this invention are also useful for the study of STING and associated proteins in biological and pathological phenomena; the study of STING occurring in bodily tissues; and the comparative evaluation of new STING agonists or other regulators of STING in vitro or in vivo.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
1. General Description of Certain Embodiments of the Invention:
[0009] Compounds of the present invention, and compositions thereof, are useful as STING ligands. [0010] As defined herein, the terms“agonist,”“binder,”“modulator,” and“ligand” are used interchangeably and describe a compound that binds to, modulates, activates, is a ligand for, or agonist of STING.
[0011] In certain embodiments, the present invention provides a compound of formula I:
Figure imgf000004_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Z is Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R6; or Z is -OR;
wherein Z is not
Figure imgf000004_0002
L is a covalent bond or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’)2-, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0)2-,
-S(0)2N(R)-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -S(0)- or -S(0)2-;
each R’ is independently hydrogen or Ci-4 aliphatic; or
two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 3-7 membered saturated or partially unsaturated carbocyclylene ring; or
two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R1 is selected from H; Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R1 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R2 is selected from H, Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R2 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R,
N(R)C(0)0R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R3 is selected from H, Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R3 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R,
N(R)C(0)0R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2, R4 is selected from H; Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R4 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R5 is -H, Ci-6 aliphatic which is substituted with q instances of Rc, or -L’-Q; or
R4 and R5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of Rc;
L’ is a covalent bond or a Ci-is bivalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one to four methylene units of the chain are optionally and independently
replaced by -Cy’-,
Figure imgf000007_0001
N(R)C(0)-, -C(0)N(R)-, -N(R)C(0)0-, -0C(0)N(R)-, -N(R)S(0)2-, -S(0)2N(R)-, -0-, - C(O)-, -OC(O)-, -C(0)0-, -S-, -S(O)-, or -S(0)2-;
each instance of -Cy’- is independently an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Q is hydrogen or a CRBN binding moiety;
each instance of R6 is independently oxo, halogen, -CN, -N02, -OR, -SR, -NR2, -S(0)2R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -C(0)NR2, -C(0)N(R)0R,
-0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, - N(R)CN, -P(0)(R)NR2, -P(0)(R)0R or -P(0)R2; or each instance of R6 is independently an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
two R6 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of Rc is independently oxo, halogen, -CN, -N02, -OR, -SR, -NR2, -S(0)2R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -C(0)NR2, -C(0)N(R)0R,
-0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, - N(R)CN, -P(0)(R)NR2, -P(0)(R)0R or -P(0)R2 ; or each instance of Rc is independently an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of n and q is independently 0, 1, 2, 3, or 4; and
each of x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 2. Compounds and Definitions:
[0012] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and“March’s Advanced Organic Chemistry”, 5th Ed., Ed. : Smith, M.B. and March, T, John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0013] The term“aliphatic” or“aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,"“cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments,“cycloaliphatic” (or“carbocycle” or“cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0014] As used herein, the term“bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a“bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a“bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
Figure imgf000010_0001
[0015] The term“lower alkyl” refers to a Ci-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
[0016] The term“lower haloalkyl” refers to a Ci-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
[0017] The term“heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3 ,4-di hydro-2//-pyrrol yl ), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).
[0018] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.
[0019] As used herein, the term“bivalent Ci-s (or Ci-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
[0020] The term“alkylene” refers to a bivalent alkyl group. An“alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
[0021] The term“alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
[0022] As used herein, the term“cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:
Figure imgf000011_0001
[0023] The term“halogen” means F, Cl, Br, or I.
[0024] The term“aryl” used alone or as part of a larger moiety as in“aralkyl,”“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term“aryl ring.” In certain embodiments of the present invention,“aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term“aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
[0025] The terms“heteroaryl” and“heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or“heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms“heteroaryl” and“heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term“heteroaryl” may be used interchangeably with the terms“heteroaryl ring,”“heteroaryl group,” or“heteroaromatic,” any of which terms include rings that are optionally substituted. The term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
[0026] As used herein, the terms“heterocycle,”“heterocyclyl,”“heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2H pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N substituted pyrrolidinyl).
[0027] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and“heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3// indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
[0028] As used herein, the term“partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term“partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
[0029] As described herein, compounds of the invention may contain“optionally substituted” moieties. In general, the term“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. Unless otherwise indicated, 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. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
[0030] Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)o-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(Cfbjo- SR0; -(CFbjo-iPh, which may be substituted with R°; -(Cfbjo- CXCIUjo-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)O- 4N(R0)C(0)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(RO)C(O)OR°;
N(R°)N(R°)C(0)R°; -N(R°)N(R0)C(0)NR°2; -N(R°)N(R°)C(0)0R°; -(CH2)o-4C(0)R°; - C(S)R°; -(CH2)< C(0)0R°; -(CH2)O-4C(0)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)0-4OC(O)R°; - OC(0)(CH2)O-4SR- SC(S)SR°; -(CH2)< SC(0)R°; -(CH2)O-4C(0)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)O-4OC(0)NR°2 ; -C(0)N(0R°)R°; -C(0)C(0)R°; -C(0)CH2C(0)R°; - C(NOR°)R°; -(CH2), SSR°; -(CH2)( S(0)2R°; -(CH2> S(0)20R°; -(CH2)0-4OS(O)2Ro; - S(0)2NR°2; -(CH2)O-4S(0)R°; -N(R°)S(0)2NR°2; -N(R°)S(0)2R°; -N(OR°)R°; -C(NH)NR°2; - P(0)2R°; -P(0)R°2; -0P(0)R°2; -0P(0)(0R°)2; SiR°3; -(Ci-4 straight or branched alkylene)0- N(R°)2; or -(Ci-4 straight or branched alkylene)C(0)0-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o- iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
[0031] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)O-2OH, -(CH2)O-2OR·, -(CH2)O-2CH(OR*)2; -0(haloR*), -CN, -N3, -(CH2)0-
2C(0)R·, -(CH2)O-2C(0)OH, -(CH2)O-2C(0)OR·, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, - (CH2)O-2NHR·, -(CH2)O-2NR*2, -N02, -SiR*3, -OSiR*3, -C(0)SR* -(Ci_4 straight or branched alkylene)C(0)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently selected from Ci-4 aliphatic, - CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.
[0032] Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: =0, =S, =NNR%, =NNHC(0)R*, =NNHC(0)OR*, =NNHS(0)2R*, =NR*, =NOR*, -0(C(R* 2))2-30-, or -S(C(R* 2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: -0(CR* 2)2- 3O-, wherein each independent occurrence of Rf is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0033] Suitable substituents on the aliphatic group of R* include halogen, R*, -(haloR*), -OH, -OR*, -0(haloR*), -CN, -C(0)OH, -C(0)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0034] Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include -R†, -NR† 2, -C(0)R†, -C(0)OR†, -C(0)C(0)R†,
C(0)CH2C(0)R†, -S(0)2R†, -S(0)2NR†2, -C(S)NR†2, -C(NH)NR†2, or -N(R†)S(0)2R†; wherein each R' is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0035] Suitable substituents on the aliphatic group of R' are independently halogen, - R*, -(haloR* ), -OH, -OR*, -0(haloR*), -CN, -C(0)OH, -C(0)OR*, -NH2, NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0036] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[0037] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci^alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0038] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. For example, it will be appreciated by those skilled in the art that the compounds of this invention may exist in tautomeric
forms including, but not limited to,
Figure imgf000017_0001
tautomeric forms.
[0039] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention
[0040] As used herein, the term“agonist” is defined as a compound that binds to and /or activates STING with measurable affinity. In certain embodiments, an agonist or activator has an EC50 and/or effective concentration of less than about 50 mM, less than about 1 mM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
[0041] A compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term“suitable substituent” refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described by Rostovtsev et al ., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al, Bioconjugate Chem., 2006, 17, 52-57.
[0042] As used herein, the term“detectable moiety” is used interchangeably with the term "label" and relates to any moiety capable of being detected, e.g., primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, 32P, 33P, 35S, or 14C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups.
[0043] The term“secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal.
[0044] The terms“fluorescent label”,“fluorescent dye”, and“fluorophore” as used herein refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone- fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.
[0045] The term“mass-tag” as used herein refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass-tags include electrophore release tags such as N-[3-[4’-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2, 3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives. The synthesis and utility of these mass-tags is described in United States Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass- tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition. A large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.
[0046] The terms“measurable affinity” and“measurably activate,” as used herein, means a measurable change in STING activity between a sample comprising a compound of the present invention, or composition thereof, and STING, and an equivalent sample comprising STING, in the absence of said compound, or composition thereof.
3. Description of Exemplary Embodiments:
[0047] As described above, in certain embodiments, the present invention provides a compound of formula I:
Figure imgf000019_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Z is Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R6; or Z is -OR;
wherein Z is not
Figure imgf000020_0001
L is a covalent bond or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’)2-, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0)2-,
-S(0)2N(R)-, -0-, -C(0)-, -OC(O)-, -C(0)0-, -S-, -S(O)- or -S(0)2-;
each R’ is independently hydrogen or Ci-4 aliphatic; or
two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 3-7 membered saturated or partially unsaturated carbocyclylene ring; or
two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R1 is selected from H; Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R1 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R2 is selected from H, Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R2 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R,
N(R)C(0)0R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R3 is selected from H, Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R3 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R,
N(R)C(0)0R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R4 is selected from H; Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R4 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R5 is -H, Ci-6 aliphatic which is substituted with q instances of Rc, or -L’-Q; or
R4 and R5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of Rc;
L’ is a covalent bond or a Ci-15 bivalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one to four methylene units of the chain are optionally and independently replaced
Figure imgf000023_0001
N(R)C(0)-, -C(0)N(R)-, -N(R)C(0)0- -0C(0)N(R)-, -N(R)S(0)2-, -S(0)2N(R)-, -0-, - C(0)-, -0C(0)-, -C(0)0- -S-, -S(0)-, or -S(0)2-;
each instance of -Cy’- is independently an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Q is hydrogen or a CRBN binding moiety;
each instance of R6 is independently oxo, halogen, -CN, -N02, -OR, -SR, -NR2, -S(0)2R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -C(0)NR2, -C(0)N(R)0R,
-0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, - N(R)CN, -P(0)(R)NR2, -P(0)(R)0R or -P(0)R2; or each instance of R6 is independently an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
two R6 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of Rc is independently oxo, halogen, -CN, -N02, -OR, -SR, -NR2, -S(0)2R,
-S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -C(0)NR2, -C(0)N(R)0R,
-0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, - N(R)CN, -P(0)(R)NR2, -P(0)(R)0R or -P(0)R2 ; or each instance of Rc is independently an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of n and q is independently 0, 1, 2, 3, or 4; and
each of x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[0048] As defined generally above, Z is Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R6; or Z
is -OR, wherein Z is not
Figure imgf000024_0001
[0049] In certain embodiments, Z is Ci-6 aliphatic; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R6.
[0050] In certain embodiments, Z is Ci-4 aliphatic; a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R6.
[0051] In some embodiments, Z is -OR.
[0052] In certain embodiments, Z is selected from -Me, -Et, -Pr, -iPr, -Bu, -sBu, -iBu, straight chain or branched pentyl, straight chain or branched hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 277,677-1, 5, 2-dithiazinyl, dihydrofuro [2,3-/>] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 377-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- l,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothi azole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2//-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6//- 1 ,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,
1.2.4-thiadiazolyl, 1,2,5-thiadiazolyl, l,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1.2.4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is substituted by n instances of R6; or Z is -OR.
[0053] In certain embodiments, Z is selected from -Me, -Et, -Pr, -CH2OCH3, -CH(Et)2, -OMe, -O/Bu,
Figure imgf000026_0001
Figure imgf000027_0001
[0054] In some embodiments, Z is -Me. In some embodiments, Z is -Et. In some embodiments, Z is -Pr. In some embodiments, Z is -CH2OCH3. In some embodiments, Z is - CH(Et)2. In some embodiments, Z is -OMe. In some embodiments, Z is -O/Bu.
[0055] In some embodiments,
Figure imgf000027_0002
[0056]
Figure imgf000027_0003
[0057]
Figure imgf000027_0004
[0058] In some embodiments,
Figure imgf000027_0005
[0059] In some embodiments,
Figure imgf000027_0006
[0060] In some embodiments,
Figure imgf000028_0001
[0061] In some embodiments,
Figure imgf000028_0002
[0062] In some embodiments,
Figure imgf000028_0003
[0063] In some embodiments,
Figure imgf000028_0004
[0064] In some embodiments,
Figure imgf000028_0005
[0065] In some embodiments,
Figure imgf000028_0006
[0066] In some embodiments,
Figure imgf000028_0007
[0067] In some embodiments, Z is
Figure imgf000028_0008
[0068] In some embodiments, Z is
Figure imgf000028_0009
[0069] In some embodiments, Z is
Figure imgf000028_0010
[0070] In some embodiments, Z is
Figure imgf000028_0011
? V-l
N-J
[0071] In some embodiments, Z is n(R6)
[0072] In some embodiments, Z is
[0073] In some embodiments, Z is
Figure imgf000029_0001
[0074] In some embodiments,
Figure imgf000029_0002
[0075] In some embodiments,
Figure imgf000029_0003
[0076] In some embodiments,
Figure imgf000029_0004
[0077] In some embodiments,
Figure imgf000029_0005
[0078] In some embodiments, Z is
Figure imgf000029_0006
. [0079]
Figure imgf000030_0001
[0080]
Figure imgf000030_0002
[0081] In certain embodiments, Z is -Me, -Et, -Pr, -CH2OCH3, -CH(Et)2, -OMe, -O-/-B11,
Figure imgf000030_0003
Figure imgf000031_0001
[0082] In some embodiments, Z is selected from those depicted in Table 1, below.
[0083] As defined generally above, L is a covalent bond or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’)2-, -N(R)-, -N(R)C(0)-, -C(0)N(R)- , -N(R)S(0)2-, -S(0)2N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -S(0)- or -S(0)2-.
[0084] In some embodiments, L is a covalent bond.
[0085] In some embodiments, L is a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’)2-, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0)2-
, -S(0)2N(R)-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -S(0)-, or -S(0)2-.
[0086] In some embodiments, L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R>, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0)2-, -S(0)2N(R)-, -0-, -C(O)-, -OC(O)- , -C(0)0-, -S-, -S(O)-, or— S(0)2-. In some embodiments, L is a Ci-4 bivalent unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’)2-, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0)2-
, -S(0)2N(R)-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -S(0)-, or -S(0)2-.
[0087] In some embodiments, L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -C(R’)2-, -N(R)-, - N(R)C(0)-, -C(0)N(R)-, -N(R)S(0)2-, -S(0)2N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -S(O)-, or— S(0)2-. In some embodiments, L is a Ci-4 bivalent unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally replaced by -C(R>, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0)2-, -S(0)2N(R)-, -0-, -C(0)-, -OC(O)- , -C(0)0-, -S-, -S(O)-, or -S(0)2-.
[0088] In some embodiments, L is a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain. In some embodiments, L is a Ci-4 bivalent saturated, straight or branched hydrocarbon chain. In some embodiments, L is a Ci-4 bivalent unsaturated, straight or branched hydrocarbon chain.
[0089] In some embodiments, L is a covalent bond, -C(R’)2-, -N(R)-, or -0-. In some embodiments, L is a covalent bond or -N(R)-. In some embodiments, L is -C(R’)2-, -N(R)-, or - 0-. In some embodiments, L is a covalent bond, -CH2-, -N(H)-, or -0-. In some embodiments, L is -CH2-, -N(H)-, or -0-.
[0090] In some embodiments, L is -CH2-.
[0091] In some embodiments, L is selected from those depicted in Table 1, below.
[0092] As defined generally above, each R’ is independently hydrogen or Ci-4 aliphatic; or two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 3-7 membered saturated or partially unsaturated carbocyclylene ring; or two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0093] In some embodiments, R’ is hydrogen. In some embodiments, R’ is Ci-4 aliphatic. In some embodiments, two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 3-7 membered saturated or partially unsaturated carbocyclylene ring. In some embodiments, two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0094] In some embodiments, R’ is selected from those depicted in Table 1, below.
[0095] As defined generally above, each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[0096] In some embodiments, R is selected from those depicted in Table 1, below.
[0097] As defined generally above, R1 is selected from H; Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R1 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, -
N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[0098] In some embodiments, R1 is H, Ci-6 aliphatic which is substituted with q instances of Rc; phenyl which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R1 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, -
N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[0099] In some embodiments, R1 is H.
[00100] In some embodiments, R1 is Ci-6 aliphatic which is substituted with q instances of Rc; phenyl which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R1 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, -
N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00101] In some embodiments, R1 is Ci-6 aliphatic which is substituted with q instances of Rc. In some embodiments, R1 is phenyl which is substituted with q instances of Rc. In some embodiments, R1 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc. In some embodiments, R1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc. In some embodiments, R1 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of RC.
[00102] In some embodiments, R1 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, -
N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00103] In some embodiments, R1 is halogen, -OR, -NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, or -N(R)C(0)NR2.
[00104] In some embodiments, R1 is H, Ci-6 aliphatic which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R1 is halogen, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, -C(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, or -N(R)S(0)2R.
[00105] In some embodiments, R1 is H, Ci-6 aliphatic which is substituted with q instances of Rc; or R1 is halogen, OR, -C(0)R, -C(0)OR.
[00106] In some embodiments, R1 is H.
[00107] In some embodiments, R1 is selected from those depicted in Table 1, below.
[00108] As defined generally above, R2 is selected from H, Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R2 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00109] In some embodiments, R2 is H, Ci-6 aliphatic which is substituted with q instances of Rc; phenyl which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R2 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R, -N(R)C(0)0R, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00110] In some embodiments, R2 is H.
[00111] In some embodiments, R2 is Ci-6 aliphatic which is substituted with q instances of Rc; phenyl which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R2 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00112] In some embodiments, R2 is Ci-6 aliphatic which is substituted with q instances of Rc. In some embodiments, R2 is phenyl which is substituted with q instances of Rc. In some embodiments, R2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc. In some embodiments, R2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc. In some embodiments, R2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc.
[00113] In some embodiments, R2 is halogen, -CN, -N02, -OR, SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R, -N(R)C(0)0R, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00114] In some embodiments, R2 is halogen, -OR, -NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R, -N(R)C(0)0R, or -N(R)C(0)NR2.
[00115] In some embodiments, R2 is H, Ci-6 aliphatic which is substituted with q instances of Rc; or R2 is halogen, -
OR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -OC(0)R, -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)NR2.
[00116] In some embodiments, R2 is H, -OR, -C(0)OR, -C(0)NR2, -OC(0)R, or -N(R)C(0)R.
[00117] In certain embodiments, R2 is -H, or -C(0)NH2.
[00118] In some embodiments, R2 is selected from those depicted in Table 1, below.
[00119] As defined generally above, R3 is selected from H, Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R3 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00120] In some embodiments, R3 is H, Ci-6 aliphatic which is substituted with q instances of Rc; phenyl which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R3 is halogen, -CN, -N02, -OR, SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R, -N(R)C(0)0R, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00121] In some embodiments, R3 is H.
[00122] In some embodiments, R3 is Ci-6 aliphatic which is substituted with q instances of Rc; phenyl which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R3 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00123] In some embodiments, R3 is Ci-6 aliphatic which is substituted with q instances of Rc. In some embodiments, R3 is phenyl which is substituted with q instances of Rc. In some embodiments, R3 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc. In some embodiments, R3 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc. In some embodiments, R3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc.
[00124] In some embodiments, R3 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00125] In some embodiments, R3 is halogen, -OR, -NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)R, -N(R)C(0)OR, or -N(R)C(0)NR2.
[00126] In some embodiments, R3 is -H, Ci-6 aliphatic which is substituted with q instances of Rc; or R3 is halogen, -
OR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -0C(0)R, -N(R)C(0)R, -N(R)C(0)0R, or -N(R)C(0)NR2.
[00127] In some embodiments, R3 is -H, -OR, -C(0)OR, -C(0)NR2, -OC(0)R, or -N(R)C(0)R.
[00128] In certain embodiments, R3 is -H or -C(0)NH2.
[00129] In some embodiments, R3 is selected from those depicted in Table 1, below.
[00130] As defined generally above, R4 is selected from H; Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R4 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, -
N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00131] In some embodiments, R4 is H, Ci-6 aliphatic which is substituted with q instances of Rc; phenyl which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R4 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, -
N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00132] In some embodiments, R4 is H.
[00133] In some embodiments, R4 is Ci-6 aliphatic which is substituted with q instances of Rc; phenyl which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R1 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, -
N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00134] In some embodiments, R4 is Ci-6 aliphatic which is substituted with q instances of Rc. In some embodiments, R4 is phenyl which is substituted with q instances of Rc. In some embodiments, R4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc. In some embodiments, R4 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc. In some embodiments, R4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc.
[00135] In some embodiments, R4 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, -
N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2.
[00136] In some embodiments, R4 is halogen, -OR, -NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, -N(R)C(0)OR, or -N(R)C(0)NR2.
[00137] In some embodiments, R4 is H, Ci-6 aliphatic which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R4 is halogen, -OR, SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, -C(0)NR2, -N(R)C(0)OR, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, or -N(R)S(0)2R.
[00138] In some embodiments, R4 is H, Ci-6 aliphatic which is substituted with q instances of Rc; or R4 is halogen, -OR, -C(0)R, -C(0)OR.
[00139] In certain embodiments, R4 is -H, -Me, -OH, -OMe, -C(0)OH,
Figure imgf000041_0001
[00140] In some embodiments, R4 is selected from those depicted in Table 1, below.
[00141] As defined generally above, R5 is -H, Ci-6 aliphatic which is substituted with q instances of Rc, or -L’-Q.
[00142] In some embodiments, R5 is -H.
[00143] In some embodiments, R5 is Ci-6 aliphatic which is substituted with q instances of Rc.
[00144] In some embodiments, R5 is Ci-4 aliphatic which is substituted with q instances of Rc.
[00145] In some embodiments, R5 is -L’-Q.
[00146] In some embodiments, R5 is -H, -Pr,
Figure imgf000042_0001
[00148] In some embodiments, R5 is selected from those depicted in Table 1, below.
[00149] As defined generally above, R4 and R5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of Rc.
[00150] In certain embodiments, R4 and R5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with n instances of Rc.
[00151] In certain embodiments, R4 and R5 taken together form
Figure imgf000043_0001
[00152] In some embodiments, R4 and R5 taken together is selected from those depicted in Table 1, below.
[00153] As defined generally above, L’ is a covalent bond or a Ci-is bivalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one to four methylene units of the
Figure imgf000043_0002
, [00156] In some embodiments, L’ is selected from those depicted in Table 1, below.
[00157] As defined generally above, each instance of -Cy’- is independently an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00158] In some embodiments, -Cy’- is an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00159] In some embodiments, -Cy’- is selected from those depicted in Table 1, below.
[00160] As defined generally above, Q is hydrogen or a CRBN binding moiety.
[00161] In some embodiments, Q is hydrogen. In some embodiments, Q is a CRBN binding moiety.
[00162] In some embodiments,
Figure imgf000044_0001
[00163] In some embodiments, Q is selected from those depicted in Table 1, below.
[00164] As defined generally above, each instance of R6 is independently oxo, halogen, -CN,
-NO2, -OR, -SR, -NR2, -S(0)2R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -
C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2,
N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, - N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, -N(R)CN, -P(0)(R)NR2, -P(0)(R)0R or -P(0)R2; or each instance of R6 is independently an optionally substituted group selected from Ci- 6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R6 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00165] In certain embodiments, each instance of R6 is independently oxo, halogen, -CN, - N02, -OR, -SR, -NR2, -S(0)2R,
-S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, -C(0)NR2, -C(0)N(R)OR,
-OC(0)R, -OC(0)NR2, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, -N(R)CN, - P(0)(R)NR2, -P(0)(R)OR or -P(0)R2; or each instance of R6 is independently an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
two R6 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
[00166] In certain embodiments, each instance of R6 is independently halogen, -CN, -N02, - OR, -NR2, -S(0)2R,
-S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, -C(0)NR2,
-OC(0)R, -0C(0)NR2, -N(R)C(0)OR, or -N(R)C(0)R; or each instance of R6 is independently an optionally substituted Ci-6 aliphatic.
[00167] In certain embodiments, each instance of R6 is independently halogen, -OR, -NR2, or optionally substituted Ci-6 aliphatic In certain embodiments, each instance of R6 is independently -Cl, -Me, -Et, -OMe, or -CF .
[00168] In some embodiments, each R6 is independently is selected from those depicted in Table 1, below.
[00169] As defined generally above, each instance of Rc is independently oxo, halogen, -CN, -N02, -OR, -SR, -NR2, -S(0)2R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, - C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2, N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, - N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, -N(R)CN, -P(0)(R)NR2, -P(0)(R)0R or -P(0)R2 ; or each instance of Rc is independently an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00170] In some embodiments, each instance of Rc is independently oxo, halogen, -CN, -N02, -OR, -SR, -NR2, -S(0)2R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)OR, -
C(0)NR2, -C(0)N(R)OR, -OC(0)R, -OC(0)NR2,
N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, - N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, -N(R)CN, -P(0)(R)NR2, -P(0)(R)OR or -P(0)R2 or an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00171] In some embodiments, each instance of Rc is selected from those depicted in Table 1, below.
[00172] As defined generally above, each hydrogen bound to carbon can be optionally and independently replaced by deuterium.
[00173] In some embodiments, a hydrogen bound to carbon is replaced by deuterium.
[00174] As defined generally above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
[00175] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 3. In some embodiments, n is 2 or 3. In some embodiments, n is 2 or 4. In some embodiments, n is 1, 2, or 4. In some embodiments, n is 1, 3, or 4. In some embodiments, n is 2, 3, or 4.
[00176] In some embodiments, n is selected from those depicted in Table 1, below.
[00177] As defined generally above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.
[00178] In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In some embodiments, q is 2 or 4. In some embodiments, q is 1, 2, or 4. In some embodiments, q is 1, 3, or 4. In some embodiments, q is 2, 3, or 4.
[00179] In some embodiments, q is selected from those depicted in Table 1, below.
[00180] As defined generally above, each of x is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[00181] In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8. In some embodiments, x is 9. In some embodiments, x is 10.
[00182] In some embodiments, x is selected from those depicted in Table 1, below. [00183] In some embodiments, the present invention provides a compound of formula II:
Figure imgf000048_0001
II
or a pharmaceutically acceptable salt thereof, wherein each of Z, R1, R2, R3, R4, and R5, is as defined above and described in embodiments herein, both singly and in combination.
[00184] In some embodiments, the present invention provides a compound of formula III:
Figure imgf000048_0002
III
or a pharmaceutically acceptable salt thereof, wherein each of Z, R1, R3, R4, and R5, is as defined above and described in embodiments herein, both singly and in combination.
[00185] In some embodiments, the present invention provides a compound of formula IV wherein L is a covalent bond, thereby forming a compound of formula IV:
Figure imgf000048_0003
IV
or a pharmaceutically acceptable salt thereof, wherein each of Z, R1, R2, R3, and R4, is as defined above and described in embodiments herein, both singly and in combination.
[00186] In some embodiments, the present invention provides a compound of formula V wherein L is a covalent bond, thereby forming a compound of formula V:
Figure imgf000049_0001
V
or a pharmaceutically acceptable salt thereof, wherein each of Z, R1, R3, and R4, is as defined above and described in embodiments herein, both singly and in combination.
[00187] In some embodiments, the present invention provides a compound of formula VI wherein L is a covalent bond, thereby forming a compound of formula VI:
Figure imgf000049_0002
VI
or a pharmaceutically acceptable salt thereof, wherein each of Z, R1, R3, and R4, is as defined above and described in embodiments herein, both singly and in combination.
[00188] Exemplary compounds of the invention are set forth in Table 1, below.
Table 1. Selected Compounds
Figure imgf000049_0003
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Uses, Formulation and Administration
Pharmaceutically acceptable compositions
[00189] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to modulate STING, or a mutant thereof, - dependent type I interferon production in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably modulate STING, or a mutant thereof, -dependent type I interferon production in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
[00190] The term“patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
[00191] The term“pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00192] A“pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite or residue thereof.
[00193] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[00194] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
[00195] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[00196] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[00197] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[00198] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
[00199] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
[00200] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
[00201] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[00202] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
[00203] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.
[00204] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
Uses of Compounds and Pharmaceutically Acceptable Compositions
[00205] In certain embodiments, the invention provides a method of inducing an immune response in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
[00206] In certain embodiments, the invention provides a method of inducing a STING- dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
[00207] In certain embodiments, the invention provides a method of inducing a STING- dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
[00208] In some embodiments, the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
[00209] In certain aspects, the invention provides a method of treating cell proliferation disorders, including cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma. [00210] In one aspect, the invention provides a method of treating a cell proliferation disorder in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, to the subject.
[00211] In certain embodiments, the cell proliferation disorder is cancer.
[00212] In certain embodiments, the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma. In another embodiment the cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
[00213] In certain embodiments, the cancer is selected from 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). In particular embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In particular embodiments, the cancer is AIDS-related.
[00214] In a further embodiment, the cancer is selected from brain and spinal cancers. In particular embodiments, the cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (olfactory blastomas). In particular embodiments, the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma), oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astorcytom a/ al i gn ant glioma, visual pathway and hypothalmic glioma, and primary central nervous system lymphoma. In specific instances of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumors (sPNET).
[00215] In specific embodiments, the cancer is selected from cancers of the head and neck, including nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), and cancers of the eye or ocular cancers. In particular embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.
[00216] In specific embodiments, the cancer is selected from leukemia and cancers of the blood. In particular embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)- associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas. Leukemias referenced herein may be acute or chronic.
[00217] In specific embodiments, the cancer is selected from skin cancers. In particular embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers.
[00218] In specific embodiments, the cancer is selected from cancers of the reproductive system. In particular embodiments, the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, prostate cancers, penile cancers, and testicular cancers. In specific instances of these embodiments, the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors. In specific instances of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In specific instances of these embodiments, the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas. In specific instances of these embodiments, the cancer is an ovarian cancer selected from the group consisting of epithelial cancers.
[00219] In specific embodiments, the cancer is selected from cancers of the gastrointestinal system. In particular embodiments, the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers), gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer. In instances of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas.
[00220] In specific embodiments, the cancer is selected from liver and bile duct cancers. In particular embodiments, the cancer is liver cancer (hepatocellular carcinoma). In particular embodiments, the cancer is bile duct cancer (cholangiocarcinoma); in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.
[00221] In specific embodiments, the cancer is selected from kidney and bladder cancers. In particular embodiments, the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers. In particular embodiments, the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas.
[00222] In specific embodiments, the cancer is selected from bone cancers. In particular embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma. [00223] In specific embodiments, the cancer is selected from lung cancers. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.
[00224] In specific embodiments, the cancer is selected from malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.
[00225] In specific embodiments, the cancer is selected from sarcomas. In particular embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.
[00226] In specific embodiments, the cancer is selected from lymphomas. In particular embodiments, the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., Reed- Stemberg cells), non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphomas, and primary central nervous system lymphomas.
[00227] In specific embodiments, the cancer is selected from glandular cancers. In particular embodiments, the cancer is selected from the group consisting of adrenocortical cancer, pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.
[00228] In specific embodiments, the cancer is selected from thyroid cancers. In particular embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.
[00229] In specific embodiments, the cancer is selected from germ cell tumors. In particular embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In specific instances of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.
[00230] In specific embodiments, the cancer is selected from heart tumors. In particular embodiments, the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma. [00231] In specific embodiments, the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases. In particular embodiments, the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma. In particular embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors).
Combination Therapies
[00232] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as“appropriate for the disease, or condition, being treated.”
[00233] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.
[00234] Examples of agents the combinations of this invention may also be combined with include, without limitation: treatments for Alzheimer’s Disease such as Aricept® and Excel on®; treatments for HIV such as ritonavir; treatments for Parkinson’s Disease such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3 A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immunodeficiency disorders such as gamma globulin.
[00235] In certain embodiments, combination therapies of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or an siRNA therapeutic.
[00236] Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
[00237] As used herein, the term“combination,”“combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
[00238] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
[00239] In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent may be administered together with a compound of formula I, or may be administered prior to or following administration of a compound of formula I. Suitable therapeutic agents are described in further detail below. In certain embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.
[00240] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofm (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL- 1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfmavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron ®) in combination with lenalidomide (Revlimid ®), or any combination(s) thereof.
[00241] In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methyl prednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofm (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-l” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®),“anti-T-cell” agents such as abatacept (Orencia®) and“anti-IL-6” agents such as tocilizumab (Actemra®).
[00242] In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.
[00243] In some embodiments, the present invention provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).
[00244] In some embodiments, the present invention provides a method of treating Crohn’s disesase, ulcerative colitis, or inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.
[00245] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).
[00246] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®,
[00247] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
[00248] In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
[00249] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al“Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).
[00250] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.
[00251] In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
[00252] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’ s disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto’s thyroiditis, Ord’s thyroiditis, Graves’ disease, autoimmune thyroiditis, Sjogren’s syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture’s syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter’s syndrome, Takayasu’s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener’s granulomatosis, psoriasis, alopecia universalis, Behcet’s disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferative disease, rejection of transplanted organs or tissues, Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B- cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/W aldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non- Hodgkin’s lymphoma, Hodgkin’s lymphoma, plasmacyto a, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., astocyto a, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joints including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter’s disease), Behcet’s disease, Sjogren’s syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, a thromboembolic disorder, (e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, deep venous thrombosis), inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn’s disease, irritable bowel syndrome, ulcerative colitis, Sjogren’s disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture’s syndrome, atherosclerosis, Addison’s disease, Parkinson’s disease, Alzheimer’s disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto’s thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet’s disease, scleraderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves’ disease.
[00253] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.
[00254] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, (including, for example, non-Hodgkin’s Lymphoma (NHL) and Hodgkin’s lymphoma (also termed Hodgkin’s or Hodgkin’s disease)), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or a leukemia, diseases include Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway is aberrantly activated, asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy, bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil- related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
[00255] In some embodiments the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin’s disease, small-cell lung cancer, non-small- cell lung cancer, myelodysplastic syndrome, lymphoma, a hematological neoplasm, or solid tumor. [00256] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
[00257] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term“patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.
[00258] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00259] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00260] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00261] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[00262] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[00263] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[00264] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, pol yvi nyl pyrroli di none, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[00265] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
[00266] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[00267] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00268] According to one embodiment, the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. [00269] According to another embodiment, the invention relates to a method of activating STING, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. In certain embodiments, the invention relates to a method of irreversibly inhibiting STING, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
[00270] The term“biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
[00271] Activation of STING (or a mutant thereof) activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
[00272] Another embodiment of the present invention relates to a method of activating STING in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
[00273] According to another embodiment, the invention relates to a method of activating STING, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. According to certain embodiments, the invention relates to a method of reversibly or irreversibly inhibiting one or more of STING, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by STING, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.
[00274] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as“appropriate for the disease, or condition, being treated.”
[00275] A compound of the current invention may also be used to advantage in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti neoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF 1010, CNF2024, CNF 1010 from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
[00276] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an anti estrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
[00277] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.
[00278] The term "topoisom erase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.
[00279] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.
[00280] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.
[00281] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.
[00282] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
[00283] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.
[00284] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™.
[00285] The term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor- receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD 180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAR, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or members of the cyclin- dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safmgol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23/RG- 50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{ [(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, El . l, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATE1-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).
[00286] The term“PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to RI3Ka, RI3Kg, RBKd, RI3Kb, PI3K-C2a, PI3K-C2p, PI3K- C2y, Vps34, pi 10-a, pi 10-b, pi 10-g, pi 10-d, p85-a, r85-b, r55-g, pl50, plOl, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATE1-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
[00287] The term“BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib. [00288] The term“SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.
[00289] The term“Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see W02008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see W02004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.
[00290] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
[00291] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02003063794, W02005007623, and W02006078846, the entirety of which are incorporated herein by reference.
[00292] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02004019973, W02004089925, W02007016176, US8138347, W02002088112, W02007084786,
W02007129161, W02006122806, W02005113554, and W02007044729 the entirety of which are incorporated herein by reference.
[00293] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in W02009114512, W02008109943, W02007053452, W02000142246, and W02007070514, the entirety of which are incorporated herein by reference.
[00294] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470. [00295] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.
[00296] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
[00297] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- g- or d- tocopherol or a- g- or d-tocotrienol.
[00298] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
[00299] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.
[00300] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.
[00301] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "famesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (Zamestra™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
[00302] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
[00303] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.
[00304] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
[00305] The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, I-b-D-arabinofuransyl cytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.
[00306] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
[00307] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors. [00308] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DMl, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
[00309] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412. In some embodiments, the present invention provides a method of treating AML associated with an ITD and/or D835Y mutation, comprising administering a compound of the present invention together with a one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitors are selected from quizartinib (AC220), a staurosporine derivative ( e.g . midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.
[00310] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetyl ase (HD AC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl){2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Heilman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).
[00311] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term“ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.
[00312] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).
[00313] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.
[00314] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
[00315] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone. [00316] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
[00317] The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.
[00318] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-l 1294A (Napp), BAY19-8004 (Bayer), SCH- 351591 (Schering- Plough), Arofylline (Almirall Prodesfarma), PD 189659 / PD 168787 (Parke- Davis), AWD-12- 281 (Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate. [00319] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.
[00320] Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH- 55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H- benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4- aminium chloride (TAK-770).
[00321] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).
[00322] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
[00323] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. [00324] Those additional agents may be administered separately from an inventive compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
[00325] As used herein, the term“combination,”“combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
[00326] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.
[00327] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 pg/kg body weight/day of the additional therapeutic agent can be administered.
[00328] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. [00329] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.
EXEMPLIFICATION
[00330] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
Synthesis of Intermediates:
Figure imgf000115_0001
[00331] Synthesis of compound 1.1. Into a 100-mL 3-necked round-bottom flask, was placed methyl 4-chloro-3-methoxy-5-nitrobenzoate (10 g, 40.65 mmol, 1 eq) and amine hydrate (100 mL). The resulting solution was stirred for 2 days at 25°C. The resulting solution was reacted with stirring for an additional 2 h at 50°C. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 7.8 g (83.08 %) of 1.1 as a light yellow solid. (ES, m/z): 229 (M-H)\
[00332] Synthesis of compound 1.2. Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1.1 (7.78 g, 33.74 mmol, 1 eq), benzyl N-{ 3- aminopropyl)carbamate(8.4 g, 40.49 mmol, 1.2 eq) and K2CO3 (10.3 g, 74.22 mmol, 2.2 eq) in DMSO (150 mL). The resulting solution was stirred for 1 day at 70°C. The reaction mixture was cooled to 25°C. The product was precipitated by the addition of H2O. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 9.5 g (59.48%) of 1.2 as an orange solid. (ES, m/z): 403 (M+H)+.
[00333] Synthesis of compound 1.3. Into a 100-mL round-bottom flask, was placed 1.2 (12.5 g, 31.06 mmol, 1 eq) in HO Ac (90 mL) and Zn (16.3 g, 248.50 mmol, 8 eq). The resulting solution was stirred for 2 h at 25°C. The solids were filtered out. The resulting solution was diluted with 100 mL of H2O. The pH value of the solution was adjusted to pH 7 with NaHC03 (10 %). The resulting solution was extracted with 3x30 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 20x20 ml of NaHCCh/^O. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2: 1). This resulted in 7.5 g (58.35%) of 1.3 as an off-white solid. (ES, m/z): 373 (M+H)+.
[00334] Synthesis of compound 1.4. Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1.3 (7.5 g, 20.14 mmol, 1.0 eq) and BrCN (2.3 g, 22.15 mmol, 1.1 eq) in MeOH (150 mL). The resulting solution was stirred overnight at 25°C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash- Prep-HPLC with the following conditions (IntelFlash-1): Column, C 18; mobile phase, H2O:CH3CN=l :0 increasing to H2O:CH3CN=0: l within 30 min, detector, UV 254 nm. This resulted in 7.5 g (94.96%) of 1.4 as an off-white solid. (ES, m/z): 398 (M+H)+.
Synthesis of Intermediates
Figure imgf000117_0001
[00335] Synthesis of compound 3.1. To a stirred mixture of 1.1 (500 mg, 2.17 mmol, 1 eq) and propan- 1 -amine (141.0 mg, 2.39 mmol, 1.1 eq) in DMF (10 mL) was added K2CO3 (449.5 mg, 3.25 mmol, 1.5 eq) at RT. The resulting mixture was stirred for 12 h at 60°C. The reaction was quenched with brine (30 mL) at RT. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2x5 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re crystallized from PE/ethyl acetate (5: 1 10 mL) to afford 3.1 (480 mg, 87.41%) as a yellow solid. (ES, m/z): 254 (M+H)+.
[00336] Synthesis of compound 3.2. To a stirred mixture of 3.1 (460 mg, 1.82 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (40 mg, 0.38 mmol, 0.21 eq) at RT. The resulting mixture was stirred for 12 h at RT under Eh atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3.2 (280 mg, 69.04%) as an off-white solid. (ES, m/z): 224 (M+H)+.
[00337] Synthesis of compound 3.3. To a stirred mixture of 3.2 (280 mg, 1.25 mmol, 1 eq) in MeOH (10 mL) was added BrCN (146.1 mg, 1.38 mmol, 1.1 eq) at RT. The resulting mixture was stirred for 4 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Ch/MeOH=10: 1) to afford 3.3 (250 mg, 80.29%) as a white solid. (ES, m/z): 249 (M+H)+.
Synthesis of Intermediates:
Figure imgf000117_0002
[00338] Synthesis of compound 25.1. Into a 100-mL 3-necked round-bottom flask, was placed methyl 4-chloro-3-nitrobenzoate (8.6 g, 40.65 mmol, 1 eq) and amine hydrate (100 mL). The resulting solution was stirred for 2 days at 25°C. The resulting solution was stirred for an additional 2 h at 50°C. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 7.8 g (83.08 %) of 25.1 as a light yellow solid. (ES, m/z ): 199 (M-H) .
[00339] Synthesis of compound 25.2. Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 25.1 (540 mg, 2.716 mmol, 1 eq), propan-1- amine (176.57 mg, 2.987 mmol, 1.1 eq), K2CO3 (562.95 mg, 4.073 mmol, 1.5 eq), DMF (10 mL). The resulting solution was stirred for 2 hr at 70°C in an oil bath. The resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3x30 mL of ethyl acetate concentrated under vacuum. The crude product was re-crystallized from EA/PE in the ratio of 1 :3. This resulted in 570 mg (94.03%) of 25.2 as a yellow solid. (ES, m/z)·. 224 (M+H)+.
[00340] Synthesis of compound 25.3. Into a 50-mL round-bottom flask, was placed 25.2 (550 mg, 2.464 mmol, 1 eq), HO Ac (20 mL, 349.031 mmol, 141.66 eq), Zn (161 1.55 mg, 24.638 mmol, 10 eq). The resulting solution was stirred for 2 hr at RT. The solids were filtered out. The pH value of the solution was adjusted to pH 7 with Na2C03(aq). The resulting solution was extracted with 4x100 mL of ethyl acetate concentrated under vacuum. The residue was applied onto a prep TLC with ethyl acetate/petroleum ether (1 : 1). This resulted in 300 mg (63.01%) of 25.3 as a yellow solid. (ES, m/z): 194 (M+H)+
[00341] Synthesis of compound 25.4. Into a 50-mL round-bottom flask, was placed 25.3 (300 mg, 1.552 mmol, 1 eq), MeOH (10 mL), BrCN (197.32 mg, 1.863 mmol, 1.2 eq). The resulting solution was stirred for 3 hr at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash -Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min; Detector, UV: 254nm. This resulted in 294 mg (86.77%) of 25.4 as a yellow solid. (ES, m/z) 219 (M+H)+
Example 1 Synthesis of benzyl 3-(5-carbamoyl-7-methoxy-2-(l-methyl-3-(trifluoromethyl)- l/ -pyrazole-4-carboxamido)-lF -benzo[</]imidazol-l-yl)propylcarbamate (1-1)
Figure imgf000119_0001
[00342] Synthesis of compound 1-1. To a solution of 1 -methyl-3 -(trifluorom ethyl)- IH- pyrazole-4-carboxylic acid (58.6 mg, 0.30 mmol, 1.2 eq) in DMF (5 mL) was added HBTU (114.5 mg, 0.30 mmol, 1.2 eq), DIEA (97.6 mg, 0.75 mmol, 3.0 eq) and 1.4 (100 mg, 0.25 mmol, 1.0 eq). The resulting solution was stirred for overnight at 85°C. The reaction was then quenched by the addition of 15 mL of water. The solids were collected by filtration. The crude product (120 mg) was purified by Prep-HPLC with the following conditions: column: X bridge Prep OBD C18 column, 30x 150mm 5um; mobile phase A: water (10MMOL/L NH4HCO3+0.1%NH3-H2O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 36% B to 50% B in 7 min; detector, UV 254/220 nm; rt: 5.92 min. This resulted in 100 mg (69.30%) of 1-1 as a white solid. (ES, m/z ): 574.1 (M+H)+, 572.1(M-H) ; 1H-NMR (400 MHz, DMSO- ppm): d 12.81 (s, 1H), 8.42 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.32-7.25 (q, 8H), 5.01 (s, 2H), 4.39-4.35 (t, 2H), 3.94-3.92 (s, 3H), 3.92-3.89 (s, 3H), 3.11-3.06 (q, 2H), 1.93-1.86 (m, 2H).
Example 2 Synthesis of benzyl 3-(5-carbamoyl-2-(l-ethyl-l/ -imidazole-5-carboxamido)-7- methoxy-l -benzo[d]imidazol-l-yl)propylcarbamate (1-2)
Figure imgf000120_0001
1.4 1-2
[00343] Synthesis of compound 1-2. To a solution of 1 -ethyl- li -imidazole-5-carboxylic acid (42.3 mg, 0.30 mmol, 1.2 eq) in DMF (5 mL) was added HBTU (114.5 mg, 0.30 mmol, 1.2 eq), DIEA (97.6 mg, 0.75 mmol, 3 eq) and 1.4 (100 mg, 0.25 mmol, 1 eq). The resulting solution was stirred overnight at 85°C. The crude product (5 mL) was purified by Prep-HPLC with the following conditions: column: X bridge Cl 8 OBD Prep column, lOOA, 5 pm, 19 mm X 250 mm; mobile phase A:water(10MMOL/L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL/min; gradient: 35% B to 45% B in 8 min; detector, UV 254/220 nm; rt: 7.10 min. This resulted in 47.5 mg (33.2%) of 1-2 as a white solid.(ES, m/z): 520.3 (M+H)+, 518.2 (M-Hf; 'H-NMR (400 MHz, DMSO- ppm) d 7.98 (s, 1H), 7.80-7.79 (d, 1H), 7.68-7.65 (d, 1H), 7.65-7.64 (d, 1H), 7.40-7.27 (m, 8H), 5.01 (s, 2H), 4.49-4.47 (q, 2H), 4.39-4.31 (m, 2H), 3.96 (s, 3H), 3.10-3.06 (q, 2H), 1.93-1.86 (t, 2H), 1.39-1.36 (t, 3H).
Example 3 Synthesis of benzyl 3-(5-carbamoyl-7-methoxy-2-(3-methyl-3//-l,2,3-triazole-4- carboxamido)-l/T-benzo imidazol-l-yl)propylcarbamate (1-3)
Figure imgf000120_0002
[00344] Synthesis of compound 1-3. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 1 -m ethyl - 1 H- 1 , 2,3 -tri azol e-5 -carboxyl i c acid (41.6 mg, 0.33 mmol, 1.30 eq) in DMF (2.5 mL ), HBTU (124.0 mg, 0.33 mmol, 1.30 eq), DIEA (162.6 mg, 1.26 mmol, 5.00 eq) and 1.4 (100 mg, 0.25 mmol, 1 eq). The resulting solution was stirred for 12 h at 85°C. The reaction was then quenched by the addition of 10 mL water. The resulting solution was extracted with 3x20 mL of ethyl acetate concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 10 minutes; detector 254/220nm. This resulted in 24.3 mg (19.07%) of 1-3 as a light yellow solid. (ES, m/z): 507.2 (M+H)+, 505.1 (M-H) ; ¾-NMR (400 MHz, DMSO-i¾ ppm): d 12.90 (s, 1H), 8.18 (s, 1H), 8.01
(s, 1H), 7.69-7 (d, 1H), 7.43-7.35 (m, 1H), 7.34-7.29 (d, 7H), 4.99 (s, 2H), 4.41-4.35 (t, 5H), 4.36 (s, 3H), 3.12-3.07 (m, 2H), 1.93-1.90 (m, 2H).
Example 4 Synthesis of benzyl 3-(5-carbamoyl-7-methoxy-2-(4-methyl-l/ -imidazole-5- carboxamido)-Li/-benzo imidazol-l-yl)propylcarbamate (1-4)
Figure imgf000121_0001
[00345] Synthesis of compound 1-4. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 5 -m eth y 1 - 1 //-i m i dazol e-4-carb ox y 1 i c acid (41.3 mg, 0.33 mmol, 1.3 eq) in DMF (2.5 mL ), HBTU (124.0 mg, 0.33 mmol, 1.3 eq), DIEA (162.6 mg, 1.26 mmol, 5 eq) and 1.4 (100 mg, 0.25 mmol, 1 eq). The reaction was stirred for 12 h at 85°C. The reaction was then quenched by the addition of 10 mL water. Then it was extracted with 3x20 mL of ethyl acetate and the organic layers were combined and concentrated under vacuum. The crude product was purified by FI ash-Prep -HPLC with the following conditions (IntelFlash-1): column, Cl 8 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within lOmin; detector, UV 254/220nm. This resulted in 33.2 mg (26.10%) of 1-4 as a white solid. (ES, m/z): 506.3 (M+H)+, 504.2 (M-H) ; 1H-NMR (400MHz, DMSO-i¾ ppm ) d 12.66 (s, 1H), 12.22-12.18 (d, 1H), 12.15 (s, 1H), 10.08 (s, 1H), 7.98-7.23 (d, 9H), 4.98-4.96 (d, 2H), 4.41- 4.23 (d, 2H), 4.21- 3.94 (d, 3H), 3.08-2.97 (d, 2H), 2.47 (s, 2H), 2.42 (s, 1H), 1.93-1.89 (m, 2H).
Example 5 Synthesis of benzyl 3-(5-carbamoyl-2-(l,5-dimethyl-lF/-imidazole-4- carboxamido)-7-methoxy-lF/-benzo[d]imidazol-l-yl)propylcarbamate (1-5)
Figure imgf000122_0001
[00346] Synthesis of compound 1-5. To a solution of 1.4 (100 mg, 0.252 mmol, 1 eq) in DMF (5 mL) was added 1, 5-dimethyl-li7-imidazole-4-carboxylic acid (42.31 mg, 0.302 mmol, 1.2 eq), HBTU (114.51 mg, 0.302 mmol, 1.2 eq) and DIEA (97.56 mg, 0.755 mmol, 3 eq). The resulting solution was stirred overnight at 85°C in an oil bath. The reaction mixture was cooled to RT with a water bath. The solids were collected by filtration. The crude product (5 mL) was purified by Flash-Prep-HPLC with the following conditions (CombiFlash-1): column, C18 silica gel; mobile phase, ACN/FhO=0/100 increasing to ACN/FhO= 100/0 within 40 min; Detector, UV 254nm. This resulted in 42.4 mg (32.44%) of 1-5 as a white solid. (ES, m/z)·. 520.2 (M+H)+, 518.2 (M-H) ; ¾- NMR (400 MHz, DMSO-i¾ ppm ) d 10.11 (s, 1H), 8.68-7.57 (m, 3H), 7.52-7.02 (m, 8H), 5.05- 4.96 (d, 2H), 4.42-4.18 (m, 2H), 3.95-3.92 (d, 3H), 3.59-3.49 (d, 3H), 3.17-2.88 (m, 2H), 2.58 (s, 1H), 2.48 (s, 2H), 1.88-1.84 (t, 2H).
Example 6 Synthesis of A-(5-carbamoyl-l-propyl-lF -benzo[</]imidazol-2-yl)isoxazole-5- carboxamide (1-80)
Figure imgf000123_0001
25.4 1-80
[00347] Synthesis of compound 1-80. To a stirred solution l,2-oxazole-5-carboxylic acid (74.60 mg, 0.660 mmol, 1.20 eq) in NMP (2 mL) were added HATU (418.10 mg, 1.100 mmol, 2 eq) and DIEA (213.17 mg, 1.649 mmol, 3 eq) at RT. To the above mixture was added 25.4 (120 mg, 0.550 mmol, 1 eq) in portions at RT. The final reaction mixture was irradiated with microwave radiation for 1 h at 140°C. The mixture was evaporated, and the residue was purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, ACN and (AcOH in water), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product (19.1mg) was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column 30* 150, 5um; Mobile Phase A: Water (l%HOAc), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 50% B in 7 min; 254;220 nm; Rt: 5.57 min). This resulted in 3.9 mg (2.18%) of 1-80 as an off-white solid. (ES, m/z): 314.1 (M+H)+, 312.1 (M-Hf; ' H-NMR (400 MHz, DMSO-de) d 12.91 (s, 1H), 8.68-8.67 (d, 1H), 8.04-7.99 (d, 2H), 7.83-7.82 (d, 1H), 7.64-7.62 (d, 1H), 7.34 (s, 1H), 7.02-7.01 (d, 1H), 4.25-4.21 (t, 2H), 1.84-1.79 (q, 2H), 0.92-0.89, 3H).
Example 7 Synthesis of benzyl 3-(5-carbamoyl-2-(2,5-dimethylfuran-3-carboxamido)-7- methoxy-l/ -benzo[d]imidazol-l-yl)propylcarbamate (1-9)
Figure imgf000123_0002
1.4 1-9
[00348] Synthesis of compound 1-9. Into a 100-mL round-bottom flask, was placed 1.4 (100 mg, 0.252 mmol, 1 eq) in DMF (5 mL), 2,5-dimethylfuran-3-carboxylic acid (70.52 mg, 0.503 mmol, 2 eq), DIEA (195.12 mg, 1.510 mmol, 6 eq) and HATU (143.51 mg, 0.377 mmol, 1.5 eq). The resulting solution was stirred for 12 h at 25°C. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): column, C18silical gel; mobile phase, ACN: FhO=15% increasing to ACN: FhO=60% within 15 min; Detector, UV 254nm. The product was obtained. The residue was applied onto Prep-TLC with ethyl acetate/petroleum ether (2: 1). This resulted in 3.2 mg (2.45%) of 1-9 as a white solid. (ES, m/z): 520.3 (M+H)+, 518.3 (M-H) , ¾- NMR (400 MHz, DMSO-i¾ ppm ) d 12.72 (s, 1H), 7.98 (s, 1H), 7.63-7.62 (d, 1H), 7.36-7.29 (d, 7H), 6.38-6.37 (d, 1H), 5.00 (s, 2H), 4.35-4.32 (t, 2H), 3.94 (s, 3H), 3.07-3.06 (q, 2H), 2.62 (s, 3H), 2.20 (s, 3H), 1.91-1.23 (q, 2H), 1.23 (s, 1H).
Example 8 Synthesis of benzyl 3-(5-carbamoyl-2-(2,5-dimethylthiophene-3-carboxamido)-7- methoxy-l/ -benzo[d]imidazol-l-yl)propylcarbamate
Figure imgf000124_0002
Figure imgf000124_0001
1.4 1-10
[00349] Synthesis of compound 1-10. Into a 100-mL round-bottom flask, was placed 1.4 (100 mg, 0.252 mmol, 1 eq) in DMF (5 mL), 2,5-dimethylthiophene-3-carboxylic acid (78.60 mg, 0.503 mmol, 2 eq), DIEA (195.12 mg, 1.510 mmol, 6 eq) and HATU (143.51 mg, 0.377 mmol, 1.5 eq). The resulting solution was stirred for 12 h at 25°C. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: H2O=60% within 15 min; Detector, UV 254nm. The residue was applied onto Prep-TLC with ethyl acetate/petroleum ether (2: 1). This resulted in 7.1 mg (5.27%) of 1-10 as a white solid. (ES, m/z): 536 (M+H)+, 534 (M-H) ; 'H-NMR (400 MHz, DMSO -d6,ppm) d 12.77 (s, 1H), 7.98 (s, 1H), 7.65-7.64 (d, 1H), 7.34-7.23 (m, 9H), 5.00 (s, 2H), 4.37-4.33 (t, 2H), 3.95 (s, 3H), 3.09-3.05 (t, 2H), 2.74 (s, 3H), 2.34 (s, 3H), 1.91-1.86 (t, 2H).
Example 9 Synthesis of 2-acetamido-l-propyl-lH-benzo[d]imidazole-5-carboxamide (1-79)
Figure imgf000125_0001
25.4 1-79
[00350] Synthesis of compound 1-79. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed acetic acid (19.81 mg, 0.330 mmol, 1.2 eq) in NMP (2 ml), HATU (156.79 mg, 0.412 mmol, 1.5 eq), DIEA (106.59 mg, 0.825 mmol, 3 eq) and 25.4 (60 mg, 0.275 mmol, 1 eq). The final reaction mixture was irradiated with microwave radiation for 1 h at 140°C. The reaction was then quenched by the addition of 10 mL water. The resulting solution was extracted with 3x10 mL of ethyl acetate concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN/H2O=10% increasing to ACN/H2O=60% within 10 minutes; Detector, UV 254/220nm. This resulted in 12.2 mg (17.06%) of 1-79 as a white solid. (ES, m/z ): 261 (M+H)+, 259 (M-H)-; ¾-NMR (400 MHz, DMSO-i¾ ppm): d 10.55 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.81-7.79 (d, 1H), 7.60-7.58 (d, 1H), 7.25 (s, 1H), 4.07 (s, 2H), 2.16 (s, 3H), 1.74-1.67 (m, 2H), 0.81-0.80 (t, 3H).
Example 10 Synthesis of 2-(3-ethyl-l-methyl-l/ -pyrazole-4-carboxamido)-l-propyl-l - benzo [d] imidazole-5-carboxamide (1-78)
Figure imgf000125_0002
[00351] Synthesis of compound 1-78. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 3-ethyl-l-methyl-lH-pyrazole-4-carboxylic acid (50.86 mg, 0.330 mmol, 1.20 eq) in NMP (2 mL), HATU (156.79 mg, 0.412 mmol, 1.50 eq), DIEA (106.59 mg, 0.825 mmol, 3.00 eq) and 25.4 (60 mg, 0.275 mmol, 1 eq). The final reaction mixture was irradiated with microwave radiation for 1 h at 140°C. The reaction was then quenched by the addition of 10 mL water. The resulting solution was extracted with 3x10 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN/H2O=10% increasing to ACN/H2O=60% within 10 min; detector, UV 254/220nm. This resulted in 9.4mg (9.66%) of 1-78 as a white solid. (ES, m z): 355 (M+H)+, 353 (M-H) ; 'H- NMR (400 MHz, DMSO-i¾ ppm): d 12.64 (s, 1H), 8.08 (s, 1H), 7.96-7.91 (m, 2H), 7.76-7.74 (d, 1H), 7.50-7.48 (d, 1H), 7.29 (s, 1H), 4.17-4.13 (t, 2H), 3.80 (s, 3H), 2.97-2.95 (m, 2H), 1.82-1.76 (m, 2H), 1.22-1.21 (t, 3H), 0.92-0.91 (t, 3H).
Example 11 Synthesis of A-(5-carbamoyl-7-(morpholinomethyl)-l-propyl-l/ - benzo[d]imidazol-2-yl)-3-methylisothiazole-4-carboxamide (1-77)
Figure imgf000126_0001
[00352] Synthesis of compound 31.1. To a stirred solution of morpholine (2.80 mL, 32.129 mmol, 1.20 eq) in THF (250.0 mL) were added methyl 3-formyl-4-nitrobenzoate (5.6 g, 26.774 mmol, 1 eq) and NaBH(OAc)3 (11.35 g, 53.548 mmol, 2.00 eq) and HOAc (3.22 g, 53.548 mmol, 2.00 eq) in portions at RT . The resulting mixture was stirred for overnight at RT. The reaction was quenched by the addition of NaiCCb (aq.) (lOOmL) at RT. The resulting mixture was extracted with EtOAc (3 x 150mL). The combined organic layers were washed with water (3x150 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The mixture was acidified to pH 4 with 1N.HC1 (10.0 mL). The resulting mixture was filtered and. The filtrate was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with K2CO3 (aq.) (3x50 mL), dried over anhydrous NaiSCE. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 6.13 g (62.49%) of 31.1 as an off-white solid. (ES, m/z): 281 (M+H)+
[00353] Synthesis of compound 31.2. To a stirred solution of 31.1 (16.7 g, 59.583 mmol, 1 eq.) in MeOH (200.0 mL) were added Pd/C (2.5 g, 23.492 mmol, 0.39 eq.) in portions at RT under nitrogen atmosphere. The resulting mixture was stirred for 2h at RT under hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. This resulted in 14 g (93.8%) of 31.2 as an off- white solid. (ES, m/z): 251 (M+H)+.
[00354] Synthesis of compound 31.3. To a stirred solution of 31.2 (14 g, 55.933 mmol, 1 eq) in dioxane (140 mL) was added TFAA (11.67 mL, 55.563 mmol, 1.50 eq) dropwise at 0°C. The resulting mixture was stirred for overnight at RT. The resulting mixture was diluted with EA (150 mL). The resulting mixture was filtered, and the filter cake was washed with Et20 (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EA (250 mL). The combined organic layers were washed with NaHCCh (aq.) (1x150 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 11.8 g (45.02%) of 31.3 as an off-white solid. (ES, m/z): 347 (M+H)+.
[00355] Synthesis of compound 31.4. To a stirred solution of 31.3 (11.80 g, 34.074 mmol, 1.00 eq.) in H2SO4 (100 mL) were added KNO3 (4.13 g, 40.849 mmol, 1.20 eq.) in portions at 0°C. The resulting mixture was stirred for overnight at RT. The mixture was basified to pH 8 with saturated NaHCCh (aq.) (15 mL). The aqueous layer was extracted with EtOAc (3x600 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2.5 g (16.88%) of 31.4 as an off-white solid. (ES, m/z): 296 (M+H)+.
[00356] Synthesis of compound 32.5. To a stirred solution ofNaH (0.31g, 12.918 mmol, 1.50 eq.) in DMF (15 mL) were added 31.4 (2.50 g, 8.466 mmol, 1.00 eq.) in portions at 0°C.To the above mixture was added 1-iodopropane (2.16 g, 12.706 mmol, 1.50eq.) dropwise over 0.5 h at 0°C. The resulting mixture was stirred for additional overnight at RT. To the above mixture was added THF (21.00 mL) and MeOH (7.00 mL) and H20 (7.00 mL) and NaOH (1.76 g, 44.024 mmol, 5.00 eq.) in portions at 0°C. The resulting mixture was stirred for additional 1 h at RT. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified to pH 4 with HC1 (15 mL). The resulting mixture was extracted with EtOAc (3 x lOOmL), dried over anhydrous NaiSCE. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1 g (35.80%) of 31.5 as an off-white solid. (ES, m z): 324 (M+H)+.
[00357] Synthesis of compound 31.6. To a stirred solution of 31.5 (1.00 g, 3.093 mmol, 1.00 eq.) in DMF (15 mL) were added HATE! (2.35 g, 6.180 mmol, 2.00 eq.) and DIEA (1.20 g, 9.278 mmol, 3 eq.) in portions at RT . To the above mixture was added NH4CI (0.83 g, 15.463 mmol, 5 eq.) in portions at 0°C. The resulting mixture was stirred for additional 1 h at 70°C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, NH4HCO3 in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 550 mg (49.65%) of 31.6 as an off-white solid. (ES, m/z ): 323 (M+H)+.
[00358] Synthesis of compound 31.6. To a stirred solution of 31.5 (1.00 g, 3.093 mmol, 1.00 eq.) in DMF (15 mL) were added HATU (2.35 g, 6.180 mmol, 2.00 eq.) and DIEA (1.20 g, 9.278 mmol, 3 eq.) in portions at RT . To the above mixture was added NH4CI (0.83 g, 15.463 mmol, 5 eq.) in portions at 0°C. The resulting mixture was stirred for additional 1 h at 70°C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, NH4HCO3 in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 550 mg (49.65%) of 31.6 as an off-white solid. (ES, m/z)·. 323 (M+H)+.
[00359] Synthesis of compound 31.7. To a stirred solution of 31.6 (550.00 mg, 1.706 mmol, 1.00 eq.) in MeOH (15 mL) was added Pd/C (110.76 mg, 1.041 mmol, 0.61 eq.) in portions at RT under ¾ (g). The resulting mixture was stirred for 2h at RT. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. This resulted in 520 mg (62.12%) of 31.7 as an off-white solid. (ES, m/z): 293 (M+H) + [00360] Synthesis of compound 31.8. To a stirred solution of 31.7 (520.00 mg, 1.778 mmol, 1.00 eq.) in MeOH (16 mL) were added BrCN (205.33 mg, 1.939 mmol, 1.09 eq.) in portions at RT. The resulting mixture was stirred for overnight at RT. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, NH4HCO3 in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 500 mg (53.15%) of 31.8 as an off-white solid. (ES, m z): 318 (M+H)+.
[00361] Synthesis of compound 1-77. To a stirred solution of 3-methylisothiazole-4-carboxylic acid (71.52 mg, 0.567 mmol, 1.2 eq) in DMF (3 mL) were added HATU (359.39 mg, 0.945 mmol, 2 eq) and DIEA (183.24 mg, 1.418 mmol, 3 eq) in portions at RT. To the above mixture was added 31.8 (150 mg, 0.473 mmol, 1 eq) . The resulting mixture was stirred for 2 h at 85°C. The residue was purified by reverse flash chromatography with the following conditions: column, C18silical gel; mobile phase, FA in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column : Xbridge prep C18 5um 19* 150mm ; Mobile phase A: Waters(0.1%NH4HCO3), Mobile phase B: ACN; Flow rate: 20 ml/min; Gradient: 32 %B to 42 %B in 8 min; 254&220nm; t: 7.30 min). This resulted in 16.1 mg (7.67%) of 1-77 as a white solid. (ES, m/z): 443.0 (M+H)+, 441.0 (M-H) ; 1H-NMR (300 MHz, DMSO-^e) d 12.90 (s, 1H), 9.54 (s, 1H), 7.96 (d, 2H), 7.64 (s, 1H), 7.33 (s, 1H), 4.47-4.42 (t, 2H), 3.71 (s, 2H), 3.54 (s, 4H), 2.77 (s, 3H), 2.49-2.38 (t, 4H), 1.83-1.81 (d, 2H), 1.00-0.95 (t, 3H).
Example 12 Synthesis of A-(5-carbamoyl-7-(morpholinomethyl)-l-propyl-l/ - benzo[</]imidazol-2-yl)-3,4-dichloroisothiazole-5-carboxamide (1-76)
Figure imgf000129_0001
31.8 1-76
[00362] Synthesis of compound 1-76. To a stirred solution 31.8 (150 mg, 0.473 mmol, 1 eq) and dichloro-l,2-thiazole-5-carboxylic acid (112.30 mg, 0.567 mmol, 1.2 eq) in NMP (3 mL) were added HATU (359.39 mg, 0.945 mmol, 2 eq) and DIEA (183.24 mg, 1.418 mmol, 3 eq) in portions at RT. The resulting mixture was stirred for 2 h at 85°C . The residue was purified by Prep-TLC (CThCh/MeOH O: 1). The crude product (59 mg) was purified by Prep-HPLC with the following conditions (Column: Xbridge RP18 5um 19* 150mm; Mobile Phase A: Waters (0.1%NH4HCO3), Mobile Phase B: ACN; Flow rate: 20ml/min; Gradient: 40%B to 65%B inlOmin; detector: 254&220nm; RT=9.15 min). This resulted in 11.5 mg (4.80%) of 1-76 as an off-white solid. (ES, m/z): 496.9 (M+H)+, 494.9 (M-H) ; 1H-NMR (300 MHz, DMSO-^e) d 13.18 (s, 1H), 8.00-7.96 (d, 2H), 7.69 (s, 1H), 7.48-7.39 (d, 1H), 4.89-4.41 (m, 2H), 3.80 (s, 2H), 3.79-3.71 (d, 4H), 2.58-2.25 (m, 4H), 1.87-1.80 (q, 2H), 0.99-0.96 (t, 3H).
Example 13 Synthesis of /V-(5-carbamoyl-l-propyl-Li/-benzo[d]imidazol-2-yl)quinoline-4- carboxamide (1-75)
Figure imgf000130_0001
[00363] Synthesis of compound 1-75. To a solutoion of 25.4 (100 mg, 0.458 mmol, 1 eq) in NMP (10 mL) was added quinoline-4-carboxylic acid (95.21 mg, 0.550 mmol, 1.2 eq), DIEA (118.43 mg, 0.916 mmol, 2 eq) and HATU (261.31 mg, 0.687 mmol, 1.5 eq). The resulting solution was stirred for 1 h at 140 °C in microwave. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min; Detector, UV: 254 nm. This resulted in 61.5 mg (42.44%) of 1-75 as a white solid. (ES, m/z)·. 374 (M+H)+, 372 (M-H) ; ¾- NMR (300 MHz, DMSO-i¾ ppm): d 13.09 (s, 1H), 9.02-8.90 (m, 2H), 8.12-8.02 (m, 4H), 7.85- 7.75 (m, 2H), 7.70-7.60 (m, 2H), 7.40-7.25 (m, 1H), 4.22-4.18 (m, 2H), 1.90-1.74 (m, 2H), 1.94- 1.80 (m, 3H).
Example 14 Synthesis of 2-(l,3-dimethyl-2-oxo-2,3-dihydro-l/ -imidazole-4-carboxamido)- 7-(morpholinomethyl)-l-propyl-l/ -benzo[</]imidazole-5-carboxamide (1-74)
Figure imgf000131_0001
[00364] Synthesis of compound 1-74. To a stirred solution of 31.8 (150 mg, 0.473 mmol, 1 eq.) and 1, 3-dimethyl-2-oxo-2, 3-dihydro-lH-imidazole-4-carboxylic acid (88.55 mg, 0.567 mmol, 1.20 eq.) in NMP (3 mL) were added HATU (359.39 mg, 0.945 mmol, 2 eq.) and DIEA (183.24 mg, 1.418 mmol, 3 eq.) in portions at RT. The resulting mixture was stirred for 2h at 85°C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product (74 mg) was purified by Prep-HPLC with the following conditions (Column : Xbridge prep Cl 8 5um 19* 150mm ; Mobile phase A: Waters(0.1%FA), Mobile phase B: ACN; Flow rate: 20 ml/min; Gradient: 8 %B to 20 %B in 8 min; 254&220nm; t: 7.68 min). This resulted in 14.5 mg (6.58%) of 1-37 as a white solid.(ES, m/z): 456 (M+H)+, 454 (M-H) ; 1H-NMR (300 MHz, DMSO-d 6, ppm) d 12.68 (s, 1H), 7.93 (s, 2H), 7.62 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 4.38-4.43 (t, 2H), 3.70-3.75 (d, 2H), 3.52-3.55 (d, 7H), 3.17-3.29 (m, 3H), 2.27-2.38 (d, 4H), 1.75-51.83 (m, 2H), 0.95-1.00 (t, 3H).
Example 15 Synthesis of /V-(l-(3-(3-benzyl-3-methylureido)propyl)-5-carbamoyl-7-methoxy- l/ -benzo[</]imidazol-2-yl)-3-methylisothiazole-4-carboxamide (1-11)
Figure imgf000132_0001
[00365] Synthesis of compound 39.1. Into a 100-mL round-bottom flask, was placed 1.4 (300.00 mg, 0.755 mmol, 1.00 eq) in DMF (10 mL), DIEA (292.67 mg, 2.265 mmol, 3.00 eq), 3- methyl-l,2-thiazole-4-carboxylic acid (216.13 mg, 1.510 mmol, 2.00 eq) and HATU (430.52 mg, 1.132 mmol, 1.50 eq). The resulting solution was stirred for 12 h at 25°C. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: H2O=60% within 15 min; Detector, UV254nm. This resulted in 300 mg (76.05%) of 39.1 as a white solid. (ES, m/z): 523 (M+H)+.
[00366] Synthesis of compound 39.2. Into a 100-mL round-bottom flask, was placed 39.1 (100 mg, 0.191 mmol, 1 eq) in acetic acid (5 mL) and hydrogen bromide (5 mL). The resulting solution was stirred for 5 h at 25°C. The resulting mixture was concentrated under vacuum. This resulted in 80 mg (107.62%) of 39.2 as a white solid. (ES, m/z): 389 (M+H)+.
[00367] Synthesis of compound 1-11. Into a 100-mL round-bottom flask, was placed 39.2 (80 mg, 0.205 mmol, 1 eq) in DMF (5 mL), Et3N (62.44 mg, 0.617 mmol, 3.00 eq), CDI (49.88 mg, 0.308 mmol, 1.50 eq), and benzyl (methyl) amine (49.67 mg, 0.410 mmol, 2.00 eq). The resulting solution was stirred for 12 h at 25 °C. The mixture was extracted with DCM and concentrated. The crude product was purified by Prep-HPLC with the following conditions: column: Cl 8, 30* 100mm, 5 um; mobile phase A: water/lOmmol/L NHdTCCh, mobile phase B: ACN flow rate: 25mL/min; gradient: 25%B to 55%B in 8min, hold 1.0 min; Detector 254nm&220nm; rt: 7.35min. This resulted in 14.9 mg (10.81%) of 1-11 as a white solid. (ES, m/z)·. 536 (M+H)+, 534 (M-H) ; 1H-NMR(400 MHz, DMSO -d6, ppm) d 12.83 (s, 1H), 9.53 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.39- 7.36 (d, 2H), 7.28-7.22 (d, 2H), 7.21 -7.13(t, 3H), 6.48-6.46 (t, 1H), 4.40-4.38 (d, 4H), 3.97 (s, 3H), 3.16-3.14 (d, 2H), 2.78-2.69 (d, 6H), 1.98-1.90 (m, 2H).
Example 16 Synthesis of A-(5-carbamoyl-l-propyl-lF -benzo[d]imidazol-2-yl)-2,4- dimethylo
Figure imgf000133_0001
25.4 1-73
[00368] Synthesis of compound 1-73. Into a 8-mL round-bottom flask, was placed 25.4 (100 mg, 0.458 mmol, 1 eq), NMP (10 mL), DIEA (118.43 mg, 0.916 mmol, 2 eq), dimethyl-1, 3- oxazole-5-carboxylic acid (77.59 mg, 0.550 mmol, 1.2 eq), HATU (261.31 mg, 0.687 mmol, 1.5 eq). The resulting solution was stirred for 1 hr at 140°C in microwave. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cl 8 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=30% within 5 mi; Detector, 254 nm. This resulted in 55.6 mg (46.66%) of 1-73 was obtained. (ES, m/z). 342 (M+H)+, 340 (M-H) ; ¾- NMR (400 MHz, DMSO-de, ppm): d 12.70(s, 1H), 8.01-7.92 (m, 2H), 7.80-7.76 (m, 1H) 7.60- 7.54 (m, 1H), 7.30(s, 1H), 7.18-7.12 (m, 2H), 2.55-2.48 (m, 3H), 2.45-2.38 (m, 3H) 1.82-1.72 (m, 2H), 1.91-1.80 (m, 3H).
Example 17 Synthesis of l-(3-(3-benzyl-3-methylureido)propyl)-2-(l-ethyl-lE/-imidazole-2- carboxamido)-Li/-benzo[d]imidazole-5-carboxamide (1-12)
Figure imgf000134_0001
1-12
[00369] Synthesis of compound 42.1. Into a 100-mL 3-necked round-bottom flask, was placed
25.1 (5 g, 24.928 mmol, 1 eq), fer/-butyl /V-(3-aminopropyl)carbamate (5.21 g, 29.91 mmol, 1.2 eq), DMF (50 mL), K2CO3 (6.89 g, 49.85 mmol, 2.00 eq). The resulting solution was stirred for 3 h at 70°C. The solids were collected by filtration. The resulting mixture was concentrated. This resulted in 6 g (71.14%) of 42.1 as a solid. (ES, m/z): 339 (M+H)+.
[00370] Synthesis of compound 42.2. Into a 100-mL 3-necked round-bottom flask, was placed
42.1 (6 g, 17.732 mmol, 1 eq) in MeOH (50 mL) and HCI (4M, 20 mL). The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. This resulted in 5.3 g (125.45%) of 42.2 as a yellow solid. (ES, m/z)·. 239 (M+H)+.
[00371] Synthesis of compound 42.3. Into a 50-mL 3-necked round-bottom flask, was placed
42.2 (3 g, 12.592 mmol, 1 eq), DMF (30 mL), CDI (4.08 g, 25.162 mmol, 2.00 eq), Et N (3.82 g, 37.751 mmol, 3.00 eq), benzyl (methyl) amine (4.58 g, 37.794 mmol, 3.00 eq). The resulting solution was stirred for 1 overnight at RT.The solids were collected by filtration. The resulting mixture was concentrated. This resulted in 4.65 g (95.81%) of 42.3 as a solid. (ES, m/z): 386 (M+H)+. [00372] Synthesis of compound 42.4. Into a 100-mL 3 -necked round-bottom flask, was placed
42.3 (4.65 g, 12.065 mmol, 1 eq) in HOAc (50 mL), Zn (15.78 g, 241.251 mmol, 20.00 eq). The resulting solution was stirred for 1 h at RT. The solids were collected by filtration. The resulting mixture was concentrated. This resulted in 4 g (93.28%) of 42.4 as a solid. (ES, m/z ): 356 (M+H)+.
[00373] Synthesis of compound 42.5. Into a 100-mL 3 -necked round-bottom flask, was placed
42.4 (4 g, 11.254 mmol, 1 eq), BrCN (1.43 g, 13.501 mmol, 1.20 eq), MeOH (30 mL). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. This resulted in 3 g (70%) of 42.5 as a solid. (ES, m/z): 381 (M+H)+.
[00374] Synthesis of compound 1-12. Into a 8-mL round-bottom flask, was placed 42.5 (100 mg, 0.263 mmol, 1 eq) in DMF (3 mL), 1 -ethyl- liT-imidazole-2-carboxylic acid (44.20 mg, 0.315 mmol, 1.20 eq), DIEA (67.94 mg, 0.526 mmol, 2.00 eq), HATU (149.91 mg, 0.394 mmol, 1.50 eq). The resulting solution was stirred for 1 h at 140°C in microwave. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cl 8 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min, Detector 254 nm. This resulted in 8.8 mg (7%) of 1-42 as a dark yellow solid. (ES, m/z): 503 (M+H)+, 501 (M- H)-; ¾-NMR (300 MHz, DMSO-i¾ ppm) d 12.84 (s, 1H), 8.06 (s, 2H), 7.99 (s, 1H), 7.87-7.78 (m, 1H), 7.55-7.53 (d, 4H), 7.33-7.29 (m, 3H), 7.25-7.17 (m, 1H), 4.54-4.48 (m, 4H), 4.22 (d, 2H), 3.14 (s, 2H), 2.80 (s, 3H), 1.9-1.87 (q, 2H), 1.41-1.36 (m, 3H).
Example 18 Synthesis of 2-(2-methoxyacetamido)-l-propyl-lF/-benzo[</]imidazole-5- carboxamide (1-72)
Figure imgf000135_0001
25.4
I -72
[00375] Synthesis of compound 1-72. Into a 20-mL round-bottom flask, was placed 25.4 (100 mg, 0.458 mmol, 1 eq), 2-methoxyacetic acid (49.53 mg, 0.550 mmol, 1.2 eq), NMP (8 mL), DIEA (118.43 mg, 0.916 mmol, 2 eq), HATU (261.31 mg, 0.687 mmol, 1.5 eq). The resulting solution was stirred for 1 hr at 140°C in microwave. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15; Detector, UV254nm. This resulted in 15.1 mg (11%) of 1-72 as a off-white solid. (ES, m/z): 291 (M+H)+, 289 (M-H) ; 'H-NMR: (d6- DMSO, 300 MHz, ppm): d 12.61 (brs, 1H), 8.04 (d, 2H), 7.65 (d, 2H), 7.28 (s, 1H), 4.21-3.96 (m, 4H), 3.37 (s, 3H), 1.73 (d, 2H), 0.85 (s, 3H).
Example 19 Synthesis of 2-acetamido-7-(morpholinomethyl)-l-propyl-l - benzo [d] imidazole-5-carboxamide (1-71)
Figure imgf000136_0001
31.8 1-71
[00376] Synthesis of compound 1-71. To a stirred solution of 31.8 (80 mg, 0.252 mmol, 1 eq) and acetic acid (18.16 mg, 0.302 mmol, 1.20 eq) in NMP (3 mL) were added HATU (191.68 mg, 0.504 mmol, 2 eq) and DIEA (97.73 mg, 0.756 mmol, 3 eq) in portions at RT . The resulting mixture was stirred for 1 h at 140°C in microwave. The mixture was quenched with H2O and the filtrate cake was purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, NH4HCO3 in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 33.5 mg (36.5%) of 1-71 as a white solid. (ES, m/z): 360 (M+H)+, 358 (M-H) ; ¾-NMR (300 MHz, DMSO-de) d 10.43 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.29 (s, 1H), 4.31-4.29 (t, 2H), 3.73 (s, 2H), 3.33 (s, 4H), 2.50-2.49 (t, 4H), 2.38-2.15 (t, 3H), 1.71-1.69 (d, 2H), 0.95-0.86 (t, 3H).
Example 20 Synthesis of 2-(2,5-dimethylthiophene-3-carboxamido)-l-propyl-l - benzo[</]imidazole-5-carboxamide (1-41)
Figure imgf000136_0002
1-41
25.4 [00377] Synthesis of compound 1-41. To a stirred solution of 2,5-dimethylthiophene-3- carboxylic acid (85.88 mg, 0.550 mmol, 1.20 eq) in NMP (3 mL) were added HATU (348.42 mg, 0.916 mmol, 2 eq) and DIEA (177.65 mg, 1.375 mmol, 3 eq) and 25.4 (100 mg, 0.458 mmol, 1 eq) in portions at RT. The resulting mixture was stirred for 1 h at 140°C in microwave. Cooled to rt and the mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 38.3 mg (22.44%) of 1-41 as a pink solid. (ES, m/z): 357 (M+H)+, 355 (M-H)-; 1H-NMR (300 MHz, DMSO-de) d 12.74 (s, 1H), 8.14 (s, 2H), 7.97-7.94 (d, 1H), 7.78- 7.75 (d, 1H), 7.29-7.22 (t, 2H), 4.19-4.14 (t, 2H), 2.76-2.69 (t, 3H), 2.58-2.50 (s, 3H), 1.83-1.76 (q, 2H), 0.93-0.88 (t, 3H).
Example 21 Synthesis of l-(3-(3-benzyl-3-methylureido)propyl)-2-(l-ethyl-l/ -pyrrole-2- carboxamido)-Li/-benzo[d]imidazole-5-carboxamide (1-13)
Figure imgf000137_0001
42.5 1-13
[00378] Synthesis of compound 1-13. Into a 20-mLwas placed 1 -ethyl- liT-pyrrole-2- carboxylic acid (43.89 mg, 0.315 mmol, 1.20 eq), DIEA (67.94 mg, 0.526 mmol, 2.00 eq), HATU (149.91 mg, 0.394 mmol, 1.50 eq), 42.5 (100 mg, 0.263 mmol, 1 eq). The reaction was stirred for 1 hr at 140 °C. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min, Detector 254 nm. This resulted in 11.1 mg (8.42%) of 1-13 as an off-white solid. (ES, m/z): 502 (M+H)+, 500 (M-H) ; 'H-NMR (300 MHz, DMSO -d6, ppm) d 12.53 (s, 1H), 7.95 (s, 2H), 7.77-7.76 (d, 1H), 7.46-7.45 (d, 1H), 7.29-7.27 (m, 3H), 7.17-7.15(m, 3H), 7.00 (s, 2H), 6.49 (s, 1H), 6.03 (s, 1H), 4.50-4.49 (d, 2H), 4.40 (s, 2H), 4.20 (s, 2H), 3.17-3.16 (d, 2H), 2.73 (s, 3H), 1.99-1.89 (m, 2H), 1.35-1.34 (t, 3H). Example 22 Synthesis of /V-(5-carbamoyl-l-propyl-Li/-benzo[d]imidazol-2-yl)-5-chloro-l- methyl-Lif-pyrrolo [2,3-b] pyridine-3-carboxamide (1-69)
Figure imgf000138_0001
25.4 1-69
[00379] Synthesis of compound 1-69. Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5 -chi oro- 1 - ethyl - 1 //-pyrrol o[2, 3 -/>] pyri di ne-3 - carboxylic acid (80 mg, 0.380 mmol, 1 eq), 25.4 (124.35 mg, 0.570 mmol, 1.50 eq), HATU (288.85 mg, 0.760 mmol, 2.00 eq) and DIEA (98.18 mg, 0.760 mmol, 2.00 eq) in NMP (5 mL). The resulting solution was irradiated with microwave radiation for 1 h at 140°C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3x5 mL of ethyl acetate. The resulting mixture was washed with 1 x5 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, silica gel; mobile phase, CFLCN/FLC O: ! increasing to CH3CN/H2OM : 1 within 20 min; Detector, UV 254nm. This resulted in 2.5 mg (2%) of 1-69 as a white solid. (ES, m/z): 411 (M+H)+; 'H-NMR (400 MHz, DMSO-rL, ppm): d 8.81 (s, 1H), 8.28 (s, 1H), 8.20-8.18 (d, 1H), 7.97(s, 1H), 7.86-7.84 (d, 1H), 7.51-7.49 (d, 1H), 4.35-4.31 (t, 2H), 3.93 (s, 3H), 2.05-1.96 (m, 2H), 1.15-1.11 (s, 3H).
Example 23 Synthesis of 2-(oxetane-3-carboxamido)-l-propyl-lF/-benzo[</]imidazole-5- carboxamide (1-68)
Figure imgf000138_0002
1-68
25.4 [00380] Synthesis of compound 1-68. To a stirred solution of oxetane-3 -carboxylic acid (84.19 mg, 0.825 mmol, 1.20 eq) in NMP (2mL) were added HATU (522.63 mg, 1.375 mmol, 2 eq), DIEA (266.47 mg, 2.062 mmol, 3 eq) and 25.4 (150 mg, 0.687 mmol, 1 eq) in portions at RT. The resulting mixture was stirred for lh at RT. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was re-crystallized from MeOH (3mL) to afford 1-68 (15 mg, 7.18%) as a white solid. (ES, m/z): 303 (M+H)+, 301 (M-H)-, H-NMR (300 MHz, DMSO-de) d 8.03 (s, 1H), 8.03-7.95 (d, 2H), 7.83-7.74 (m, 1H), 7.57- 7.54 (d, 1H), 7.29 (s, 1H), 4.75-4.07 (m, 4H), 4.12-4.07 (t, 2H), 3.91 (s, 1H), 1.77-1.70 (q, 2H), 0.87-0.82 (t, 3H).
Example 24 Synthesis of (S)-l-propyl-2-(tetrahydro-2/ -pyran-3-carboxamido)-l - benzo[</]imidazole-5-carboxamide (1-40)
Figure imgf000139_0001
25.4
[00381] Synthesis of compound 1-40. Into a 100-mL round-bottom flask, was placed 25.4 (100 mg, 0.458 mmol, 1 eq) in DMF (8 mL), DIEA (588.5mg, 4.562mmol, 10 eq),(3S)-oxane-3- carboxylic (150 mg, 1.153 mmol, 2.5 eq) , EDCI(438.17mg, 2.294mmol, 5 eq), and HOAT (311.9mg, 2.293mmol, 5 eq). The resulting solution was stirred for 12 h at 25°C. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: ¾()= 60% within 15 min; Detector 254nm. This resulted in 16.1 mg (9.04%) of 1-40 as a white solid. (ES, m/z): 331 (M+H)+, 329 (M-H) ; ¾-NMR (300 MHz, DMSO-de) d 12.60 - 10.60 (d, 1H), 8.13-7.95 (d, 2H), 7.78 (s, 1H), 7.55 (s, 1H), 7.28 (s, 1H), 4.03 (d, 3H), 3.78 (d, 1H), 3.50 (d, 1H), 3.20 (d, 1H), 2.81 (d, 1H), 2.03 (d, 1H), 1.73 - 1.54 (m, 5H), 0.85 (s, 3H).
Example 25 Synthesis of (R)-l-propyl-2-(tetrahydro-2FT-pyran-3-carboxamido)-l/ - benzo [d] imidazole-5-carboxamide 1-67
Figure imgf000140_0001
25.4
I-67
[00382] Synthesis of compound 1-67. Into a 100-mL round-bottom flask, was placed 25.4 (100.00 mg, 0.458 mmol, 1.00 eq) in DMF (5.00 mL), DIEA (296.08 mg, 2.291 mmol, 5 eq), (3R)- oxane-3 -carboxylic acid (178.88 mg, 1.375 mmol, 3 eq), HOAT (93.54 mg, 0.687 mmol, 1.5 eq) and EDCI (131.75 mg, 0.687 mmol, 1.5 eq). The resulting solution was stirred for 12 h at 25°C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: H2O=60% within 15 min; Detector 254 nm. The crude product was purified by Prep-SFC with the following conditions (Prep SFCIOO): Column, Lux 5u Cellulose-4, 2.12*25cm, 5um; mobile phase, CO2 (g) and EtOH (2mM NFL- MeOH) (50%) within 3.472 min; Detector, 254 nm. This resulted in 24.9 mg (16.45%) of 1-67 as a white solid. (ES, m/z): 331 (M+H)+, 329 (M-H)\ ¾ NMR (300 MHz, DMSO-de) d 12.60 - 10.60 (d, 1H), 8.13-7.95 (d, 2H), 7.78 (s, 1H), 7.55 (s, 1H), 7.28 (s, 1H), 4.03 (d, 3H), 3.78 (d, 1H), 3.50 (d, 1H), 3.20 (d, 1H), 2.81 (d, 1H), 2.03 (d, 1H), 1.73 - 1.54 (m, 5H), 0.85 (s, 3H).
Example 26 Synthesis of cyclopentyl (3-(5-carbamoyl-7-methoxy-2-(3-methylisothiazole-4- carboxamido)-Li/-benzo[d]imidazol-l-yl)propyl)carbamate (1-14)
Figure imgf000140_0002
[00383] Synthesis of compound 53.1. Into a 100-mL round-bottom flask, was placed 20.3 (200 mg, 0.550 mmol, 1 eq) in DMF (8 mL), DIEA (426.76 mg, 3.302 mmol, 6 eq), 3-methyl-l,2- thiazole-4-carboxylic acid (236.36 mg, 1.651 mmol, 3.00 eq) and HATU (313.88 mg, 0.825 mmol, 1.5 eq). The resulting solution was stirred for 12 h at 85 °C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: H2O=60% within 15 min, Detector UV 254 nm. This resulted in 100 mg (37.19%) of 53.1 as a light yellow solid. (ES, m/z) 489 (M+H)+.
[00384] Synthesis of compound 53.2. Into a 100-mL round-bottom flask, was placed 53.1(100.00 mg, 0.205 mmol, 1 eq) in DCM (5.00 mL), TFA (2.00 mL). The resulting solution was stirred for 2 h at 25 °C. The resulting mixture was concentrated under vacuum. This resulted in 120 mg (150.93%) of 53.2 as a light yellow solid. (ES, m/z)·. 389 (M+H)+.
[00385] Synthesis of compound 1-14. Into a 100-mL round-bottom flask, was placed 53.2 (140 mg, 0.360 mmol, 1 eq) in DMF (10 mL), Et3N (109.33 mg, 1.080 mmol, 3.00 eq), cyclopentyl carbonochloridate (64.17 mg, 0.432 mmol, 1.20 eq). The resulting solution was stirred for 12 h at 25 °C. The mixture was quenched by MeOH and concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: H2O=60% within 15 min; Detector 254nm. This resulted in 32.5 mg (25.22%) of 1-14 as a white solid. (ES, m/z) 501.1 (M+H)+, 499.0 (M-H) ; ¾- NMR (300 MHz, DMSO-i¾ ppm ) d 12.83 (s, 1H), 9.56 (s, 1H), 8.02 (s, 1H), 7.68 (s, 1H), 7.39- 7.38 (d, 2H), 7.07 (s, 1H), 4.91 (s, 1H), 4.39 (s, 2H), 3.99 (s, 3H), 2.78-2.77 (d, 2H), 2.76 (s, 3H), 1.91-1.73 (d, 4H), 1.54 (s, 6H).
Example 27 Synthesis of A-(5-carbamoyl-7-methoxy-l-propyl-lF -benzo[</]imidazol-2-yl)- 2,4-dimethyloxazole-5-carboxamide 1-66
Figure imgf000142_0001
[00386] Synthesis of compound 1-66. To a stirred solution of dimethyl- 1, added HATU (306.28 mg, 0.806 mmol, 2 eq) and DIEA (156.16 mg, 1.208 mmol, 3 eq) and 3.3 (100 mg, 0.403 mmol, 1 eq) in portions at RT.The resulting mixture was stirred for 2 h at 85°C. The resulting mixture was diluted with water (5 mL). The precipitated solids were collected by filtration and washed with water (2x2 mL).The crude product was re-crystallized from MeOH (3 mL) to afford 1-66 (14.7mg, 9.47%) as a brown solid. (ES, m/z): 372 (M+H)+, 370 (M-H) ; 1H-NMR (300 MHz, DMSO-de) d 12.73 (s, 1H), 7.98 (s, 1H), 7.67-7.66 (d, 1H), 7.38-7.35 (t, 2H), 4.32-4.27 (t, 2H), 3.98 (s, 3H), 2.51-2.43 (q, 6H), 1.81-1.74 (q, 2H), 0.91-0.87 (t, 3H).
Example 28 Synthesis of cyclopentyl (3-(5-carbamoyl-2-(2,5-dimethylfuran-3-carboxamido)- 7-methoxy-l -benzo[d]imidazol-l-yl)propyl)carbamate (1-15)
Figure imgf000142_0002
[00387] Synthesis of compound 55.1. Into a 100-mL round-bottom flask, was placed 53.4 (200 mg, 0.550 mmol, 1 eq), DMF (8 mL), DIEA (426.76 mg, 3.302 mmol, 6 eq), HATU (313.88 mg, 0.825 mmol, 1.5 eq), 2,5-dimethylfuran-3-carboxylic acid (231.37 mg, 1.651 mmol, 3.00 eq). The resulting solution was stirred for 5 hr at 25 °C. The mixture was quenched with H2O and the filtrate cake was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN: H20=13% increasing to ACN: H2O=60% within 19 min, Detector 254nm. This resulted in 90 mg (33.68%) of 55.1 as a white solid. (ES, m/z): 486 (M+H)+. [00388] Synthesis of compound 55.2. Into a 100-mL round-bottom flask, was placed 55.1 (90 mg, 0.185 mmol, 1 eq), DCM (4.5 mL), TFA (0.9 mL). The resulting solution was stirred for 2 hr at 25°C. The resulting mixture was concentrated under vacuum. This resulted in 110 mg (153.97%) of 55.2 as a grey solid. (ES, m/z): 386 (M+H)+.
[00389] Synthesis of compound 1-15. Into a 100-mL round-bottom flask, was placed 55.2 (90 mg, 0.233 mmol, 1 eq), DMF (10 mL), Et3N (70.71 mg, 0.699 mmol, 3.00 eq), cyclopentyl carbonochloridate (42.12 mg, 0.280 mmol, 1.20 eq). The resulting solution was stirred for 12 hr at 25 °C. The mixture was quenched with MeOH and evaporated. The crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep C18 OBD Column, 19150mm 5um; mobile phase, Water (0.1%FA) and ACN (35% PhaseB up to 70% in 8 min); Detector254 nm. This resulted in 25.4 mg (14.05%) of 1-15 as an off-white solid. (ES, m/z): 498 (M+H)+, 496 (M-Hf; 'H-NMR (400 MHz, DMSO-rA// /??) d 12.72 (s, 1H), 7.98 (s, 1H), 7.63-7.62 (d, 1H), 7.49-7.21 (m, 2H), 7.03 (s, 1H), 6.37 (s, 1H), 4.92 (s, 1H), 4.34-4.31 (t, 2H), 3.97 (s, 3H), 3.02-3.01 (d, 2H), 2.63 (s, 3H), 2.23 (s, 3H), 1.90-1.82 (m, 2H), 1.82-1.68 (m, 2H), 1.53 (s, 6H).
Example 29 Synthesis of /V-(l-(3-(3-benzyl-3-methylureido)propyl)-5-carbamoyl-Li/- benzo[</]imidazol-2-yl)-2,4-dimethyloxazole-5-carboxamide (1-16)
Figure imgf000143_0001
[00390] Synthesis of compound 1-16. Into a 20-mL Other (input in right blank), was placed dimethyl-1, 3-oxazole-5-carboxylic acid (74.19 mg, 0.526 mmol, 2.00 eq), NMP (10 mL), DIEA (101.91 mg, 0.789 mmol, 3.00 eq), HATU (199.88 mg, 0.526 mmol, 2.00 eq), 42.5 (100 mg, 0.263 mmol, 1 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by FI ash-Prep -HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/FhO=15% increasing to ACN/FhO=60% within 15 min, detector, 254 nm. This resulted in 19.1 mg (14.43%) of 1-16 as a light pink solid. (ES, m/z) 504 (M+H)+, 502 (M-H)-; 1H-NMR (300 MHz, DMSO -d6,ppm) d 12.73 (s, 1H), 8.01-8.00 (d, 2H), 7.98 (s, 1H), 7.78-7.54 (d, 1H), 7.28-7.17 (m, 3H), 7.21-7.13 (m, 3H), 6.47-6.45 (t, 1H), 4.40 (s, 2H), 4.24-4.20 (t, 2H), 3.16-3.12 (q, 2H), 2.72 (s, 3H), 2.53 (s, 3H), 2.43 (s, 3H), 1.95-1.92 (t, 2H). Example 30 Synthesis of /V-(5-carbamoyl-7-(morpholinomethyl)-l-propyl-Li/- benzo [d] imidazol-2-yl)-2,4-dimethyloxazole-5-carboxamide (1-65)
Figure imgf000144_0001
[00391] Synthesis of compound 1-65. Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 31.8 (100 mg, 0.315 mmol, 1.00 eq) in NMP (3 mL), HATU (239.7 mg, 0.630 mmol, 2.00 eq), DIEA (122 mg, 0.944 mmol, 3.00 eq) and dimethyl- 1, 3-oxazole-5-carboxylic acid (253.3 mg, 1.795 mmol, 5.70 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN/Water=0: 100% increasing to CH^CN/WaterM 00% :0 within 15 min; Detector 254 nm. This resulted in 5.5 mg (3.96%) of 1-65 as a light yellow solid. (ES, m/z)·. 441 (M+H)+, 439 (M- H)-; 1H-NMR (400 MHz, DMSO-de, ppm) d 12.80 (s, 1H), 7.99 - 7.94 (d, 2H), 7.64 (s, 1H), 7.33 (s, 1H), 4.44 - 4.40 (t, 2H), 3.72(s, 2H), 3.55 (s, 4H), 2.53 (s, 3H), 2.44 (s, 3H), 2.40 - 2.38 (d, 4H), 1.88 - 1.81 (d, 2H), 0.98 - 0.95 (t, 3H). Example 31 Synthesis of /V-(5-carbamoyl-l-propyl-Li/-benzo[d]imidazol-2-yl)-2,4- dimethylthiazole-5-carboxamide (1-64)
Figure imgf000145_0001
25.4 1-64
[00392] Synthesis of compound 1-64. Into a 8-mL round-bottom flask, was placed 25.4 (100 mg, 0.458 mmol, 1 eq) in NMP (8 mL), dimethyl-1, 3-thiazole-5-carboxylic acid (86.42 mg, 0.550 mmol, 1.20 eq), DIEA (118.43 mg, 0.916 mmol, 2.00 eq) and HATU (261.31 mg, 0.687 mmol, 1.50 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by FI ash-Prep -HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/FLC O: 100% increasing to ACN/FhO=100%:0 within 15 min; Detector, 254 nm. This resulted in 31 mg (18.93%) of 1-64 as a off-white solid. (ES, m/z): 358.2 (M+H)+; ¾-NMR (400MHz, DMSO-de, ppm): d 12.78 (s, 1H), 57.99 (s, 2H), 57.79-7.78 (d, 1H), 57.59-7.57 (d, 1H), 57.35(s, 1H), 54.18-4.14 (m, 2H), 52.72 (s, 3H), 52.60 (s, 3H), 51.85-1.79 (m, 2H), 50.93-0.90(m, 3H).
Example 32. Synthesis of benzyl 3-(5-carbamoyl-2-(2,4-dimethyloxazole-5-carboxamido)- l/ -benzo[</]imidazol-l-yl)propylcarbamate (1-17)
Figure imgf000146_0001
[00393] Synthesis of compound 62.1. Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 25.1 (1.00 g, 4.986 mmol, 1.00 eq) in DMF (15.00 mL), benzyl N-(3-aminopropyl)carbamate (1.24 g, 5.954 mmol, 1.19 eq) and K2CO3 (2.06 g, 14.905 mmol, 2.99 eq). The resulting solution was stirred for 12hr at 70°C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x20 mL of ethyl acetate. The resulting mixture was washed with 10 ml of Water. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 1.8 g (96.96%) of 62.1 as a white solid. (ES, m/z): 373 (M+H)+.
[00394] Synthesis of compound 62.2. Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 62.1 (1.00 g, 2.685 mmol, 1.00 eq) in AcOH (20.00 mL) and Zn (2.62 g, 40.056 mmol, 14.92 eq). The resulting solution was stirred for 2 hr at RT. The solids were collected by filtration. The resulting mixture was concentrated. The resulting mixture was washed with 3 xl5 ml of MeOH. The solids were collected by filtration. This resulted in 0.8 g (87.01%) of 62.2 as a white solid. (ES, m/z): 343 (M+H)+.
[00395] Synthesis of compound 62.3. Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 62.2 (1.20 g, 3.505 mmol, 1.00 eq) in MeOH (15.00 mL) and BrCN (0.44 g, 4.211 mmol, 1.20eq). The resulting solution was stirred for 2 hr at RT. The resulting mixture was concentrated. The resulting mixture was washed with 3 xlO of MeOH. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN/water=0: 100% increasing to CH3CN/water= 100:0 within 40 min; Detector, UV 254nm. This resulted in 330 mg (25.63%) of 62.3 as a off-white solid. LC-MS-PH-NST-812-3 (ES, m/z): 368 (M+H)+.
[00396] Synthesis of compound 1-17. Into a 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 62.3 (100 mg, 0.272 mmol, 1 eq) in NMP (5 mL), DIEA (175.75 mg, 1.360 mmol, 5.00 eq) and HATU (207.1 mg, 0.545 mmol, 2.00 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x10 mL of ethyl acetate. The resulting mixture was washed with 1 xlO ml of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN/water=0: 100% increasing to CH3CN/water=100%:0 within 40 min; Detector, UV 254nm. This resulted in 12.1 mg (9.06%) of 1-17 as a off-white solid. (ES, m/z)·. 491 (M+H)+, 489 (M-H) ; ¾-NMR (300 MHz, DMSO-i¾ ppm ) d 12.74 (s, 1H), 7.81 (s, 2H), 7.80-7.78 (d, 1H), 7.58-7.55 (d, 1H), 7.34 (s, 7H), 5.00 (s, 2H), 4.24-4.19 (t, 2H), 3.11-3.05 (m, 2H), 2.51 (s, 3H), 2.40-2.38 (s, 3H), 1.93-1.88 (t, 2H).
Example 33. Synthesis of /V-(5-carbamoyl-l-propyl-Li/-benzo[d]imidazol-2-yl)-4-ethyl-2- methyloxazole-5-carboxamide (1-63)
Figure imgf000147_0001
25.4 1-63
[00397] Synthesis of compound 1-63. Into a 20-mL round-bottom flask, was placed 4-ethyl-2- methyl-l,3-oxazole-5-carboxylic acid (117.29 mg, 0.756 mmol, 1.1 eq) in NMP (6 mL), HATU (522.63 mg, 1.375 mmol, 2 eq), DIEA (355.29 mg, 2.749 mmol, 4 eq) and 25.4 (150 mg, 0.687 mmol, 1 eq). The resulting solution was stirred for 1 h at 140°C in microwave. Cooled to rt and the reaction was then quenched by the addition of 15 mL of water. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 minutes; Detector, UV 254nm. This resulted in 46.5 mg (19.04%) of 1-63 as a light pink solid. (ES, m/z ): 356 (M+H)+, 354 (M- H)-; ¾-NMR (400MHz, DMSO -d6, ppm): d 12.72 (s, 1H), 8.00-7.97 (m, 2H), 7.80-7.78 (m, 1H), 7.59-7.56 (m, 1H), 7.33 (s, 1H), 4.16-4.13 (m, 2H), 3.05-2.99 (m, 2H), 2.50-2.45 (m, 3H), 1.81- 1.76 (m, 2H), 1.23-1.19 (m, 3H), 0.94-0.90 (m, 3H).
Example 34. Synthesis of benzyl 3-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5- carboxamido)-Li/-benzo[</]imidazol-l-yl)propylcarbamate (1-18)
Figure imgf000148_0001
62.3
1-18
[00398] Synthesis of compound 1-18. To a stirred solution of 4-ethyl-2-methyl-l,3-oxazole-5- carboxylic acid (69.68 mg, 0.449 mmol, 1.1 eq) in NMP (3 mL) was added HATU (310.47 mg, 0.817 mmol, 2 eq) and DIEA (211.06 mg, 1.633 mmol, 4 eq). After stirred at rt for 10 min, 62.3 (150 mg, 0.408 mmol, 1 eq) was added. The final reaction mixture was irradiated with microwave radiation for lh at 140 °C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The residue was purified by reverse flash chromatography with the following conditions: Column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted 1-18 (50.6 mg, 24.56%) as a off-white solid. (ES, m z): 505 (M+H)+, 503 (M-H) ; 1H-NMR (300 MHz, DMSO-i¾ ppm): d 12.75 (s, 1H), 8.00-7.99 (m, 2H), 7.79-7.78 (m, 1H), 7.57- 7.54(m, 1H), 7.34 (s, 7H), 5.01 (s, 2H), 4.21-4.20 (m, 2H), 3.10-2.98 (m, 4H), 2.41 (s, 3H),1.92- 1.91 (m, 2H), 1.22-1.18 (m, 3H).
Example 35. Synthesis of /V-(5-carbamoyl-l-propyl-Li/-benzo[d]imidazol-2-yl)-2-ethyl-4- methyloxazole-5-carboxamide (1-62)
Figure imgf000149_0001
25.4
1-62
[00399] Synthesis of compound 1-62. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed NMP (2 mL), 25.4 (200 mg, 1.20 eq), 2-ethyl -4-methyl - l,3-oxazole-5-carboxylic acid (118.5 mg, 1.00 eq), HATU (174.3 mg, 2.00 eq), DIEA (59.1 mg, 2.00 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140oC in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC.This resulted in 1-62 (36.5 mg, 11.21%) as an off-white solid. (ES, m/z): 356 (M+H)+, 354 (M-H) ; 1H-NMR (400 MHz, de-DMSO, ppm): d 12.69 (s, 1H), 8.00-7.96 (d, 2H), 7.81-7.80 (d, 1H), 7.58-7.56 (d, 1H), 7.32(s, 1H), 4.14-4.19(t, 2H), 2.74-2.80 (m, 2H), 2.50-2.54 (t, 3H), 1.77-1.84 (m, 2H), 1.22-1.28 (t, 3H), 0.88-0.95 (t, 3H).
Example 36. Synthesis of /V-(5-carbamoyl-l-propyl-l//-benzo[</|imidazol-2-yl)-4, 5,6,7- tetrahydrobenzo[c]isoxazole-3-carboxamide (1-61)
Figure imgf000149_0002
[00400] Synthesis of compound 1-61. To a stirred mixture of 4,5,6,7-tetrahydro-2, l- benzoxazole-3-carboxylic acid (76.60 mg, 0.458 mmol, 1 eq) and HATU (348.47 mg, 0.916 mmol, 2 eq) in NMP (10 mL) were added DIEA (236.89 mg, 1.833 mmol, 4 eq) and 25.4 (150.02 mg, 0.687 mmol, 1.50 eq) in portions at RT under nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, ACN in water, 5% to 80% gradient in 30 min; detector, UV 254 nm. The crude product was re-crystallized from ACN (5 mL) to afford 1-61 (58.2mg, 23.04%) as a purple solid. (ES, m/z): 368 (M+H)+, 366 (M-H)-; 1H-NMR (300 MHz, DMSO-de): d 12.89 (s,lH), 8.02-7.99 (t, 2H), 7.83-7.81 (d, 1H), 7.65- 7.61 (d, 1H), 7.61-7.31 (s, 1H), 4.22-4.18 (t, 2H), 2.92-2.89 (t, 2H), 2.73-2.70 (t, 2H), 1.84-1.73 (m, 6H), 0.89-0.93 (t, 3H).
Example 37 Synthesis of 4-(5-carbamoyl-2-(2,4-dimethyloxazole-5-carboxamido)-7-methyl- l -benzo[d]imidazol-l-yl)butanoic acid (1-60)
Figure imgf000150_0001
67.4
1-60
[00401] Synthesis of compound 67.1. Into a 100-mL 3-necked round-bottom flask, was placed 2.2 (6.00 g, 27.958 mmol, 1.00 eq), DMSO (60.00 mL), DIEA (18066.71 mg, 139.788 mmol, 5.00 eq), methyl 4-aminobutanoate (4.91 g, 41.913 mmol, 1.50 eq). The resulting solution was stirred for 1 overnight at 100 °C. The resulting mixture was washed with 1 x60 ml of EhO. The resulting solution was extracted with 3x60 mL of ethyl acetate concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 1.3 g (15.75%) of 67.1 as a yellow solid. (ES, m/z ): 296 (M+H)+.
[00402] Synthesis of compound 67.2. Into a 50-mL 3-necked round-bottom flask, was placed
67.1 (1.30 g, 4.402 mmol, 1.00 eq) in AcOH (20.00 mL), Zn (5.76 g, 88.061 mmol, 20.00 eq). The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/FhO=15% increasing to ACN/H2O=60% within 15min, detector, 254 nm. This resulted in 980 mg (83.90%) of 67.2 as a solid. (ES, m/z): 266 (M+H)+.
[00403] Synthesis of compound 67.3. Into a 50-mL 3-necked round-bottom flask, was placed
67.2 (730.00 mg, 2.751 mmol, 1.00 eq) in MeOH (11.1 mL), BrCN (349.73 mg, 3.302 mmol, 1.20 eq). The resulting solution was stirred for 1 hr at RT. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15min, detector, 254 nm. This resulted in 740 mg (92.64%) of 67.3 as a solid. (ES, m/z): 291 (M+H)+.
[00404] Synthesis of compound 67.4. Into a 50-mL 3-necked round-bottom flask, was placed dimethyl-1, 3-oxazole-5-carboxylic acid (194.44 mg, 1.378 mmol, 2.00 eq), NMP (10.00 mL), DIEA (267.10 mg, 2.067 mmol, 3.00 eq), HATU (523.87 mg, 1.378 mmol, 2.00 eq), 67.3 (200.00 mg, 0.689 mmol, 1.00 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15min, detector, 254 nm. This resulted in 90 mg (31.60%) of 67.4 as a solid. (ES, m/z): 414 (M+H)+.
[00405] Synthesis of compound 1-60. Into a 50-mL 3-necked round-bottom flask, was placed 67.4 (85 mg, 0.206 mmol, 1 eq), MeOH (5 mL), H20 (5 mL), NaOH (41.12 mg, 1.028 mmol, 5.00 eq). The resulting solution was stirred for 3 hr at RT. The mixture was adjusted to PH=5 with HC1 (1M) and filtered. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/FhO=15% increasing to ACN/FhO=60% within 15 min, detector, 254 nm. This resulted in 18.5 mg (22.53%) of 1-60 as a off-white solid. (ES, m/z): 400 (M+H)+, 398 (M-Hf; 'H-NMR (400 MHz, DMSO-^e) d 12.53 (s, 1H), 7.69 (d, 2H), 7.38 (s, 1H), 7.09 (s, 1H), 4.23 - 4.14 (m, 2H), 2.31 (d, 8H), 2.24 (d, 3H), 2.16 (d, 2H).
Example 38 Synthesis of 2-(6-carbamoyl-2-(2,4-dimethyloxazole-5-carboxamido)-3-propyl- 3F/-benzo[</]imidazol-4-yloxy)acetic acid (1-59)
Figure imgf000152_0001
[00406] Synthesis of compound 68.1. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1.1 (4 g, 17.35 mmol, 1.0 eq) in DCE (50 mL). This was followed by the addition of BBr3 (11.9 g, 47.0 mmol, 3.0 eq) drop wise with stirring at 0°C in 30 min. The resulting solution was stirred for 1 overnight at 50°C in an oil bath. The resulting mixture was washed with 1x200 mL of water. The solids were filtered out. This resulted in 4.02 g(crude) of 68.1 as a dark yellow solid.
[00407] Synthesis of compound 68.2. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 68.1 (2.02 g, 9.327 mmol, 1 eq) in CH3CN (80 mL), ethyl 2-bromoacetate (2.38 g, 14.251 mmol, 1.53 eq), K2CO3 (3.82 g, 27.640 mmol, 2.96 eq) and KI (0.31 g, 1.867 mmol, 0.20 eq). The resulting solution was stirred for 1 overnight at 25°C. The resulting mixture was washed with 1x150 mL of water. The resulting solution was extracted with 3x150 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (3 : 1). This resulted in 1.2 g (42.51%) of 68.2 as a dark yellow solid. (ES, m/z): 289 (M+H) +.
[00408] Synthesis of compound 68.3. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 68.2 (1.1 g, 3.634 mmol, leq) in DMSO (15 mL), propan- 1 -amine (0.32 g, 5.413 mmol, 1.49 eq) and DIEA (1.41 g, 10.910 mmol, 3.00 eq). The resulting solution was stirred for 2 h at 100°C. The resulting mixture was washed with 1x250 mL of water. The resulting solution was extracted with 3x250 mL of ethyl acetate and the organic layers combined. This resulted in 1.6 g (37.89%) of 68.3 as a dark yellow solid. (ES, m/z): 312 (M+H) +.
[00409] Synthesis of compound 68.4. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 68.3 (1.6 g, 4.918 mmol, 1 eq) in AcOH (20 mL) and Zn (4.8 g, 73.384 mmol, 14.92 eq). The resulting solution was stirred for 1 h at 25°C. The resulting mixture was washed with 3x100 mL of MeOH. This resulted in 1.7 g (15.21%) of 68.4 as a dark yellow solid. (ES, m/z): 282 (M+H)+.
[00410] Synthesis of compound 68.5. Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 68.4 (1.7 g, 5.756 mmol, 1 eq) in MeOH (20 mL) and BrCN (1.2 g, 11.329 mmol, 1.97 eq). The resulting solution was stirred for 1 overnight at 25°C. The resulting mixture was washed with 3x20 mL of MeOH. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: H2O=60% within 20 min; Detector, UV 254 nm. This resulted in 130 mg (3.32%) of 68.5 as a dark yellow solid. (ES, m/z): 307 (M+H) +.
[00411] Synthesis of compound 68.6. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 68.5 (130 mg, 0.424 mmol, 1 eq) in NMP (2 mL), dimethyl-1, 3-oxazole-5-carboxylic acid (86 mg, 0.609 mmol, 1.44 eq), HATU (309 mg, 0.813 mmol, 1.91 eq) and DIEA (158 mg, 1.223 mmol, 2.88 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: H2O=60% within 20 min; Detector, UV 254 nm. The product was obtained. This resulted in 65 mg (26.04%) of 68.6 as a dark yellow solid. (ES, m/z) 430 (M+H)
+
[00412] Synthesis of compound 1-59. Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 68.6 (65 mg, 0.147 mmol, 1 eq), THF (3 mL, 37.029 mmol, 252.63 eq), MeOH (1 mL), LhO (1 mL) and LiOH (7 mg, 0.292 mmol, 1.99 eq). The resulting solution was stirred for 2 h at 25°C. HC1 (1 mol/L) was employed to adjust the pH to 3. The residue was applied onto a silica gel column with chloroform/methanol (10: 1). This resulted in 8.1 mg (13.17%) of 1-59 as a white solid. (ES, m/z): 416 (M+H) +; ¾-NMR (300 MHz, DMSO- d6,ppm) d 8.00 (s, 1H), 57.63 (s, 1H), 57.30 (s, 2H), 54.64 (s, 2H), 54.47-4.41 (t, 2H) , 52.52-2.50 (d, 3H), 52.44 (s, 3H), 51.86-1.72 (m, 2H) , 50.92-0.84 (m, 3H).
Example 39 Synthesis of 4-(5-carbamoyl-7-methyl-2-(3-methylisothiazole-4-carboxamido)- l/ -benzo[d]imidazol-l-yl)butanoic acid (1-58)
Figure imgf000154_0001
[00413] Synthesis of compound 69.1. Into a 50-mL 3-necked round-bottom flask, was placed 3 -methyl- l,2-thiazole-4-carboxylic acid (197.24 mg, 1.378 mmol, 2.00 eq), DMF (10.00 mL, 129.218 mmol, 187.57 eq), DIEA (267.10 mg, 2.067 mmol, 3.00 eq), HATU (523.87 mg, 1.378 mmol, 2.00 eq), 67.3 (200.00 mg, 0.689 mmol, 1.00 eq). The resulting solution was stirred for 2 h at 85 °C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min, detector UV 254nm. The product was obtained. This resulted in 135 mg (47.17%) of 69.1 as a solid. (ES, m/z): 416 (M+H) +.
[00414] Synthesis of compound 1-58. Into a 50-mL 3-necked round-bottom flask, was placed 69.1 (110 mg, 0.265 mmol, 1 eq), MeOH (5 mL), H20 (5 mL), NaOH (52.95 mg, 1.324 mmol, 5.00 eq). The resulting solution was stirred for 3 hr at RT. The mixture was adjusted to PH=4 with HC1 (1M) and extracted with EA. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cl 8 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min, detector UV 254nm. The product was obtained. This resulted in 54.9 mg (51.65%) of 1-61 as an off-white solid. (ES, m/z): 402 (M+H)+, 400 (M-H) ; 1H-NMR (400 MHz, DMSO-de, ppm) d 12.84 (s, 1H), 12.23 (s, 1H), 9.63 (t, 1H), 7.87-7.90 (d, 2H), 7.58 (s, 1H), 7.29 (s, 1H), 4.44 (s, 2H), 2.77 (s, 3H), 2.70 (s, 3H), 2.41-2.50 (m, 2H), 1.90-2.05 (t, 2H).
Example 40 Synthesis of cycloheptyl 3-(5-carbamoyl-2-(2,4-dimethyloxazole-5- carboxamido)-7-methoxy-lE/-benzo[</]imidazol-l-yl)propylcarbamate (1-19)
Figure imgf000155_0001
[00415] Synthesis of compound 70.1. A solution of 2,4-dimethyloxazole-5-carboxylic acid (46.6 mg, 0.33 mmol, 1.2 eq.) in DMF (5 mL) was treated with HATU (210 mg, 0.55 mmol, 2 eq.) and DIEA (102 mg, 0.826 mmol, 3 eq.) for 30 min at RT followed by the addition of 53.4 (100 mg, 0.275 mmol, 1 eq.) dropwise in portions at RT. The final reaction mixture was stirred for overnight at 85 0 C. The mixture was allowed to cool down to RT. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cix silica gel; mobile phase, ACN: FhO=15% increasing to ACN: FhO=60% within 15 min, detector, 254 nm. This resulted in 110 mg (82.16%) of 70.1 as a white solid. (ES , m/z) 487 (M+H) +.
[00416] Synthesis of compound 70.2. To a stirred solution of 70.1 (110 mg, 0.23 mmol) in DCM (5mL) were added TFA (1.5mL) dropwise in portions at 0 0 C.
The resulting mixture was stirred for lh at RT. The resulting mixture was concentrated under vacuum. This resulted in 70.2 (100 mg, 89%) as a pink solid. (ES, m/z ): 387 (M+H) +.
[00417] Synthesis of compound 1-19. Into a 100-mL round-bottom flask, was placed 70.2 (70.00 mg, 0.181 mmol, 1.00 eq.), DMF/DCM (5.00 mL/5mL), DIEA (70.20 mg, 0.543 mmol, 3.00 eq.), cycloheptyl carbonochloridate (64 mg, 0.362 mmol, 2.00 eq.). The resulting solution was stirred for 12 h at 25 0 C. The mixture was quenched with MeOH and concentrated. The crude product (90 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cis silica gel; mobile phase, ACN: H2O =15% increasing to ACN: H2O=60% within 15 min. This resulted in 50.9 mg (53.36%) of 1-19 as a white solid. (ES, m/z): 527 (M+H) +, 525 (M- H) -; 1H-NMR (300 MHz, DMSO-d6,ppm) d 12.75 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.39 (s, 2H), 7.02 (s, 1H), 4.64 (m, 1H), 4.65-4.62 (t, 2H), 4.00(s, 3H), 3.03-2.99 (m, 2H), 2.52 (s, 3H), 2.44 (s, 3H), 1.90-1.77 (m, 3H), 1.61-1.24 (m, 11H).
Example 41 Synthesis of A-(5-carbamoyl-7-(morpholinomethyl)-l-propyl-l/ - benzo[</]imidazol-2-yl)-4-ethyl-2-methyloxazole-5-carboxamide (1-57)
Figure imgf000156_0001
[00418] Synthesis of compound 1-57. Into a 20-mL round-bottom flask, was placed 4-ethyl-2- methyl-l,3-oxazole-5-carboxylic acid (87.99 mg, 0.567 mmol, 1.2 eq), NMP (6.00 mL), HATU (359.39 mg, 0.945 mmol, 2 eq), DIEA (244.32 mg, 1.890 mmol, 4 eq), 31.8 (150.00 mg, 0.473 mmol, 1.00 eq). The resulting solution was stirred overnight at 85 degrees C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash- Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 minutes; Detector, 254nm. This resulted in 93 mg (64.94%) of 1-57 as a yellow solid. (ES, m/z): 455 (M+H)+, 453 (M-H) ; 1H-NMR (400 MHz, DMSO-de, ppm): 512.79 (s, 1H), 7.98-7.94 (m, 2H), 7.63 (s, 1H), 7.33 (s, 1H), 4.41-4.37 (m, 2H), 3.70 (s, 2H), 3.55 (s, 4H), 3.33-3.00 (m, 2H), 2.50-2.49 (m, 3H), 2.38 (s, 4H), 1.86-1.80 (m, 2H), 1.23-1.20 (m, 3H) ,0.99-0.97 (m, 3H).
Example 42 Synthesis of /V-(5-carbamoyl-7-methoxy-l-propyl-Li/-benzo[</]imidazol-2-yl)-4- ethyl-2-methyloxazole-5-carboxamide (1-56)
Figure imgf000157_0001
3.3 1-56
[00419] Synthesis of compound 1-56. Into a 20-mL round-bottom flask, was placed 4-ethyl-2- methyl-l,3-oxazole-5-carboxylic acid (112.48 mg, 0.725 mmol, 1.2 eq), NMP (4 mL), HATU (0.45g, 1.208 mmol, 2 eq), DIEA (0.31g, 2.417 mmol, 4 eq), 3.3 (150 mg, 0.604 mmol, 1 eq). The resulting solution was stirred overnight at 85 degrees C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 minutes; Detector, 254nm. This resulted in 59.5 mg (25.55%) of 1-56 as a light brown solid. (ES, m/z): 386 (M+H)+, 384 (M-H) ; 'H-NMR (400MHz, DMSO-de, ppm): d 12.73 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.38-7.36 (m, 2H), 4.30-4.26 (m, 2H), 3.98 (s, 3H), 3.04-2.98 (m, 2H), 2.44 (s, 3H), 1.79-1.74 (m, 2H), 1.22-1.18 (m, 3H) ,0.92-0.89 (m, 3H) .
Example 43 Synthesis of methyl 4-(5-carbamoyl-2-(2,4-dimethyloxazole-5-carboxamido)-7- methyl-Li/-benzo[d]imidazol-l-yl)butanoate (1-55)
Figure imgf000158_0001
[00420] Synthesis of compound 1-55. Into a 50-mL 3-necked round-bottom flask, was placed dimethyl-1, 3-oxazole-5-carboxylic acid (194.44 mg, 1.378 mmol, 2.00 eq) in NMP (10.00 mL), DIEA (267.10 mg, 2.067 mmol, 3.00 eq), HATU (523.87 mg, 1.378 mmol, 2.00 eq) and 67.3 (200.00 mg, 0.689 mmol, 1.00 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=0: 100% increasing to ACN/H20=100%:0 within 15 min; Detector, 254 nm. The product was obtained. This resulted in 90 mg (31.60%) of 1-55 as a solid. (ES, m/z): 414 (M+H)+, 412 (M-H) , H-NMR (300 MHz, DMSO-de, ppm): 512.75 (s, 1H), 7.94-7.86 (m, 2H), 7.56 (s, 1H), 7.30 (s, 1H), 4.42-4.32 (m, 2H), 3.51 (s, 3H), 3.34 (s, 2H), 3.70 (s, 3H), 2.51-2.40 (m, 6H), 2.10-1.98 (m, 2H).
Example 44 Synthesis of A-(5-carbamoyl-7-(morpholinomethyl)-l-propyl-l/ - benzo [d] imidazol-2-yl)-4-methyloxazole-5-carboxamide (1-54)
Figure imgf000159_0001
31.8 I -54
[00421] Synthesis of compound 1-54. Into a 20-mL round-bottom flask, was placed 4-methyl- l,3-oxazole-5-carboxylic acid (48.05 mg, 0.378 mmol, 1.2 eq), NMP (3 mL), HATU (239.60 mg, 0.630 mmol, 2 eq), DIEA (162.88 mg, 1.260 mmol, 4 eq), 31.8 (100 mg, 0.315 mmol, 1 eq). The resulting solution was stirred overnight at 85 degrees C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 minutes; Detector, 254nm. This resulted in 71.1 mg (52.91%) of 1-54 as a light yellow solid. (ES, m/z): 427 (M+H)+, 425 (M-Hf; 'H-NMR (400MHz, DMSO-de, ppm): d 12.88 (s, 1H), 8.36 (s, 1H), 7.98 (m, 2H), 7.65 (s, 1H), 7.35 (m, 1H), 4.45-4.40 (m, 2H), 3.71 (s, 2H), 3.55 (s, 4H), 2.58 (m, 3H), 2.38 (m, 4H), 1.88-1.80 (m, 2H), 0.99-0.0.94 (m, 3H).
Example 45 Synthesis of /V-(5-carbamoyl-7-(3-hydroxypropoxy)-l-propyl-Li/- benzo [d] imidazol-2-yl)-2,4-dimethyloxazole-5-carboxamide 1-53
Figure imgf000159_0002
[00422] Synthesis of compound 76.1. Into an 8-mL round-bottom flask, was placed 1-66 (300.0 mg, .081 mmol, 1.00 eq), tribromoborane (20 mL). The resulting solution was stirred overnight at 65°C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL of EA and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=30% within 4 min; Detector, 254 nm. This resulted in 70 mg (24.25%) of 76.1 as a yellow solid. (ES, m/z): 358 (M+H)+.
[00423] Synthesis of compound 1-53. Into a 8-mL round-bottom flask, was placed 76.1 (50.00 mg, 0.140 mmol, 1.00 eq), DMF (2.00 mL), Cs2C03 (91.17 mg, 0.280 mmol, 2.00 eq), 3- bromopropan-l-ol (58.34 mg, 0.420 mmol, 3.00 eq) and Nal (0.5 mg, 0.014mmol, 0.1 eq). The resulting solution was stirred overnight at RT. The mixture was filtered and concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15; Detector, 254 nm. This resulted in 9.5 mg (16.34%) of 1-53 as a white solid. (ES, m/z): 416 (M+H)+, 414 (M-H)-; 1H-NMR (400 MHz, DMSO-de, ppm): d 12.72 (s, 1H), 8.00 (s, 1H), 7.65 (s, 1H), 7.42-7.32 (m, 2H), 4.66-4.64 (m, 1H), 4.22-4.38 (m, 4H), 3.68-3.62 (m, 2H), 2.50 (s, 1H), 2.35 (s, 1H), 2.02-1.95 (m, 2H), 1.85-1.74 (m, 2H), 0.94-0.88 (m, 3H).
Example 46 Synthesis of A-(5-carbamoyl-7-methoxy-l-propyl-l/ -benzo[</]imidazol-2-yl)-4- methyloxazole-5-carboxamide 1-52
Figure imgf000160_0001
3.3 1-52
[00424] Synthesis of compound 1-52. Into an 8-mL vial, was placed 4-methyl-l,3-oxazole-5- carboxylic acid (61.43 mg, 0.483 mmol, 1.20 eq), DMF (1.00 mL), HATU (229.71 mg, 0.604 mmol, 1.50 eq), DIEA (104.11 mg, 0.806 mmol, 2.00 eq), 3.3 (100.00 mg, 0.403 mmol, 1.00 eq). The resulting solution was stirred overnight at RT. The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column,: XBridge Prep OBD C18 Mobile Phase A: Water (10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to 50% B in 7 min; 254; 220 nm; Rt: 6.35 min; This resulted in 21.7 mg (15.08%) of 1-52 as a white solid. (ES, m/z): 358 (M+H)+, 356 (M-H) ; ¾-NMR (400 MHz, DMSO-de) d 12.81 (s, 1H), 8.35 (s, 1H), 8.00 (s, 1H), 7.68 (d, 1H), 7.52-7.13 (m, 2H), 4.33 (t, 2H), 4.00 (s, 3H), 2.57 (s, 3H), 1.80 (q, 2H), 0.91 (t, 3H).
Example 47 Synthesis of A-(5-carbamoyl-7-methoxy-l-propyl-lF -benzo[</]imidazol-2- yl)isoxazole-5-carboxamide 1-51
Figure imgf000161_0001
3.3
[00425] Synthesis of compound 1-51. Into 8-mL round-bottom flask, was placed 3.3 (100.00 mg, 0.403 mmol, 1.00 eq), DMF (2.00 mL), 1, 2-oxazole-5-carboxylic acid (54.65 mg, 0.483 mmol, 1.20 eq), DIEA (104.11 mg, 0.806 mmol, 2.00 eq), HATU (229.71 mg, 0.604 mmol, 1.50 eq). The final reaction mixture was irradiated with microwave radiation for 1 hr at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by FI ash-Prep -HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=40% within 15 min, Detector, 254 nm. This resulted in 8.5 mg (6.15%) of 1-51 as a white solid. (ES, m/z): 344 (M+H)+, 342 (M-H)-; 1H-NMR (400 MHz, DMSO-de, ppm): d 12.95 (s, 1H), 9.00-8.55 (s, 1H), 8.25-7.90 (s, 1H), 7.85-7.59 (s, 1H), 7.56-7.24 (m, 2H), 7.17-6.79 (s, 1H), 4.67-4.18 (m, 2H), 4.17-3.85 (s, 3H), 1.94-1.71 (m, 2H), 1.05-0.65 (m, 3H).
Example 48 Synthesis of A-(5-carbamoyl-7-methoxy-l-propyl-lF -benzo[d]imidazol-2-yl)- 2,4-dimethylthiazole-5-carboxamide (1-50)
Figure imgf000162_0001
[00426] Synthesis of compound 1-50. Into a 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed dimethyl-1, 3-thiazole-5-carboxylic acid (105.71 mg, 0.672 mmol, 1.11 eq), DMF (3.00 mL), HATU (345.19 mg, 0.908 mmol, 1.50 eq), DIEA (156.32 mg, 1.210 mmol, 2.00 eq), 3.3 (150.00 mg, 0.605 mmol, 1.00 eq). The resulting solution was stirred for 2 hr at 85°C. The reaction was then quenched by the addition of 12 mL of water. The solids were collected by filtration. The crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 Column, 19*250mm, 5um; mobile phase, Water (l%HOAc) and MeOH-(60% PhaseB up to 80% in 7 min); Detector, UV 254 nm. This resulted in 33.2 mg (21.27%) of 1-50 as a off-white solid. (ES, m/z): 388 (M+H)+, 386 (M-H) ; 1H-NMR (400 MHz, DMSO -d6,ppm) d 12.84-12.78(d, 1H), 8.00 (s, 1H), 7.64 (s, 1H), 7.38-7.37 (d, 2H), 4.30-4.26 (t, 2H), 3.97 (s, 3H), 2.70 (s, 3H), 2.56 (s, 3H), 1.84- 1.74 (m, 2H), 0.91-0.86 (t, 3H).
Example 49 Synthesis of /V-(5-carbamoyl-7-hydroxy-l-propyl-Li/-benzo[</]imidazol-2-yl)- 2,4-dimethylo
Figure imgf000162_0002
[00427] Synthesis of compound 1-49. Into an 8-mL round-bottom flask, was placed 1-66 (30.00 mg, 0.081 mmol, 1.00 eq), tribromoborane (0.20 mL). The resulting solution was stirred overnight at 65°C in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL of EA and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=30% within 4 min; Detector, 254 nm. This resulted in 7 mg (24.25%) of 1-49 as a yellow solid. (ES, m/z): 358 (M+H)+, 356 (M-H) ; 1H-NMR (400 MHz, DMSO-i¾ ppm): d 12.62 (s, 1H), 10.45 (s, 1H), 7.82 (s, 1H),
7.45 (d, 1H), 7.22-7.16 (d, 2H), 4.50-4.27 (t, 2H), 2.45 (s, 3H), 2.43 (s, 3H), 1.83-1.78 (m,2H),
0.90-0.82 (m, 3H).
Example 50 Synthesis of benzyl 3-(5-carbamoyl-7-methoxy-2-(4, 5,6,7- tetrahydrobenzo[c]isoxazole-3-carboxamido)-l -benzo[d]imidazol-l-yl)propylcarbamate (1-20)
Figure imgf000163_0001
1.4
1-20
[00428] Synthesis of compound 1-20. Into a 20-mL Microwave tube, was placed 1.4 (200.00 mg, 0.503 mmol, 1.00 eq), NMP (4.00 mL), 4,5,6,7-tetrahydro-2, l-benzoxazole-3- carboxylic acid (84.12 mg, 0.503 mmol, 1.00 eq), DIEA (455.27 mg, 3.523 mmol, 7.00 eq), HATU (956.71 mg, 2.516 mmol, 5.00 eq). The resulting solution was stirred for 1 h at 140°C in microwave. The reaction was then quenched by the addition of 15 mL of water. The solids were filtered out. The resulting mixture was concentrated. The solution was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H20=45% within 5min; Detector, 254 nm. The product was obtained. This resulted in 15.7 mg (5.71%) of 1-20 as an off-white solid. (ES, m/z): 547 (M+H)+, 545 (M-H) ; 'H- NMR (400 MHz, DMSO -d^ppm): d 12.94 (s, 1H), 8.03 (s, 1H), 7.71-7.70 (d, 1H), 7.41-7.29 (m, 8H), 5.00 (s, 2H), 4.39 (s, 2H), 3.97 (s, 3H), 3.10-3.08 (d, 2H), 2.90 (s, 2H), 2.71 (s, 2H), 1.95- 1.92 (t, 2H), 1.72 (s, 4H).
Example 51 Synthesis of benzyl 3-(5-carbamoyl-2-(2,4-dimethyloxazole-5-carboxamido)-7- methoxy-l/ -benzo[d]imidazol-l-yl)propylcarbamate (1-21)
Figure imgf000164_0001
[00429] Synthesis of compound 1-21. Into a 8-mL Microwave tube purged and maintained with an inert atmosphere of argon, was placed dimethyl- 1, 3 -oxazole-5-carboxylic acid (64.00 mg, 0.453 mmol, 1.20 eq), NMP (2.00 mL), DIEA (146.00 mg, 1.130 mmol, 2.99 eq), HATU (431.00 mg, 1.134 mmol, 3.00 eq), 1.4 (150.00 mg, 0.377 mmol, 1.00 eq). The final reaction mixture was irradiated with microwave radiation for 1 h at 140°C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The solution was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep OBD; mobile phase, Water (lOmmol/L NHzdTCCL) and ACN (26% Phase B up to 36% in 10 min); Detector UV: 254 nm. This resulted in 29.6 mg (14.78%) of 1-21 as a white solid. (ES, m/z): 521 (M+H)+, 519 (M-H) ; 'H- NMR (300MHz, DMSO-i¾ ppm): 512.72 (s, 1H), 8.02 (s, 1H), 7.67 (s, 1H), 7.29-7.38 (m, 8H), 5.01 (s, 2H), 4.36-4.34 (t, 2H), 3.96 (s, 3H), 3.09-3.06 (q, 2H), 2.52-2.50 (m, 3H) , 2.40 (s, 3H), 1.91-1.90 (m, 2H).
Example 52 Synthesis of A-(5-carbamoyl-7-(3-morpholinopropoxy)-l-propyl-l - benzo[</]imidazol-2-yl)-2,4-dimethyloxazole-5-carboxamide (1-47)
Figure imgf000164_0002
1-49 1-47 [00430] Synthesis of compound 1-47. Into a 8-mL round-bottom flask, was placed 1-49 (200.00 mg, 0.560 mmol, 1.00 eq) in DMF (5 mL), CS2CO3 (547.03 mg, 1.679 mmol, 3.00 eq) and 4-(3- chloropropyl)morpholine (109.90 mg, 0.672 mmol, 1.20 eq). The resulting solution was stirred for overnight at RT. The mixture was filtered and concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=0: 100% increasing to ACN/H20=100%:0 within 15min; Detector, UV254 nm. This resulted in 15.8 mg (5.83%) of 1-47 as off-white solid. (ES, m/z): 485 (M+H)+, 483 (M-H) ; 1H-NMR (400 MHz, DMSO- ppm): d 12.74-12.69 (m, 1H), 8.01-7.96 (m, 1H), 7.67-7.66 (d, 1H), 7.38-7.36 (d, 2H), 4.33-4.21 (t, 4H), 3.62-3.60 (t, 4H), 2.51-2.48 (m, 2H), 2.43 (s, 3H), 2.44 (s, 3H), 2.40 (s, 4H), 2.03-2.01 (q, 2H), 1.80-1.77 (m, 2H), 0.92-0.89 (t, 3H).
Example 53 Synthesis of A-(5-carbamoyl-l-propyl-7-(tetrahydro-2F -pyran-4-yloxy)-lF - benzo [d] imidazol-2-yl)-2,4-dimethyloxazole-5-carboxamide (1-46)
Figure imgf000165_0001
1-49 1-46
[00431] Synthesis of compound 1-46. Into a 8-mL round-bottom flask, was placed 1-49 (200.00 mg, 0.560 mmol, 1.00 eq), DMF (2 mL), 4-iodooxane (355.98 mg, 1.679 mmol, 3 eq), CS2CO3 (364.69 mg, 1.119 mmol, 2 eq). The resulting solution was stirred overnight at RT. The mixture was filtered and concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN: H20=15% increasing to ACN: H2O=60% within 15 min, Detector, 254 nm. This resulted in 6.8 mg (2.75%) of 1-46 as off-white solid. (ES, m/z): 442 (M+H)+, 440 (M-Hf; 'H-NMR (400 MHz, DMSO-rA ppm): d 12.71 (s, 1H), 7.99 (s, 1H), 7.67-7.66 (d, 1H), 7.42-7.35 (m, 2H), 4.89-4.87 (dt,lH), 4.35- 4.33 (t, 2H), 3.91-3.89 (dt, 2H), 3.59-3.54 (d, 2H), 2.50-2.44 (m, 5H), 2.16-2.09 (m, 3H), 1.87-1.63 (m, 4H), 0.95-0.93 (t, 3H).
Example 54 Synthesis of A-(5-carbamoyl-7-methoxy-l-propyl-lF -benzo[</]imidazol-2-yl)- 4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide (1-45)
Figure imgf000166_0001
[00432] Synthesis of compound 1-45. Into a 8-mL small seal tube, was placed 3.3 (100.00 mg, 0.403 mmol, 1.00 eq), DMF (2.0mL), 4,5,6,7-tetrahydro-2, l-benzoxazole-3-carboxylicacid (74.06 mg, 0.443 mmol, 1.10 eq), DIEA (104.11 mg, 0.806 mmol, 2.00 eq), HATU (229.71 mg, 0.604 mmol, 1.50 eq). The resulting solution was stirred for 2 h at 60°C. The reaction was then quenched by the addition of 15 mL of water. The solids were filtered out. The solids were purified by Flash- Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=40% within 15 min ; Detector, 254 nm. This resulted in 54.9 mg (34.30%) of 1-45 as a white solid. (ES, m/z): 398 (M+H)+, 396 (M-H) ; 1H-NMR (400 MHz,DMSO-d6, ppm) 512.90-13.00 (d, 1H), 7.99-8.05 (d, 1H), 7.69 (s, 1H), 7.38-7.41 (d, 2H), 4.30-4.33 (d, 2H), 4.00 (s, 3H), 2.89-2.90 (d, 2H), 2.72-2.74 (m, 2H), 1.74-1.78 (m, 6H), 0.88-0.92 (t, 3H).
Example 55 Synthesis of /V-(l-(4-(l//-benzo[</]imidazol-l-yl)butyl)-5-carbamoyl-Li/- benzo[d]imidazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxamide (1-22)
Figure imgf000166_0002
87.3 87.4
Figure imgf000167_0001
1-22
[00433] Synthesis of compound 87.1. Into a 100-mL 3-necked round-bottom flask, was placed lH-l,3-benzodiazole (5.25 g, 44.439 mmol, 1.00 eq) in DMF (50 mL), NaH (1.50 g, 62.506 mmol, 1.41 eq), 2-(4-bromobutyl)-2,3-dihydro-lH-isoindole-l,3-dione (15.05 g, 53.343 mmol, 1.20 eq) at 0°C. The resulting solution was stirred for 3 h at RT. The resulting mixture was quenched with 50 ml of H2O. The resulting solution was extracted with 3x50 mL of ethyl acetate concentrated. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 9.43 g (66.44%) of 87.1 as a white solid. (ES, m/z): 320 (M+H)+.
[00434] Synthesis of compound 87.2. Into a 250-mL 3-necked round-bottom flask, was placed
87.1 (9.43 g, 29.527 mmol, 1.00 eq) in EtOH (100 mL) and N2H4.H2O (5 mL). The resulting solution was stirred for 1 h at RT. The resulting mixture was filtered and concentrated. The crude product was purified by FI ash-Prep -HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min, UV: 254 nm. This resulted in 4.8 g (85.89%) of 87.2 as a white solid. (ES, m/z): 190 (M+H)+.
[00435] Synthesis of compound 87.3. Into a 100-mL 3 -necked round-bottom flask, was placed
87.2 (3.00 g, 15.851 mmol, 1.00 eq) in DMSO (30 mL), DIEA (20.49 g, 158.510 mmol, 10.00 eq), 4-chloro-3-nitrobenzamide (3.82 g, 19.021 mmol, 1.20 eq). The resulting solution was stirred for 1 h at 100°C. The resulting mixture was diluted with 30 ml of FLO. The resulting solution was extracted with 3x30 mL of ethyl acetate and concentrated. The residue was applied onto a silical gel column with ethyl acetate/petroleum ether (1 :5). This resulted in 2.6 g (46.42%) of 87.3 as a yellow solid. (ES, m/z): 354 (M+H)+. [00436] Synthesis of compound 87.4. Into a 100-mL 3 -necked round-bottom flask, was placed
87.3 (2.60 g, 7.357 mmol, 1.00 eq) in HOAc (30 mL), Zn (9.62 g, 147.150 mmol, 20.00 eq). The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min; Detector UV: 254 nm. This resulted in 1.8 g (75.65%) of 87.4 as a white solid. (ES, m/z): 324 (M+H)+.
[00437] Synthesis of compound 87.5. Into a 50-mL 3-necked round-bottom flask, was placed
87.4 (1.80 g, 5.566 mmol, 1.00 eq) in MeOH (20 mL), BrCN (0.71 g, 6.679 mmol, 1.20 eq). The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min; Detector UV: 254 nm. The product was obtained. This resulted in 480 mg (24.75%) of 87.5 as a white solid. (ES, m/z): 349 (M+H)+.
[00438] Synthesis of compound 1-22. Into a 10-mL round-bottom flask, was placed 4, 5, 6, 7- tetrahydro-2, l-benzoxazole-3 -carboxylic acid (47.98 mg, 0.287 mmol, 1.00 eq), DMF (5.0 mL), DIEA (111.29 mg, 0.861 mmol, 3.00 eq), HATU (218.27 mg, 0.574 mmol, 2.00 eq), 87.5 (100.00 mg, 0.287 mmol, 1.00 eq). The resulting solution was stirred for 2 h at 85°C. The solids were collected by filtration. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN/Water=0: 100% increasing to CH3CN/Water=100%:0 within 15 min; Detector 254 nm. This resulted in 15.1 mg (10.57%) of 1-22 as a light yellow solid. (ES, m/z): 498 (M+H)+, 496 (M-H) ; 1H-NMR (400 MHz, DMSO -de,ppm) d 9.59 (s, 1H), 8.18-8.01 (d, 3H), 7.98-7.82 (d, 2H), 7.80-7.58 (d, 3H), 4.75-4.55 (t, 2H), 4.53-4.30 (d, 2H), 3.04-2.74 (m, 2H), 2.70-2.67 (d, 2H), 2.13-1.80 (m, 4H), 1.78-1.66 (d, 4H).
Example 56 Synthesis of /V-(l-(4-(l//-benzo[</]imidazol-l-yl)butyl)-5-carbamoyl-Li/- benzo[</]imidazol-2-yl)-2,4-dimethyloxazole-5-carboxamide (1-23)
Figure imgf000169_0001
87.5 1-23
[00439] Synthesis of compound 1-23. Into a 10-mL round-bottom flask, was placed 87.5 (100.00 mg, 0.287 mmol, 1.00 eq), DMF (5.00mL), DIEA (111.29 mg, 0.861 mmol, 3.00 eq), HATU (218.27 mg, 0.574 mmol, 2.00 eq), dimethyl-1, 3-oxazole-5-carboxylic acid (81.01 mg, 0.574 mmol, 2.00 eq). The resulting solution was stirred for 2 h at 85°C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15 min; Detector UV: 254 nm. The product was obtained. This resulted in 10.6 mg (7.83%) of 1-23 as a white solid. (ES, m/z): 472 (M+H)+, 470 (M-H)-; ¾-NMR (400 MHz, DMSO -de,ppm) d 12.72 (s, 1H), 8.20 (s, 1H), 8.00-7.98 (d, 2H), 7.78-7.76 (d, 1H), 7.63-7.51 (m, 3H), 7.32 (s, 1H), 7.20-7.16 (d, 2H), 4.35-4.30 (t, 2H), 4.23-4.20 (t, 2H), 2.40-2.38 (d, 6H), 1.91-1.73 (m, 4H).
Example 57 Synthesis of A-(l-(4-(lF -benzo[d]imidazol-l-yl)butyl)-5-carbamoyl-l/ - benzo[</]imidazol-2-yl)-4-ethyl-2-methyloxazole-5-carboxamide (1-24)
Figure imgf000169_0002
1-24
87.5 [00440] Synthesis of compound 1-24. Into a 10-mL round-bottom flask, was placed 4-ethyl-2- methyl-l,3-oxazole-5-carboxylic acid (89.06 mg, 0.574 mmol, 2.00 eq), DMF (5.00 mL), DIEA (111.29 mg, 0.861 mmol, 3.00 eq), HATU (218.27 mg, 0.574 mmol, 2.00 eq), 87.5 (100.00 mg, 0.287 mmol, 1.00 eq). The resulting solution was stirred for 2 h at 85°C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3x15 mL of ethyl acetate. The resulting mixture was washed with 1 xl 5 ml of water. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15min; Detector UV: 254 nm. This resulted in 27.2 mg (19.52%) of 1-24 as a light yellow solid. (ES, m/z): 486 (M+H)+, 484 (M-H) ; ¾-NMR (300 MHz, DMSO-de, ppm) d 12.73 (s, 1H), 8.21 (s, 1H), 8.00-7.96 (d, 2H), 7.78-7.76 (d, 1H), 7.68-7.49 (m, 3H), 7.33 (s, 1H), 7.22-7.18 (t, 2H), 4.35 -4.19 (t, 4H), 2.93-2.86 (q, 2H), 2.41 (s, 3H), 1.90- 1.78 (d, 4H), 1.11-1.10 (t, 3H).
Example 58 Synthesis of cyclopentyl 3-(5-carbamoyl-2-(2,4-dimethyloxazole-5- carboxamido)-7-methoxy-lL/-benzo[d]imidazol-l-yl)propylcarbamate 1-25
Figure imgf000170_0001
90.2 1-25
[00441] Synthesis of compound 90.1. Into a 20-mL Microwave tube purged and maintained with an inert atmosphere of argon, was placed dimethyl- 1, 3 -oxazole-5-carboxylic acid (63.95 mg, 0.453 mmol, 1.20 eq) in NMP (2 mL), DIEA (146.20 mg, 1.131 mmol, 3.00 eq), 1.4 (150.00 mg, 0.377 mmol, 1.00 eq), HATU (430.75 mg, 1.133 mmol, 3.00 eq). The final reaction mixture was irradiated with microwave radiation for 1 h at 140°C. The resulting mixture was diluted with 30 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 1). This resulted in 320 mg (81.44%) of 90.1 as a solid. (ES, m/z): 521 (M+H)+.
[00442] Synthesis of compound 90.2. Into a 100-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 90.1 (300.00 mg, 0.576 mmol, 1.00 eq) in AcOH (15.00 mL), HBr (6.00 mL). The resulting solution was stirred overnight at 25°C. The pH value of the solution was adjusted to pH 10 with NaiCCh (aqueous). The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined, then concentrated under vacuum. This resulted in 240 mg (107.77%) of 90.2 as a solid. (ES, m/z): 387 (M+H)+.
[00443] Synthesis of compound 1-25. Into an 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 90.2 (250.00 mg, 0.647 mmol, 1.00 eq), DMF (2.50 mL), Et3N (327.10 mg, 3.233 mmol, 5.00 eq), cyclopentylcarbonochloride (143.70 mg, 0.967 mmol, 1.49 eq). The resulting solution was stirred for 90 min at 25°C. The resulting mixture was diluted with 20 mL of water. The resulting solution was extracted with 2x20 mL of ethyl acetate and the organic layers combined. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel ; mobile phase, ACN/H20=15% increasing to ACN/H2O=60% within 15min; Detector UV 254 nm. This resulted in 60.8 mg (18.17%) of 1-25 as an off-white solid. (ES, m/z): 499 (M+H)+, 497 (M-H) ; ¾-NMR (300 MHz, DMSO-d6,ppm) d 12.75 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.39-7.37 (d, 2H), 7.04-7.01 (t, 1H) , 4.94-4.91 (t, 1H), 4.36-4.32 (t, 2H) , 3.98 (s, 3H), 3.03-3.01 (m, 2H), 2.52-2.50 (t, 3H), 2.44 (d, 3H) , 1.90-1.83 (m, 4H), 1.78-1.76 (m, 6H). Example 59 Synthesis of 2-(4,5,6,7-tetrahydro-2,l-benzoxazole-3-amido)-9-oxa-l,3- diazatricyclo[6.4.1.0A [4,13]]trideca-2,4(13),5,7-tetraene-6-carboxamide (1-44)
Figure imgf000172_0001
Synthesis of compound 93.1. To a solution of 68.1 (432 mg, 1.995 mmol, 1 eq) in NMP (5 mL) was added tert-butyl N-(3-bromopropyl)carbamate (949.95 mg, 3.989 mmol, 2 eq) and DIEA (1.286 g, 9.975 mmol, 5 eq). The resulting solution was stirred overnight at 100°C. The reaction was cooled to RT and diluted with water. The solids were collected by filtration. This resulted in 630 mg (84.50%) of 93.1 as an off-white solid. (ES, m/z): 374 (M+H)+.
[00444] Synthesis of compound 93.2. To a solution of 93.1 (640 mg, 1.716 mmol, 1 eq) in DCM (10 mL) was added TFA (5 mL). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. This resulted in 500 mg crude of 93.2 as a dark grey solid. (ES, m/z): 274 (M+H)+.
[00445] Synthesis of compound 93.3. To a solution of 93.2 (500 mg, 1.825 mmol, 1 eq) in DMF (5 mL) was added K2CO3 (755.55 mg, 5.475 mmol, 3 eq). The resulting solution was stirred overnight at 80°C. The reaction was cooled to RT and diluted with water. The solids were collected by filtration. This resulted in 287 mg (73.58%) of 93.3 as an orange solid. (ES, m/z): 238 (M+H)+.
[00446] Synthesis of compound 93.4. To a solution of 93.3 (220 mg, 0.927 mmol, 1 eq) in conHCl (10 mL) was added SnCh 2H20 (1.05 g, 4.637 mmol, 5 eq). The resulting solution was stirred overnight at RT. The resulting mixture was concentrated. The residue was adjusted to pH 10 with sat. Na2CC>3 solution. The solids were filtered out. This resulted in 30 mL of 93.4 as a brown yellow liquid. (ES, m/z): 208 (M+H)+.
[00447] Synthesis of compound 93.5. To a solution of 93.4 (30 mL) in MeOH (20 mL) was added BrCN (138 mg, 1.303 mmol, 1.5 eq). The resulting solution was stirred overnight at RT. The resulting mixture was concentrated. The residue was diluted with DMF. The solids were filtered out. The mixture was concentrated. This resulted in 100 mg (49.57%) of 93.5 as a brown solid. (ES, m/z): 233 (M+H)+.
[00448] Synthesis of compound 1-44. To a solution of 4,5,6,7-tetrahydro-2, l-benzoxazole-3- carboxylic acid (100.00 mg, 0.598 mmol, 1.00 eq) in NMP (2 mL) were added HATU (454.92 mg, 1.196 mmol, 2 eq) and DIEA (231.95 mg, 1.795 mmol, 3 eq), 93.5 (150.00 mg, 0.598 mmol, 1.00 eq) in portions at RT. The resulting mixture was stirred for lh at 140°C under microwave radiation. The resulting mixture was diluted with water (3mL). The resulting mixture was filtered, and the filter cake was washed with water (3x1 mL). The filtrate was concentrated under reduced pressure. The residue was washed with MeOH (1 mL) and DMF (1 mL). The resulting mixture was concentrated under vacuum. This resulted in 8mg (8.33%) of 1-44 as an off-white solid. (ES, m/z): 382 (M+H)+, 380 (M-H) ; 1H-NMR (300 MHz, mASO-d6,ppm) d 12.95 (s, 1H), 7.95 (s, 1H), 7.68- 7.67 (d, 1H), 7.35-7.34 (d, 2H), 4.42 (s, 2H), 4.19-4.18 (t, 2H), 2.90 (s, 2H), 2.75-2.70 (m, 2H), 2.38 (s, 2H), 1.74 (s, 4H).
Example 60. *H NMR and Mass Spectral Data for exemplary compounds
[00449] Table 2 below provides ¾ NMR and MS data for additional exemplary compounds which were prepared using similar synthetic methodology and routes as Examples 1-59.
Table 2. *H NMR and Mass Spectral Data for Exemplary Compounds.
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Example 61. STING Surface Plasmon Resonance (SPR) Protocol (human).
[00450] Surface plasmon resonance experiments were performed on Biacore™ T200 (GE Healthcare). Briefly, recombinant STING (H232R, aal49-341) was chemically biotinylated using Sulfo-NHS-LC-LC-Biotin kits (Thermofisher) and captured on the streptavidin surface in the buffer of 20mM Tris.HCl pH 7.5, 150 mM NaCl at 10°C to give final capture levels of 7000-10000 RU. Kinetics study of the compound binding was performed in the buffer of 20mM Tris.HCl pH 7.5, 150 mM NaCl, 0.005% tween-20, 5% DMSO, at 10°C. For multi-cycle kinetics study, compounds were series diluted in the buffer and injected over the STING surface for 60s followed by a dissociation time of 60-200s. Data were corrected for DMSO excluded volume effects. All data were double-referenced for blank injections and reference surface using standard processing procedures. Data were fitted using a 1 : 1 binding model to determine KD, kd and ka as appropriate.
[00451] Results of exemplary compounds tested in the SPR assay are provided in Table 3, below. Compounds that provided a KD of ^5 mM in the SPR assay are designated“A”; compounds that provided a KD of >5 mM and <10 mM are designated“B”; and compounds that provided a KD of >10 mM are designated“C”.
Table 3. hSTING SPR Assay Results.
Figure imgf000176_0001
Example 62. 293T-luc2p-h232R Agonist Assay
[00452] HEK293T cells (ATCC CRL-3216) were stably co-transfected with plasmids expressing full length human STING (NM_198282 with the Histidine at position 232 mutated to an Arginine) (Genewiz) and the enzyme firefly luciferase driven by the interferon stimulated response element promoter (pISRE-luc2p) (Promega). Transfections were prepared using a cell suspension with Fugene ® 6 following the manufacturer’s instructions (3 : 1 Fugene® 6 :DNA). Stable clones were selected in media containing puromycin and hygromycin. 25 microliters of cell suspension containing 20,000 cells was dispensed into a 384 well plate containing 125 nanoliters of a compound. Control wells expected to generate maximal activation of STING were treated with 2’,3’-cyclic-GAMP. Plates were sealed and incubated for 16 hours at 37° C. The expression of firefly luciferase was processed using Steady-Glo luciferase assay system (Promega) following the manufacturer’s instructions and was analyzed using a Perkin Elmer EnVision 2104 luminescence plate reader. EC o was generated by non-linear regression plot of log compound concentration versus luminescence value. Percent activity was determined using the following equation: (Tope - Low)* 100/(TopR - Low) where Tope is the top luminescence value of compound; Low is luminescence value of low control and TopR is the top luminescence value of the reference compound.
[00453] Results of exemplary compounds tested in the 293T-luc2p-h232R agonist assay are provided in Table 4, below. Compounds that provided an ECso of ^5 mM in the assay are designated“A”; compounds that provided a EC50 of >5 mM and <30 pM are designated“B”; and compounds that provided a EC50 of >30 pM are designated“C”.
Table 4. 293T-luc2p-h232R Agonist Assay Results
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Example 63. 293T-luc2p-mouse STING Agonist Assay.
[00454] HEK293T cells (ATCC CRL-3216) were stably co-transfected with plasmids expressing full length mouse STING (NM_028261) and the enzyme firefly luciferase driven by the interferon stimulated response element promoter (pISRE-luc2p) (Promega). Transfections were prepared using a cell suspension with Fugene ® 6 following the manufacturer’s instructions (3:1 Fugene® 6 :DNA). Stable clones were selected in media containing puromycin and hygromycin. 25 microliters of cell suspension containing 20,000 cells was dispensed into a 384 well plate containing 125 nanoliters of a compound. Control wells expected to generate maximal activation of STING were treated with 2’,3’-cyclic-GAMP. Plates were sealed and incubated for 16 hours at 37° C. The expression of firefly luciferase was processed using Steady-Glo luciferase assay system (Promega) following the manufacturer’s instructions and was analyzed using a Perkin Elmer EnVision 2104 luminescence plate reader. EC50 was generated by non-linear regression plot of log compound concentration versus luminescence value. Percent activity was determined using the following equation: (Tope - Low)* 100/(TopR - Low) where Tope is the top luminescence value of compound; Low is luminescence valueDof low control and TopR is the top luminescence value of the reference compound.
[00455] Results of exemplary compounds tested in the 293T-luc2p-mouse STING agonist assay are provided in Table 5, below. Compounds that provided an ECso of <5 mM in the assay are designated“A”; compounds that provided a ECso of >5 mM and <30 mM are designated“B”; and compounds that provided a ECso of >30 mM are designated“C”.
Table 5. 293T-luc2p-mouse STING Agonist Assay Results.
Figure imgf000180_0002
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Example 64. Human STING SPA Binding Assay
[00456] A radioligand binding assay was used to measure interactions of compound binding to STING protein by competition with [3H]2’,3’-cGAMP. Test compound is pre-incubated with 0.2ug/well His-tagged human STING (NM_198282) protein spanning residues 149-341 for 10 minutes at room temperature in a Perkin-Elmer Isoplate. 150nM of the [3H]2’,3’-cGAMP probe along with lOOug/well PVT Cu-His-tag SPA beads are then added to the plate and the reaction mixture is incubated at room temperature for another 45 minutes. Following incubation, the plates are placed in counting cassettes and counted on a Microbeta microplate counter for radiometric detection. Compound binding IC50 is calculated using non-linear regression of the dose-response curve.
[00457] Results of exemplary compounds tested in the human STING SPA binding assay are provided in Table 6, below. Compounds that provided an IC50 of <10 mM in the assay are designated“A”; compounds that provided a IC50 of >10 mM and <50 mM are designated“B”; compounds that provided a IC50 of >50 mM and <100 mM are designated“B”; and compounds that provided a IC50 of >100 mM are designated“D”.
[00458] Table 6. Human STING SPA Binding Assay Results
Figure imgf000184_0001
Figure imgf000185_0001
Example 65. Mouse STING SPA Binding Assay
[00459] A radioligand binding assay was used to measure interactions of compound binding to mouse STING protein by competition with [3H]2’,3’-cGAMP. Test compound is pre-incubated with 0.04ug/well His-tagged mouse STING (NM_028261) protein spanning residues 149-341 for 10 minutes at room temperature in a Perkin-Elmer Isoplate. 20nM of the [3H]2’,3’-cGAMP probe along with 20ug/well PVT Cu-His-tag SPA beads are then added to the plate and the reaction mixture is incubated at room temperature for another 45 minutes. Following incubation, the plates are placed in counting cassettes and counted on a Microbeta microplate counter for radiometric detection. Compound binding IC50 is calculated using non-linear regression of the dose-response curve.
[00460] Results of exemplary compounds tested in the mouse STING SPA binding assay are provided in Table 7, below. Compounds that provided an IC50 of <10 mM in the assay are designated“A”; compounds that provided a IC50 of >10 mM and <50 mM are designated“B”; compounds that provided a IC50 of >50 mM and <100 mM are designated“B”; and compounds that provided a IC50 of >100 mM are designated“D”.
[00461] Table 7. Mouse STING SPA Binding Assay
Figure imgf000185_0002
[00462] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS We claim:
1. A compound of formula I:
Figure imgf000187_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Z is Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R6; or Z is -OR;
wherein Z is not
Figure imgf000187_0002
L is a covalent bond or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R’)2-, -N(R)-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S(0)2-,
-S(0)2N(R)-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -S-, -S(0)- or -S(0)2-;
each R’ is independently hydrogen or Ci-4 aliphatic; or
two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 3-7 membered saturated or partially unsaturated carbocyclylene ring; or
two instances of R’ on the same carbon are optionally taken together with the carbon to form an optionally substituted bivalent 4-7 membered saturated or partially unsaturated heterocyclylene ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:
two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R1 is selected from H; Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R1 is halogen, -CN, -NO2, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R2 is selected from H, Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R2 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R,
N(R)C(0)0R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R3 is selected from H, Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R3 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)R,
N(R)C(0)0R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2, R4 is selected from H; Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with q instances of Rc; or R4 is halogen, -CN, -N02, -OR,
SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -C(0)N(R)0R, -0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, - N(R)C(NR)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, or -P(0)R2;
R5 is -H, Ci-6 aliphatic which is substituted with q instances of Rc, or -L’-Q; or
R4 and R5 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aromatic ring having one nitrogen atom and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of Rc;
L’ is a covalent bond or a Ci-is bivalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one to four methylene units of the chain are optionally and independently
replaced by -Cy’-,
Figure imgf000190_0001
N(R)C(0)-, -C(0)N(R)-, -N(R)C(0)0-, -0C(0)N(R)-, -N(R)S(0)2-, -S(0)2N(R)-, -0-, - C(O)-, -OC(O)-, -C(0)0-, -S-, -S(O)-, or -S(0)2-;
each instance of -Cy’- is independently an optionally substituted bivalent ring selected from phenylene, napththylene, 3-7 membered saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Q is hydrogen or a CRBN binding moiety;
each instance of R6 is independently oxo, halogen, -CN, -N02, -OR, -SR, -NR2, -S(0)2R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -C(0)NR2, -C(0)N(R)0R,
-0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, - N(R)CN, -P(0)(R)NR2, -P(0)(R)0R or -P(0)R2; or each instance of R6 is independently an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
two R6 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated or partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of Rc is independently oxo, halogen, -CN, -N02, -OR, -SR, -NR2, -S(0)2R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -C(0)NR2, -C(0)N(R)0R,
-0C(0)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(0)2NR2, -N(R)S(0)2R, -N=S(0)R2, -S(NR)(0)R, -N(R)S(0)R, - N(R)CN, -P(0)(R)NR2, -P(0)(R)0R or -P(0)R2 ; or each instance of Rc is independently an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of n and q is independently 0, 1, 2, 3, or 4; and
each of x is independently 1,
2,
3,
4,
5, 6, 7, 8, 9, or 10. The compound of claim 1 wherein the compound is of formula II:
Figure imgf000192_0001
II
or a pharmaceutically acceptable salt thereof. The compound of claim 1 wherein the compound is of formula III:
Figure imgf000192_0002
III
or a pharmaceutically acceptable salt thereof. The compound of claim 1 wherein the compound is of formula IV:
Figure imgf000192_0003
IV
or a pharmaceutically acceptable salt thereof. The compound of claim 1 wherein the compound is of formula V:
Figure imgf000193_0001
V
or a pharmaceutically acceptable salt thereof.
6. The compound of any preceding claim, wherein Z is C1-4 aliphatic; a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorous, silicon and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-14 membered bicyclic heteroaryl or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-14 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by n instances of R6.
7. The compound of any preceding claim, wherein Z is selected from -Me, -Et, -Pr, - CH2OCH3, -CH(Et)2, -OMe, -O/Bu,
Figure imgf000193_0002
Figure imgf000194_0001
8. The compound of any preceding claim, wherein R1 is H, Ci-6 aliphatic which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R1 is halogen, -OR, - SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, or -N(R)S(0)2R.
9. The compound of any preceding claim, wherein R1 is H, Ci-6 aliphatic which is substituted with q instances of Rc; or R1 is halogen, -OR, -C(0)R, -C(0)0R.
10. The compound of any preceding claim, wherein R2 is H, Ci-6 aliphatic which is substituted with q instances of Rc; or R2 is halogen, -
OR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -0C(0)R, -N(R)C(0)R, -N(R)C(0)0R, or -N(R)C(0)NR2.
11. The compound of any preceding claim, wherein R2 is H, -OR, -C(0)0R, - C(0)NR2, -0C(0)R, or -N(R)C(0)R.
12. The compound of any preceding claim, wherein R3 is -H, Ci-6 aliphatic which is substituted with q instances of Rc; or R3 is halogen, -
OR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, - C(0)NR2, -0C(0)R, -N(R)C(0)R, -N(R)C(0)0R, or -N(R)C(0)NR2.
13. The compound of any preceding claim, wherein R4 is H, Ci-6 aliphatic which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, which is substituted with q instances of Rc; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is substituted with q instances of Rc; or R4 is halogen, -OR, - SR, -NR2, -S(0)2R, -S(0)(NR)R, -S(0)2NR2, -S(0)R, -S(0)NR2, -C(0)R, -C(0)0R, -C(0)NR2, -N(R)C(0)0R, -N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)S(0)2NR2, or -N(R)S(0)2R.
14. The compound of any preceding claim, wherein R4 is H, Ci-6 aliphatic which is substituted with q instances of Rc; or R4 is halogen, -OR, -C(0)R, -C(0)0R.
15. The compound of any preceding claim, wherein R5 is -H, -Pr,
Figure imgf000196_0001
16. The compound of any one of the preceding claims, wherein said compound is selected from any one of the compounds depicted in Table 1, or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of any one of the preceding claims, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
18. A pharmaceutical composition comprising an effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
19. A method of inducing a STING-dependent type I interferon production in a subject, comprising administering a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
20. A method of inducing a STING-dependent cytokine production in a subject, comprising administering a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
21. A method of treating a cell proliferation disorder, comprising administering a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof to the subject.
22. The method according to claim 21, wherein the cell proliferation disorder is cancer, benign papillomatosis, gestational trophoblastic diseases, or benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma.
23. The method of claim 21, wherein the cell proliferation disorder is cancer.
24. The method of claim 23, wherein the benign neoplastic disease is skin papilloma or genital papilloma.
25. The method of claim 23, wherein the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
26. The method of claim 23, wherein the cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10875872B2 (en) 2018-07-31 2020-12-29 Incyte Corporation Heteroaryl amide compounds as sting activators
US10947227B2 (en) 2018-05-25 2021-03-16 Incyte Corporation Tricyclic heterocyclic compounds as sting activators
US11008344B2 (en) 2018-07-31 2021-05-18 Incyte Corporation Tricyclic heteroaryl compounds as STING activators
US11155567B2 (en) 2019-08-02 2021-10-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
US11596692B1 (en) 2018-11-21 2023-03-07 Incyte Corporation PD-L1/STING conjugates and methods of use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009084614A (en) * 2007-09-28 2009-04-23 Dowa Electronics Materials Co Ltd Copper powder and method for producing the same, copper paste, laminated ceramic capacitor, and method for judging copper powder
US20110071130A1 (en) * 2006-05-08 2011-03-24 Pharmacopeia, Inc. 2-aminobenzimidazoles for treating neurodegenerative diseases
WO2017175156A1 (en) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110071130A1 (en) * 2006-05-08 2011-03-24 Pharmacopeia, Inc. 2-aminobenzimidazoles for treating neurodegenerative diseases
JP2009084614A (en) * 2007-09-28 2009-04-23 Dowa Electronics Materials Co Ltd Copper powder and method for producing the same, copper paste, laminated ceramic capacitor, and method for judging copper powder
WO2017175156A1 (en) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SNOW ET AL.: "Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, 2007, pages 3660 - 3665, XP022114557, DOI: 10.1016/j.bmcl.2007.04.045 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10947227B2 (en) 2018-05-25 2021-03-16 Incyte Corporation Tricyclic heterocyclic compounds as sting activators
US11713317B2 (en) 2018-05-25 2023-08-01 Incyte Corporation Tricyclic heterocyclic compounds as sting activators
US10875872B2 (en) 2018-07-31 2020-12-29 Incyte Corporation Heteroaryl amide compounds as sting activators
US11008344B2 (en) 2018-07-31 2021-05-18 Incyte Corporation Tricyclic heteroaryl compounds as STING activators
US11427597B2 (en) 2018-07-31 2022-08-30 Incyte Corporation Heteroaryl amide compounds as sting activators
US11912722B2 (en) 2018-07-31 2024-02-27 Incyte Corporation Tricyclic heteroaryl compounds as sting activators
US11596692B1 (en) 2018-11-21 2023-03-07 Incyte Corporation PD-L1/STING conjugates and methods of use
US11155567B2 (en) 2019-08-02 2021-10-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
US11939343B2 (en) 2019-08-02 2024-03-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use

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