EP4323066A1 - Inhibiteurs de mek et leurs utilisations - Google Patents

Inhibiteurs de mek et leurs utilisations

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Publication number
EP4323066A1
EP4323066A1 EP22720905.3A EP22720905A EP4323066A1 EP 4323066 A1 EP4323066 A1 EP 4323066A1 EP 22720905 A EP22720905 A EP 22720905A EP 4323066 A1 EP4323066 A1 EP 4323066A1
Authority
EP
European Patent Office
Prior art keywords
compound
ring
cancer
optionally substituted
membered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP22720905.3A
Other languages
German (de)
English (en)
Inventor
Alfredo C. Castro
Michael J. Burke
John Proudfoot
Sabine K. RUPPEL
Thomas A. Wynn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ikena Oncology Inc
Original Assignee
Ikena Oncology Inc
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Filing date
Publication date
Application filed by Ikena Oncology Inc filed Critical Ikena Oncology Inc
Publication of EP4323066A1 publication Critical patent/EP4323066A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—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
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and methods useful for inhibiting mitogen- activated protein kinase/extracellular signal-regulated kinase kinase (MEK).
  • MEK mitogen- activated protein kinase/extracellular signal-regulated kinase kinase
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of proliferative disorders, such as cancers.
  • MEK mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK
  • ERK mitogen-activated protein kinase/extracellular signal-regulated kinase
  • MEK-ERK pathway is often activated by mutation of upstream factors, BRAF or Ras, or by the signals of constitutively activated cell-surface receptors. Inhibition of MEK can be a promising strategy for controlling the growth of tumors, for example, the tumors associated with MEK pathway signaling.
  • the instant invention provides a compound of formula (G):
  • the instant invention provides a compound of formula (I):
  • Another aspect of the invention provides a method of treating a disorder mediated by
  • the method comprises administering a therapeutically effective amount of a compound described herein to a subject in need thereof to treat the disorder mediated by MEK, as further described in the detailed description.
  • Another aspect of the invention provides a method of inhibiting MEK activity.
  • the method comprises contacting MEK or a KSR-MEK complex or a RAF-MEK complex with an effective amount of a compound described herein, as further described in the detailed description.
  • a method provided herein comprises contacting a MEK- KSR-RAF complex with an effective amount of a compound described herein, as further described in the detailed description.
  • compounds of the present invention are useful for treating proliferative disorders, such as the cancers as described herein.
  • Compounds of the present invention, and pharmaceutical compositions thereof, are useful as MEK inhibitors.
  • the compounds of the present invention may directly engage members of the RAF family of proteins at the MEK interface, and that RAF family members, specifically BRAF or CRAF, may remodel the prototypical allosteric pocket of the MEK inhibitor in the RAF-MEK complex.
  • RAF family members specifically BRAF or CRAF
  • the compounds of the present invention may bind the RAF-MEK complex and may disrupt the related RAF-MEK complex.
  • the present invention provides a compound of Formula (I’): ( ) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: R 3 R 3 N each R 1 is independently H, halogen, -CN, or optionally substituted C 1-6 aliphatic; X is C, CH, or N; Y is CR 6 , C(O), or N; L’ is a covalent bond, -O-, -C(R 9 ) 2 -, or -NR 8 -; each of R 2 , R 5 , and R 8 is independently H or optionally substituted C 1-6 aliphatic; each of R 3 , R 4 , R 6 , and R 9 is independently H, halogen, or optionally substituted C1-6 aliphatic; Ring B is an optionally substituted ring selected from a 3-8 membered monocyclic carbocyclic ring, a 3-8 membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from N
  • the present invention provides a compound of Formula (I’): or a pharmaceutically acceptabl Ring A is selected from: R 3 R 3 each R 1 is independently H, halogen, -CN, or optionally substituted C 1-6 aliphatic; X is C, CH, or N; Y is CR 6 , C(O), or N; L’ is a covalent bond, -O-, -C(R 9 ) 2 -, or -NR 8 -; each of R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 is independently H or optionally substituted C 1-6 aliphatic; Ring B is an optionally substituted ring selected from a 3-8 membered monocyclic carbocyclic ring, a 3-8 membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, a 5-11 membered bicyclic carbocyclic ring, a 5-11 membered
  • X is C or N
  • Y is CR 6 , C(O), orN; each of R 2 , R 3 , R 4 , R 5 , and R 6 is independently H or optionally substituted Ci- 6 aliphatic;
  • Ring B is an optionally substituted ring selected from a phenyl ring, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, a 8-10 membered bicyclic aromatic ring, and a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S;
  • L is a covalent bond or a Ci-io bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -0-, -S-, -
  • each -Cy- is independently an optionally substituted ring selected from a 3-7 membered carbocyclic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, a phenyl ring, and a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S;
  • R 7 is -CN, -S(O)2-N(R)2, -NR-S(O)2-R, -P(O)(OR)-N(R)2, -C(
  • 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.
  • bicyclic ring or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho- fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “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.
  • 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.
  • 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 bicyclic rings include:
  • Exemplary bridged bicyclics include: NH H
  • lower alkyl refers to a C1-4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 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-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • 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.
  • 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.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl 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 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, 3H indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted 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.
  • R * is C1–6 aliphatic
  • R * is optionally substituted with halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or – NO 2
  • each R ⁇ is independently selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently –R ⁇ , –NR ⁇ 2, – C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH2C(O)R ⁇ , -S(O)2R ⁇ , -S(O)2NR ⁇ 2, –C(S)NR ⁇ 2, – C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic, 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, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstitute
  • 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 al., 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.
  • 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.
  • the term “provided compound” refers to any MEK inhibitor genus, subgenus, and/or species set forth herein.
  • the terms “inhibitor” or “MEK inhibitor” or “MEK antagonist” are defined as a compound that binds to and/or inhibits MEK with measurable affinity. In some embodiments, inhibition in the presence of a MEK inhibitor or a MEK antagonist is observed in a dose-dependent manner.
  • the measured signal (e.g ., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 mM, 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.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change or inhibition in MEK activity between a sample comprising a compound of the present invention, or composition thereof, and MEK, and an equivalent sample comprising MEK, in the absence of said compound, or composition thereof.
  • an effective amount refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result).
  • An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.
  • treating includes any effect, e.g, lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • treatment can be administered after one or more symptoms have developed.
  • treatment can be administered in the absence of symptoms.
  • treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g ., in light of a history of symptoms and/or in light of genetic or other susceptibility factors).
  • Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.
  • the phrases “disorder mediated by MEK” or “disease mediated by MEK” or “MEK- associated disease or disorder,” as used herein, refer to diseases or disorders associated with, or mediated by, MEK or MEK activity.
  • a non-limiting example of a MEK-associated disease or disorder is a MEK-associated cancer.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see e.g, Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975],
  • a “non- ATP competitive” or “ATP non-competitive” MEK inhibitor refers to an inhibitor of MEK that does not bind in the ATP pocket of MEK, or does not displace ATP from the MEK active site, and can form direct contacts when co-bound to the MEK-ATP complex.
  • Non- ATP competitive inhibition by a compound of the invention can be confirmed by art-recognized methods such as enzymology studies, competition assays, biophysical methods, including X-ray co-crystallography.
  • An exemplary non-ATP competitive inhibitor of the invention inhibits recombinant MEK1 or MEK2 with an IC 50 of from about 1 nM to about 50 mM.
  • an exemplary non-ATP competitive inhibitor of the invention inhibits recombinant MEK1 or MEK2 with an IC 50 of about 1 nM to about 1000 nM, about 1 mM to about 50 mM, about 1 mM to about 25 mM, about 1 mM to about 10 mM, about 500 nM to about 5 mM, or about 10 nM to about 500 nM, [0049]
  • a compound of the invention “allosterically binds an inhibitor pocket” when a compound binds outside the active site, including, for example, outside or adjacent to the ATP-binding site of a kinase.
  • an “inhibitor-inhibitor pocket complex” describes a species in which an inhibitor of the invention allosterically binds an inhibitor pocket formed at an interaction interface between human MEK (MEKl or MEK2) and human Kinase Suppressor of Ras (KSR1, KSR2, or the KSR homolog BRAF or CRAF) adjacent to ATP in a physiological complex between MEK and KSR.
  • a 4 Angstrom contact is reasonable based on the nature of the trametinib-KSR interaction and precedence of known drug-receptor complexes. This contact is within the range of known contacts as defined by several independent groups (PMID 29308120, 26517868, 19221587), 3. Description of Exemplary Embodiments:
  • X is C, CH, orN
  • Y is CR 6 , C(O), orN;
  • L’ is a covalent bond, -0-, -C(R 9 )2-, or -NR 8 -; each of R 2 , R 5 , and R 8 is independently H or optionally substituted Ci- 6 aliphatic; each of R 3 , R 4 , R 6 , and R 9 is independently H, halogen, or optionally substituted Ci- 6 aliphatic; Ring B is an optionally substituted ring selected from a 3-8 membered monocyclic carbocyclic ring, a 3-8 membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, a 5-11 membered bicyclic carbocyclic ring, a 5-11 membered bicyclic heterocyclic ring having 1-5 heteroatoms independently selected from N, O, or S, a phenyl ring, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, a 8-11 membered
  • the present invention provides a compound of Formula (I’): or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: R 3 R 3 ; each R 1 is independently H, halogen, -CN, or optionally substituted C 1-6 aliphatic; X is C, CH, or N; Y is CR 6 , C(O), or N; each of R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 is independently H or optionally substituted C 1-6 aliphatic; Ring B is an optionally substituted ring selected from a 3-8 membered monocyclic carbocyclic ring, a 3-8 membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, a 5-11 membered bicyclic carbocyclic ring, a 5-11 membered bicyclic heterocyclic ring having 1-5 heteroatoms independently selected from N, O, or S, a phenyl
  • the present invention provides a compound of Formula (I): or a pharmaceutically acceptabl Ring A is selected from: R 3 R 3 a double bond; each R 1 is independently H, halogen, -CN, or optionally substituted C1-6 aliphatic; X is C or N; Y is CR 6 , C(O), or N; each of R 2 , R 3 , R 4 , R 5 , and R 6 is independently H or optionally substituted C1-6 aliphatic; Ring B is an optionally substituted ring selected from a phenyl ring, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, a 8-10 membered bicyclic aromatic ring, and a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S; L is a covalent bond or a C1-10 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3
  • Ring A is an optionally substituted 6-membered ring R 3 R 3 selected f , wherein each of R 3 and R 4 is independe [0057] In some embodiments, Ring A is an optionally substituted 6-membered ring selected R 3 R 3 N from , wherein each of R 3 and R 4 is inde [0058] In some embodiments, Ring A is an optionally substituted 6-membered ring selected R 3 R 3 N from , wherein each of R R 3 N [0059] In some embodiments, Ring A i , wherein each of R 3 and R 4 is independently as defined and described in emb n. In some embodiments, Ring A is .
  • Ring A i wherein each of R 3 and R 4 is independently as defined and described in emb in.
  • Ring A is [0061] In some embodiments, Ring A , wherein R 3 is as defined and described in embodiments herein. In some embodiments, Ring A [0062] In some embodiments, Rin . [0063] In some embodiments, Rin , wherein each of R 3 and R 4 is as defined and described in embodiments herein. In some embodiments, Rin . [0064] In some embodiments, Ring A is selected from those d , below. [0065] As defined generally above, each independently represents a single bond or a double bond. [0066] In some embodiments, represents a single bond.
  • R 1 is H, halogen, -CN, or optionally substituted C 1-6 aliphatic.
  • R 1 is H.
  • R 1 is halogen.
  • R 1 is F.
  • R 1 is Cl.
  • R 1 is Br.
  • R 1 is I.
  • R 1 is -CN.
  • R 1 is optionally substituted C 1-6 aliphatic.
  • X is C or N.
  • X is C.
  • X is CH.
  • X is N.
  • X is selected from those depicted in Table 1, below.
  • Y is CR 6 , C(O), or N.
  • Y is CR 6 , wherein R 6 is as defined and described in embodiments herein.
  • Y is C(O).
  • Y is N.
  • Y is selected from those depicted in Table 1, below.
  • L’ is a covalent bond, -O-, -C(R 9 )2-, or -NR 8 -, wherein in R 8 is as defined and described in embodiments herein.
  • L’ is a covalent bond.
  • L’ is -O-.
  • L’ is -C(R 9 ) 2 -.
  • L’ is -CH 2 -.
  • L’ is -NR 8 -.
  • L’ is -NH-.
  • L’ is selected from those depicted in Table 1, below.
  • each of R 2 , R 3 , R 4 , R 5 , and R 6 is independently H or optionally substituted C1-6 aliphatic.
  • R 2 is H or optionally substituted C1-6 aliphatic.
  • R 2 is H.
  • R 2 is optionally substituted C 1-6 aliphatic.
  • R 2 is optionally substituted C1-6 alkyl.
  • R 2 is C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • R 2 is C1-6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • R 3 is H, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R 3 is H or optionally substituted C1-6 aliphatic. In some embodiments, R 3 is H. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -F. In some embodiments, R 3 is -Cl. In some embodiments, R 3 is -I. In some embodiments, R 3 is optionally substituted C 1-6 aliphatic. In some embodiments, R 3 is optionally substituted C1-6 alkyl. In some embodiments, R 3 is C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • R 4 is H, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is H or optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is H. In some embodiments, R 4 is halogen. In some embodiments, R 4 is -F. In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -I. In some embodiments, R 4 is optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is optionally substituted C 1-6 alkyl. In some embodiments, R 4 is C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • R 5 is H or optionally substituted C1-6 aliphatic. In some embodiments, R 5 is H. In some embodiments, R 5 is optionally substituted C 1-6 aliphatic. In some embodiments, R 5 is optionally substituted 3, 4, 5, or 6 membered saturated or unsaturated carbocyclyl. In some embodiments, R 5 is optionally substituted C1-6 alkyl. In some embodiments, R 5 is C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R 5 is C 1-6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R 5 is C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -OH.
  • R 5 is C 1-6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by -OH.
  • R 5 is methyl, ethyl, propyl, or isopropyl.
  • R 5 is cyclopropyl.
  • R 5 is .
  • R 5 is .
  • R 5 is -CH2F, -CHF2, or -CF3.
  • R 5 i is H, halogen, or optionally substituted C1-6 aliphatic.
  • R 6 is H or optionally substituted C 1-6 aliphatic. In some embodiments, R 6 is H. In some embodiments, R 6 is halogen. In some embodiments, R 6 is -F. In some embodiments, R 6 is -Cl. In some embodiments, R 6 is -I. In some embodiments, R 6 is optionally substituted C1-6 aliphatic. In some embodiments, R 6 is optionally substituted C 1-6 alkyl. In some embodiments, R 6 is C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R 6 is C 1-6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by halogen.
  • R 8 is H. In some embodiments, R 8 is optionally substituted C1-6 aliphatic. In some embodiments, R 8 is optionally substituted C 1-6 alkyl. In some embodiments, R 8 is C 1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R 8 is C 1-6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R 8 is C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -OH. In some embodiments, R 8 is C 1-6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by -OH.
  • R 9 is halogen. In some embodiments, R 9 is -F. In some embodiments, R 9 is -Cl. In some embodiments, R 9 is -I. In some embodiments, R 9 is optionally substituted C 1-6 aliphatic. In some embodiments, R 9 is optionally substituted C 1-6 alkyl. In some embodiments, R 9 is C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R 9 is C1-6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R 9 is C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -OH.
  • each of R 2 , R 3 , R 4 , R 5 , and R 6 is independently selected from those depicted in Table 1, below.
  • Ring B is an optionally substituted ring selected from a phenyl ring, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, a 8-10 membered bicyclic aromatic ring, and a 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S.
  • Ring B is an optionally substituted ring selected from a 3-8 membered monocyclic carbocyclic ring, a 3-8 membered monocyclic heterocyclic ring having 1- 3 heteroatoms independently selected from N, O, or S, a 5-11 membered bicyclic carbocyclic ring, a 5-11 membered bicyclic heterocyclic ring having 1-5 heteroatoms independently selected from N, O, or S, a phenyl ring, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, a 8-11 membered bicyclic aromatic ring, and a 8-11 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S.
  • Ring B is an optionally substituted phenyl ring.
  • Ring B is an optionally substituted 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S.
  • Ring B is an optionally substituted 5 membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • Ring B is an optionally substituted 5 membered heteroaromatic ring selected from , and H which is substituted by a methyl group.
  • Ring B is an optionally substituted 5 membered heteroaromatic ring selected from .
  • Ring B is an optionally substituted 6 membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • Ring B is an optionally substituted phenyl ring.
  • Ring B is an optionally substituted 8, 9, or 10 membered bicyclic aromatic ring. In some embodiments, Ring B is an optionally substituted 11 membered bicyclic aromatic ring.
  • Ring B is an optionally substituted 8, 9, or 10 membered bicyclic heteroaromatic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, or S. In some embodiments, Ring B is an optionally substituted 11 membered bicyclic heteroaromatic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, or S. In some embodiments, Ring B is an optionally substituted 9 membered bicyclic heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, Ring B is an optionally substituted 11 membered bicyclic heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • Ring B is an optionally substituted 9 membered bicyclic heteroaromatic ring selected from In some ng , ents, . nally substituted 3, 4, 5, 6, 7, or 8 membered monocyclic carbocyclic ring. In some embodiments, Ring B is . [0099] In some embodiments, Ring B is an optionally ted 3, 4, 5, 6, 7, or 8 membered monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, Ring B is . [00100] In some embodiments, Ring B is an optionally substituted 5, 6, 7, 8, 9, 10, or 11 membered bicyclic carbocyclic ring. In some embodiments, Ring B is .
  • Ring B is an optionally substituted 7, 8, 9, 10, or 11 membered bicyclic heterocyclic ring having 1-5 heteroatoms independently selected from N, O, or S. In some embodiments, Ring B i .
  • Ring B is substituted 1-2 times by halogen. In some embodiments, Ring B is substituted 1-2 times by R, wherein each R is independently as defined and described in embodiments herein.
  • R is optionally substituted C1-6 alkyl. In some embodiments, R is C 1-6 aliphatic substituted 1-6 times by halogen. In some embodiments, R is C1-6 alkyl substituted 1-6 times by halogen.
  • L is a covalent bond.
  • R is hydrogen.
  • R is methyl.
  • R is -CN.
  • the moiety -(CH 2 -CH 2 -O) 1-10 - can be -CH 2 -CH 2 -O-, -(CH 2 - CH 2 -O) 2 -, -(CH 2 -CH 2 -O) 3 -, -(CH 2 -CH 2 -O) 4 -, -(CH 2 -CH 2 -O) 5 -, -(CH 2 -CH 2 -O) 6 -, -(CH 2 -CH 2 -O) 7 - , -(CH2-CH2-O)8-, -(CH2-CH2-O)9-, or -(CH2-CH2-O)10-.
  • R is hydrogen.
  • R is methyl.
  • R is -CN.
  • L is selected from -CH2-, -NH-, -S(O)2-, -NH-S(O)2-, -CH2- S(O) 2 -, -CH 2 -P(O)(OH)-, -CH(CF 3 )-, -CH(CF 3 )-S(O) 2 -, -NH-C(O)-NH-, -NH-C(O)-, -O-, -O- d , [00111] As defined generally above, each -Cy- is independently an optionally substituted ring selected from a 3-7 membered carbocyclic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, a phenyl ring, and a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S.
  • -Cy- is an optionally substituted 3, 4, 5, 6, or 7 membered carbocyclic ring.
  • -Cy- is an optionally substituted 3, 4, 5, 6, or 7 membered heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • . ents, -Cy- is an optionally
  • -Cy- is an optionally substituted 5 or 6 membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiment .
  • R 7 is -CN, -S(O)2-N(R)2, -NR-S(O)2-R, -P(O)(OR)- , [00118] In some embodiments, R 7 is R, -CN, -S(O)2-N(R)2, -NR-S(O)2-R, -P(O)(OR)-N(R)2, - . . In some embodiments, R 7 is -CN. In some embodiments, R 7 is -S(O)2-N(R)2. In some embodiments, R 7 is -S(O) 2 -NHR.
  • R 7 is -N(R)2. In some embodiments, R 7 is -NHR. In some embodiments, R 7 is -OR. In some embodiments, R 7 is -SR. In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R is hydrogen. In some embodiments, R is methyl. In some embodiments, R is -CN. , or ents, R 7 is H O N S In some
  • R 7 is selected from those depicted in Table 1, below.
  • each R is independently H, -CN, or optionally substituted Ci- 6 aliphatic.
  • R is H. In some embodiments, R is -CN.
  • R is optionally substituted Ci- 6 aliphatic. In some embodiments, R is optionally substituted Ci- 6 alkyl. In some embodiments, R is Ci- 6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R is Ci- 6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by halogen. In some embodiments, R is Ci- 6 aliphatic substituted 1, 2, 3,
  • R is Ci- 6 alkyl substituted 1, 2, 3, 4, 5, or 6 times by -OH.
  • R is methyl, ethyl, propyl, or isopropyl.
  • R is cyclopropyl.
  • n 0, 1, 2, 3, 4, or 5.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. [00128] In some embodiments, R is selected from those depicted in Table 1, below.
  • the present invention provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound selected from Formulae (Il-a) to (II-o):
  • the present invention provides a compound of Formula (III):
  • the present invention provides a compound selected from Formulae (Ill-a) to (Ill-e): or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formula (IV): or a pharmaceutically acceptable sa h variable is as defined above and described in embodiments herein, both singly and in combination.
  • the present invention provides a compound selected from Formulae (IV-a) to (IV-e): or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination. Table 1: Exemplary Compounds.
  • the present invention provides a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound selected from the starting materials, intermediates, and products as described in the Examples herein, or a salt thereof.
  • the compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
  • LG includes, but is not limited to, halogens (e.g. , fluoride, chloride, bromide, iodide), sulfonates (e.g, mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
  • halogens e.g. , fluoride, chloride, bromide, iodide
  • sulfonates e.g, mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate
  • diazonium and the like.
  • oxygen protecting group includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, and Philip Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which is incorporated herein by reference.
  • Suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • esters include formates, acetates, carbonates, and sulfonates.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy- crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxy carbonyl ethers or derivatives.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-
  • arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.
  • Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, and Philip Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which is incorporated herein by reference.
  • Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like.
  • Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyl oxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • LG is a leaving group
  • each of the variables for example, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , L, n, and Ring B, is as defined above and described in embodiments herein, both singly and in combination.
  • Compound C for example by a condensation with an d acetic anhydride to form a ring.
  • Compound C is reduced to Compound D, for example by reacting with POCb and R 3 NH2.
  • Compound D can be converted to Compound E, for example, by a reaction with O O , followed by activating the resulting alcohol to form a leaving group, for example by reacting the resulting alcohol with TsCl and a base.
  • Compound E is then converted to
  • Compound F for example, by a coupling reaction with .
  • Compound F can undergo a rearrangement to provide compound G, for example, in a basic condition.
  • Compound G is then converted to Compound H, for example, by reacting with L-R 7 .
  • the present invention provides a synthesis method as depicted in Scheme 1, above.
  • the present invention provides a method of preparing compound B from Compound A, as depicted in Scheme 1, above.
  • the present invention provides a method of preparing compound C from Compound B, as depicted in Scheme 1, above.
  • the present invention provides a method of preparing compound D from Compound C, as depicted in Scheme 1, above.
  • the present invention provides a method of preparing Compound E from Compound D, as depicted in Scheme 1, above.
  • the present invention provides a method of preparing compound F from Compound E, as depicted in Scheme 1, above.
  • the present invention provides a method of preparing compound G from Compound F, as depicted in Scheme 1, above.
  • the present invention provides a method of preparing compound H from Compound G, as depicted in Scheme 1, above.
  • the present invention provides a compound selected from Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, and Compound H, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.
  • compositions are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical 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 measurably inhibit MEK, or a variant or mutant thereof, in a biological sample or in a patient.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit MEK, or a variant or mutant thereof, 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 terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention.
  • Such organisms preferably include, but are not limited to, mammals (e.g ., murines, simians, equines, bovines, porcines, canines, felines, and the like), and, most preferably, humans.
  • compositions of this invention refers to a nontoxic 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.
  • active metabolite or residue thereof means that a metabolite or residue thereof also inhibits MEK, or a variant or mutant thereof.
  • compositions of the present invention can 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, intrastemal, 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 can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can 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 can 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 can be employed including synthetic mono- or diglycerides.
  • 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 polyoxyethylated versions.
  • These oil solutions or suspensions can 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 can 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 can also be added.
  • compositions of this invention can be administered in the form of 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 can 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 can also be used.
  • compositions can 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 can be formulated in an ointment such as petrolatum.
  • compositions of this invention can 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 can 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 inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient depends 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 also depends upon the particular compound in the composition.
  • the present invention provides a method of using a compound as described herein for treating a disease or disorder associated with MEK.
  • a disease or disorder associated with MEK is a proliferative disorder.
  • a disease or disorder associated with MEK is a cancer.
  • a disease or disorder associated with MEK is a cancer as described herein.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, of a disease or disorder characterized by or associated with increased MEK expression and/or increased MEK activity, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of MEK activity is beneficial, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • a compound as described herein is an “ATP non-competitive MEK inhibitor” that stabilizes or “glues” the complex formed between MEK and KSR, and/or BRAF/CRAF.
  • a compound as described herein allosterically binds an “inhibitor pocket” formed at an interaction interface between human MEK (MEK1 or MEK2) and human Kinase Suppressor of Ras (KSR1 or KSR2 or the KSR homolog BRAF or CRAF) adjacent to ATP in a physiological complex between MEK and KSR (or BRAF or CRAF), forming an inhibitor-inhibitor pocket complex.
  • a compound as described herein is an ATP non-competitive kinase inhibitor.
  • a compound as described herein has a structure such that when bound to the inhibitor-inhibitor pocket complex, the complex comprises the structural elements: (a) at least one moiety of the inhibitor engaging A825 of hKSRl, or P878 of hKSR2, or R662 of BRAF, or R554 of CRAF (b) at least one moiety engaging R234 of hMEKl or R238 of hMEK2, wherein R234 is within about 5 A to about 8 A from any atoms of hKSRl or hKSR2 or BRAF or CRAF.
  • a compound as described herein does not engage one or more of 1216 in hMEKl or 1220 of hMEK2 and A825 in KSR1 or P878 in KSR2.
  • a compound as described herein comprises a structural element according to (a) as described in the above paragraph, which is an H-bond acceptor, inter alia , an oxygen or nitrogen atom, or a fluorine atom attached to an aromatic ring, or an H bond donor.
  • a compound as described herein comprises a structural element according to (a) as described in the above paragraph, which is a moiety of a linker engaging the backbone of A825 of hKSRl, or P878 of hKSR2, or R662 of hBRAF, or R554 of CRAF, directly or through a water-mediated contact.
  • a compound as described herein comprising one or more of the following:
  • At least one moiety is a H-bond acceptor or donor engaging the backbone carbonyl of N823 of hKSRl, or T876 of hKSR2 through a water-mediated contact or backbone amino group of R662 of hBRAF or R554 of hCRAF directly;
  • At least one moiety is a heteroaryl group engaging Ml 43 of hMEKl or Ml 47 of hMEK2;
  • At least one moiety is a heteroaryl group engaging F209 of hMEKl or F213 of hMEK2;
  • (l) at least one moiety engaging M219 of hMEKl or M223 of hMEK2 where hMEKl residues 215-219 adopt a helical conformation.
  • a moiety corresponding to (c) as described above is selected from substituted or unsubstituted alkyl or cycloalkyl.
  • a backbone CO residue of a compound as described herein engages with T876 of hKSR2 or N823 of hKSRl.
  • a compound as described herein engages with a binding pocket, which is lined by the hMEKl residues R234 and M230, or hMEK2 residues R238 and M234, and P877 ofKSR2 or A825 ofKSRl orR662 ofBRAF orR554 of CRAF.
  • a compound as described herein engages a binding pocket via multiple hydrogen bond contacts, including through a water mediated H-bond to Argl89 and Arg234 in hMEKl or ARG193 and A238 of hMEK2, as well as a direct H-bond to the backbone of the pre-helix aG loop -NH- of Arg662 ofBRAF or ARG 554 of CRAF.
  • a compound as described herein engage A825 of hKSRl or P878 of hKSR2 or R662 ofBRAF or R554 of CRAF. In some embodiments, a compound as described herein has a distance of less than or equal to about 5 A to about 8 A from at least one moiety selected from A825 of hKSRl, P878 of hKSR2, and R662 ofBRAF and R554 of CRAF.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a MEK inhibitor compound as described herein, or a pharmaceutical salt or composition thereof.
  • the cellular proliferative disorder is cancer.
  • the cancer is characterized by increased MEK expression and/or increased MEK activity, i.e., “increased activated MEK.”
  • an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3- fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10- fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.
  • the terms "increased expression” and/or “increased activity" of a substance, such as MEK, in a sample or cancer or patient refers to an increase in the amount of the substance, such as MEK, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6- fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to the amount of the substance, such as MEK, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., a control sample or control samples, such
  • a subject can also be determined to have an "increased expression” or “increased activity” of MEK if the expression and/or activity of MEK is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of MEK in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.
  • the present invention provides a method for treating or preventing or reducing the risk of a cancer in patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a "cancer,” as used herein, refers a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth divide and grow results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream.
  • the cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, a lung cancer, a head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, and lung carcinoid tumor.
  • the cancer is a K-Ras mutant cancer.
  • the K-Ras mutant cancer is a K-Ras G12 mutant cancer.
  • the K-Ras mutant G12 cancer is a K-Ras G12D mutant cancer, K-Ras G12V mutant cancer, K-Ras G12C mutant cancer, K-Ras G12R mutant cancer, or K-Ras G12S mutant cancer.
  • the K- Ras mutant cancer is a K-Ras G12D mutant cancer.
  • the K-Ras mutant cancer is a K-Ras G12V mutant cancer.
  • the K-Ras mutant cancer is a K- Ras G12C mutant cancer.
  • the cancer is a mutant B-Raf cancer, such as a B-Raf V600E mutant cancer.
  • the K-Ras mutant cancer is a K-Ras G13 mutant cancer.
  • the K-Ras mutant cancer is a K-Ras G13D mutant cancer.
  • the K-Ras mutant cancer is a K-Ras G12R mutant cancer.
  • the K-Ras mutant cancer is a K-Ras G12S mutant cancer.
  • the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma.
  • the cancer is mesothelioma, such as malignant mesothelioma.
  • a cancer includes, without limitation, leukemias (e.g ., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma
  • a cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma oligodendroglioma
  • schwannoma neurofibrosarcoma
  • meningioma
  • a cancer is acoustic neuroma, astrocytoma (e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • astrocytoma e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV -
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymph
  • a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyo
  • HCC hepatocellular
  • a cancer is hepatocellular carcinoma (HCC).
  • the cancer is hepatoblastoma.
  • the cancer is colon cancer.
  • the cancer is rectal cancer.
  • the cancer is ovarian cancer, or ovarian carcinoma.
  • the cancer is ovarian epithelial cancer.
  • the cancer is fallopian tube cancer.
  • the cancer is papillary serous cystadenocarcinoma.
  • the cancer is uterine papillary serous carcinoma (UPSC).
  • the cancer is hepatocholangiocarcinoma.
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • MPNST peripheral nerve sheath tumors
  • the cancer is neurofibromatosis- 1 associated MPNST.
  • the cancer is Waldenstrom
  • a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papillomavirus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HCV human immunodeficiency virus
  • HPV human papillomavirus
  • the methods or uses described herein inhibit or reduce or arrest or ameliorate the growth or spread of a cancer or tumor.
  • the tumor is treated by arresting, reducing, or inhibiting further growth of the cancer or tumor.
  • the methods or uses described herein increase or potentiate or activate one or more immune responses to inhibit or reduce or arrest or ameliorate the growth or spread of a cancer or tumor.
  • the cancer or tumor is treated by reducing the size (e.g ., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the size of the cancer or tumor prior to treatment.
  • cancers or tumors are treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the quantity of cancers or tumors prior to treatment.
  • a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.
  • a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.
  • a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • ORR objective response rate
  • 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 inhibiting MEK and treating or lessening the severity of a disease, for example, as those described herein.
  • dosage unit form 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.
  • 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 disease or disorder 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 adj
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, polyvinylpyrrolidinone, 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
  • 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.
  • additional therapeutic agents that are normally administered to treat that condition can 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.”
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • 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.
  • One or more other therapeutic agent(s) can be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen.
  • one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • one or more other therapeutic agent(s) and a compound or composition of the invention can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent(s) and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart.
  • 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 can be administered with one or more other therapeutic agent(s) 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, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered.
  • compositions which comprise one or more other therapeutic agent(s) can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 g/kg body weight/day of the one or more other therapeutic agent(s) can be administered.
  • the amount of one or more other therapeutic agent(s) present in the compositions of this invention may 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 one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent.
  • the phrase "normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.
  • the compounds of this invention, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • 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).
  • 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.
  • the one or more other therapeutic agent is a TEAD inhibitor.
  • the TEAD inhibitor is selected from those described in WO 2020/243415, the contents of which are herein incorporated by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from those described in WO 2020/243423, the contents of which are herein incorporated by reference in their entirety. In certain embodiments, the TEAD inhibitor is selected from those described in US Patent No. 11,247,082, the contents of which are herein incorporated by reference in their entirety.
  • TEAD inhibitors can be produced by organic synthesis methods known to one of ordinary skill in the art. Additionally, certain TEAD inhibitors can be prepared as described in Pobbati et al ., “Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy," Structure 2015, 23, 2076-2086; Gibault et al., “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem.
  • the one or more other therapeutic agent is an ERK5 inhibitor.
  • the ERK5 inhibitor is selected from those described in WO 2022/051567, the contents of which are herein incorporated by reference in their entirety.
  • the ERK5 inhibitor is selected from those described in WO 2022/051565, the contents of which are herein incorporated by reference in their entirety.
  • the ERK5 inhibitor is selected from those described in WO 2022/051569, the contents of which are herein incorporated by reference in their entirety.
  • the ERK5 inhibitor is selected from those described in WO 2022/051568, the contents of which are herein incorporated by reference in their entirety.
  • one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor.
  • PARP Poly ADP ribose polymerase
  • a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).
  • one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • an HDAC inhibitor is selected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®, Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (EPIDAZA®, HBI-8000, Chipscreen Biosciences, China).
  • one or more other therapeutic agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor.
  • a CDK 4/6 inhibitor is selected from palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
  • one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor.
  • PI3K phosphatidylinositol 3 kinase
  • a PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).
  • one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins.
  • Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells.
  • a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).
  • one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division.
  • a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis/Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).
  • one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
  • a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene
  • one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist.
  • Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/Sanofi).
  • VEGFR inhibitors such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech/Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (
  • kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S.
  • ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib ( Amgen/T akeda) .
  • one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake.
  • an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).
  • one or more other therapeutic agent is a proteasome inhibitor.
  • Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).
  • one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).
  • PDGF platelet-derived growth factor
  • EGF epidermal growth factor
  • EGFR antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly).
  • Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).
  • one or more other therapeutic agent is an aromatase inhibitor.
  • an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).
  • one or more other therapeutic agent is an antagonist of the hedgehog pathway.
  • Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (ODOMZO®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma.
  • one or more other therapeutic agent is a folic acid inhibitor.
  • Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).
  • one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor.
  • CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan).
  • one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor.
  • IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).
  • one or more other therapeutic agent is an arginase inhibitor.
  • Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).
  • AEB1102 pegylated recombinant arginase, Aeglea Biotherapeutics
  • NCT02732184 myelodysplastic syndrome
  • NCT02561234 solid tumors
  • CB-1158 Calithera Biosciences
  • one or more other therapeutic agent is a glutaminase inhibitor.
  • Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).
  • one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells.
  • Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (RITUXAN®, Genentech/Biogenldec); ofatumumab (anti-CD20, ARZERRA®, GlaxoSmithKline); obinutuzumab (anti-CD20, GAZYVA®, Genentech), ibritumomab (anti- CD20 and Yttrium-90, ZEVALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab e
  • one or more other therapeutic agent is a topoisomerase inhibitor.
  • Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline).
  • Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).
  • one or more other therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2.
  • Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie/Genentech); and blinatumomab (BLINCYTO®, Amgen).
  • Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).
  • one or more other therapeutic agent is an androgen receptor inhibitor.
  • Approved androgen receptor inhibitors useful in the present invention include enzalutamide (XTANDI®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals).
  • one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens.
  • SERMs useful in the present invention include raloxifene (EVISTA®, Eli Lilly).
  • one or more other therapeutic agent is an inhibitor of bone resorption.
  • An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases.
  • Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).
  • one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2.
  • Inhibitors of p53 suppression proteins being studied include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53.
  • ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).
  • one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGF-b).
  • TGF-beta transforming growth factor-beta
  • Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165).
  • the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787).
  • the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) IntT J. Biological Sciences 8:964-978.
  • M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PD- Ll/TGF-b trap compound (NCT02699515); and (NCT02517398).
  • M7824 is comprised of a fully human IgGl antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF-b “trap.”
  • one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti -gly coprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE.
  • MMAE glembatumumab vedotin-monomethyl auristatin E
  • gpNMB anti -gly coprotein NMB
  • gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.
  • one or more other therapeutic agents is an antiproliferative compound.
  • 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; antineoplastic 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
  • 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 ARTMTDEXTM 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 FASLODEXTMFulvestrant 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.
  • topoisom erase 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.
  • 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 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 (IGF
  • 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- C2 g, 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 ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
  • 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.
  • Bcl-2 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.
  • SYK inhibitor 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.
  • 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.
  • 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.
  • TAALOMIDTM thalidomide
  • TNP-470 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 ( [00270] 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.
  • CELEBREXTM CELEBREXTM
  • VIOXXTM rofecoxib
  • etoricoxib 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 (ZARNESTRA TM).
  • 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-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • 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 (RTFUXAN ® ), PR064553 (anti-CD40) and 2C4 Antibody.
  • HERCEPTINTM trastuzumab
  • Trastuzumab-DMl erbitux
  • bevacizumab AVASTINTM
  • rituximab rituximab
  • PR064553 anti-CD40
  • 2C4 Antibody 2C4 Antibody.
  • 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.
  • AML acute myeloid leukemia
  • 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.
  • drugs useful for the treatment of AML such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • 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 deacetylase (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 deacetylase
  • 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 ah, Eds., 4 th Edition, Vol. 1 , pp.
  • 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-1 ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • 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; AN GIO S T ATINTM ; ENDOSTATINTM; anthranilic acid amides; ZD4190; Zd 6 474; 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 (AVASTINTM).
  • VEGF aptamer such as Macugon
  • 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, desoxy corticosterone, testosterone, estrone and dexamethasone.
  • angiogenesis such as, e.g ., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxy corticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • 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.
  • one or more other therapeutic agent is an immuno-oncology agent.
  • an immuno-oncology agent refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject.
  • the administration of an immuno-oncology agent with a compound of the invention has a synergic effect in treating a cancer.
  • An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • an antibody is a monoclonal antibody.
  • a monoclonal antibody is humanized or human.
  • an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses.
  • Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • IgSF immunoglobulin super family
  • B7 family which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/ Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGETL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin a/TNFp, TNFR2, TNFa, LTpR, Lymphotoxin a1b2, FAS,
  • an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g ., IL-6, IL-10, TGF-b, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
  • T cell activation e.g ., IL-6, IL-10, TGF-b, VEGF, and other immunosuppressive cytokines
  • an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIRl, TIM-1, and TIM- 4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD 137), 4-1BBL, ICOS, ICOS-L, 0X40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD
  • an antagonist of a protein that inhibits T cell activation e.g., immune checkpoint inhibitors
  • an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonist of activating receptors on NK cells.
  • an immuno-oncology agent is an antagonist of KIR, such as lirilumab.
  • an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WOl 1/70024, WOl 1/107553, WOl 1/131407, W013/87699, W013/119716, WO13/132044) or FPA-008 (WOl 1/140249; W013169264; WO14/036357).
  • CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WOl 1/70024, WOl 1/107553, WOl 1/131407, W013/87699, W013/119716, WO13/132044) or FPA-008 (WOl 1/140249; W013169264; WO14/036357).
  • an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g ., block inhibitory receptor engagement (e.g, PD-Ll/PD-1 interactions), deplete or inhibit Tregs (e.g, using an anti-CD25 monoclonal antibody (e.g, daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • block inhibitory receptor engagement e.g, PD-Ll/PD-1 interactions
  • Tregs e.g, using an anti-CD25 monoclonal antibody (e.g, daclizumab) or by ex vivo
  • an immuno-oncology agent is a CTLA-4 antagonist.
  • a CTLA-4 antagonist is an antagonistic CTLA-4 antibody.
  • an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.
  • an immuno-oncology agent is a PD-1 antagonist.
  • a PD-1 antagonist is administered by infusion.
  • an immuno- oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity.
  • a PD-1 antagonist is an antagonistic PD-1 antibody.
  • an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MED 1-0680 (AMP-514; WO2012/145493).
  • an immuno-oncology agent may be pidilizumab (CT- Oil).
  • an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP -224.
  • an immuno-oncology agent is a PD-L1 antagonist.
  • a PD-L1 antagonist is an antagonistic PD-L1 antibody.
  • a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS- 936559 (W02007/005874), and MSB0010718C (WO2013/79174).
  • an immuno-oncology agent is a LAG-3 antagonist.
  • a LAG-3 antagonist is an antagonistic LAG-3 antibody.
  • a LAG3 antibody is BMS-986016 (W010/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).
  • an immuno-oncology agent is a CD137 (4-1BB) agonist.
  • a CD137 (4-1BB) agonist is an agonistic CD137 antibody.
  • a CD137 antibody is urelumab or PF-05082566 (W012/32433).
  • an immuno-oncology agent is a GITR agonist.
  • a GITR agonist is an agonistic GITR antibody.
  • a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, W0009/009116), or MK- 4166 (WOl 1/028683).
  • an immuno-oncology agent is an indoleamine (2,3)- dioxygenase (IDO) antagonist.
  • IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (W009/73620, WO009/1156652, WOl 1/56652, W012/142237).
  • an immuno-oncology agent is an 0X40 agonist.
  • an 0X40 agonist is an agonistic 0X40 antibody.
  • an 0X40 antibody is MEDI-6383 or MEDI-6469.
  • an immuno-oncology agent is an OX40L antagonist.
  • an OX40L antagonist is an antagonistic 0X40 antibody.
  • an OX40L antagonist is RG-7888 (WO06/029879).
  • an immuno-oncology agent is a CD40 agonist.
  • a CD40 agonist is an agonistic CD40 antibody.
  • an immuno- oncology agent is a CD40 antagonist.
  • a CD40 antagonist is an antagonistic CD40 antibody.
  • a CD40 antibody is lucatumumab or dacetuzumab.
  • an immuno-oncology agent is a CD27 agonist.
  • a CD27 agonist is an agonistic CD27 antibody.
  • a CD27 antibody is varlilumab.
  • an immuno-oncology agent is MGA271 (to B7H3) (WO 11/109400).
  • an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab
  • an immuno-oncology agent is an immunostimulatory agent.
  • antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor- reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g ., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou etal. (2016) Sci. Transl. Med. 8.
  • the anti-PD-1 antibody nivolumab (OPDIVO ® , Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti -angiogenic therapy.
  • the immunomodulatory therapeutic specifically induces apoptosis of tumor cells.
  • Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma).
  • an immuno-oncology agent is a cancer vaccine.
  • the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma.
  • sipuleucel-T PROVENGE®, Dendreon/Valeant Pharmaceuticals
  • IMLYGIC® BioVex/Amgen, previously known as T-VEC
  • an immuno-oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS -activated, in numerous cancers, including colorectal cancer (NCTO 1622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCTO 1166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (
  • an immuno-oncology agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5- fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3-E2F-delta24-hTNFa-IRES- hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can
  • an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR.
  • the T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.
  • CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes.
  • TCR T-cell receptor
  • the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et a/. ; hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD 19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta).
  • an antigen binding domain such as a domain that binds to CD 19
  • CD3 zeta intracellular signaling domain of the T cell antigen receptor complex zeta chain
  • the CAR When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD 19, the antigen is expressed on malignant B cells.
  • Over 200 clinical trials are currently in progress employing CAR-T in a wide range of indications. [https://clinicaltrials.gov/ct2/results?term
  • an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor g (RORyt).
  • RORyt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Thl7) and CD8+ (Tcl7) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells.
  • an activator of RORyt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).
  • an immunostimulatory agent is an agonist or activator of a tolllike receptor (TLR).
  • TLR tolllike receptor
  • Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax).
  • SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772).
  • Agonists or activators of TLR8 which may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).
  • immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol- Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti -KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.
  • urelumab BMS-663513, Bristol
  • an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORyt.
  • an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15).
  • rbll.- l 5 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453).
  • an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12).
  • an IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/ Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268).
  • a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.
  • an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al ., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages 603-622, the content of which is incorporated herein by reference in its entirety.
  • an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al.
  • an immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al.
  • an immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.
  • an immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the content of which is incorporated herein by reference in its entirety.
  • an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.
  • an immuno-oncology agent is selected from those described in Sandra L.
  • an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct is a CD19/CD3 bispecific antibody construct.
  • abispecific T cell engager (BITE®) antibody construct is an EGFR/CD3 bispecific antibody construct.
  • abispecific T cell engager (BITE®) antibody construct activates T cells.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis.
  • the bystander cells are in solid tumors.
  • the bystander cells being lysed are in proximity to the BITE®-activated T cells.
  • the bystander cells comprises tumor-associated antigen (TAA) negative cancer cells.
  • the bystander cells comprise EGFR-negative cancer cells.
  • an immuno- oncology agent is an antibody which blocks the PD-L1/PD1 axis and/or CTLA4.
  • an immuno-oncology agent is an ex vivo expanded tumor-infiltrating T cell.
  • an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs).
  • CARs chimeric antigen receptors
  • an immuno-oncology agent is an immune checkpoint inhibitor as described herein.
  • checkpoint inhibitor as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient.
  • T-cell exhaustion One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.
  • PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.
  • CTL-4 cytotoxic T-lymphocyte antigen 4
  • BTLA B and T Lymphocyte Attenuator
  • Tim-3 T cell Immunoglobulin and Mucin domain-3
  • Lag-3 Lymphocyte Activation Gene-3
  • an immune checkpoint inhibitor is an antibody to PD-1.
  • PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti -turn or immune response.
  • PD-1 programmed cell death 1 receptor
  • the checkpoint inhibitor is a biologic therapeutic or a small molecule.
  • the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof.
  • the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof.
  • the interleukin is IL-7 or IL-15.
  • the interleukin is glycosylated IL-7.
  • the vaccine is a dendritic cell (DC) vaccine.
  • DC dendritic cell
  • Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands.
  • Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, gd, and memory CD8 + (ab) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands.
  • CTLA-4 CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, gd, and memory CD8 + (ab) T cells
  • CD160 also referred to as B
  • B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7- H4, B7-H5, B7-H6 and B7-H7.
  • Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049.
  • Illustrative immune checkpoint inhibitors include, but are not limited to, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS- 936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor).
  • Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3.
  • the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist.
  • the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®).
  • the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-Ll antibody, TECENTRIQ®, Genentech).
  • nivolumab anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb
  • pembrolizumab anti-PD-1 antibody, KEYTRUDA®, Merck
  • ipilimumab anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb
  • durvalumab anti-PD-Ll antibody, IMFINZI®,
  • the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab.
  • MK-3475 lambrolizumab
  • BMS-936558 nivolumab
  • CT-011 pidilizumab
  • AMP-224 pidilizumab
  • MDX-1105 MEDI4736
  • MPDL3280A MPDL3280A
  • BMS-936559 ipilimumab
  • lirlumab IPH2101, pembrolizumab (KEYTRUDA®)
  • tremelimumab tremelimum
  • an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT- 011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or P
  • Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma.
  • AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).
  • a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3).
  • TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367 and MBG453.
  • TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633).
  • LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109).
  • MBG453 Novartis
  • NCT02608268 is an anti- TIM-3 antibody which is being studied in advanced malignancies
  • a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells.
  • TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).
  • a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3).
  • LAG-3 inhibitors that may be used in the present invention include BMS- 986016 and REGN3767 and IMP321.
  • BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981).
  • REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782).
  • IMP321 is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).
  • Checkpoint inhibitors that may be used in the present invention include 0X40 agonists.
  • 0X40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155
  • Checkpoint inhibitors that may be used in the present invention include CD137 (also called 4-1BB) agonists.
  • CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).
  • Checkpoint inhibitors that may be used in the present invention include CD27 agonists.
  • CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).
  • Checkpoint inhibitors that may be used in the present invention include glucocorticoid- induced tumor necrosis factor receptor (GITR) agonists.
  • GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR-ligand molecule with
  • Checkpoint inhibitors that may be used in the present invention include inducible T- cell co-stimulator (ICOS, also known as CD278) agonists.
  • ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).
  • Checkpoint inhibitors that may be used in the present invention include killer IgG-like receptor (KIR) inhibitors.
  • KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti -KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).
  • KIR3DL2 killer IgG-like receptor
  • Checkpoint inhibitors that may be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa).
  • CD47/SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgGl, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 andNCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and
  • Checkpoint inhibitors that may be used in the present invention include CD73 inhibitors.
  • CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).
  • Checkpoint inhibitors that may be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173).
  • STING stimulator of interferon genes protein
  • Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU- S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).
  • Checkpoint inhibitors that may be used in the present invention include CSF1R inhibitors.
  • CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-lR antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((lR,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2- carboxylic
  • Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors.
  • NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
  • His-tagged MEK1 ( ⁇ compound) was diluted in buffer containing 10 mM HEPES, pH 7.4, 150 mM NaCl, 10 mM MgCh, 1 mM DTT, 0.01% Tween-20, 500 mM ATP and 1% DMSO.
  • Running buffer was lxPBS, 10 mM MgCh, 1 mM DTT, 0.01% Tween-20, 500 mM ATP and 1% DMSO.
  • MEKl was serially diluted three-fold from the top doses of 200 nM with 3 mM compound solution for a total of 5 doses. In each cycle, association time was 60 seconds and dissociation time was 600 seconds with an extra wash of 50% DMSO. Analyte binding was collected at 15°C with a flow rate of 30 pL/min.
  • the K D ratio is defined as the (K D of CRAF-MEKl binary complex)/(K D of ternary complex).
  • Immunoprecipitation experiments are performed by plating about 450,000 HCT116 cells per well in 6-well plates. Cells are plated for 48 h so as to reach approximately 70% confluency before transfection. Then, 24 h after transfection, cells are treated with vehicle (0.1% DMSO) or a compound (about 200 nM) for 1 h. Cells are washed twice in cold PBS and then transferred to a pre-chilled tube in 0.6 ml of PBS solution. Cells are spun at 1 ,800# in a cold centrifuge for 10 min, and supernatant is aspirated.
  • vehicle 0.1% DMSO
  • a compound about 200 nM
  • pellets are resuspended in NP-40 buffer (50 mM Tris pH 7.8, 100 mM NaCl, 0.5% (v/v) NP-40, 10% (v/v) glycerol, 1 mM EDTA) supplemented with protease and phosphatase inhibitor cocktail (Thermo Fisher, 78440) and incubated on ice for 30 min. Lysates are centrifuged for 20 min at 2,100#, and supernatants are collected. Cleared lysates are quantified using BCA reagent (Pierce, 23225), with BSA as a standard.
  • Example 3 Biological Assay for Inhibiting Mouse Xenograft Tumor Growth
  • a second anti-cancer agent such as a TEAD inhibitor or an ERK5 inhibitor
  • Assay procedures are described below.
  • mice are inoculated subcutaneously in the right flank with a primary human tumor xenograft model tumor fragment (2-3 mm 3 in diameter) for tumor development.
  • mice are inoculated with a human lung adenocarcinoma tumor model (MSCLC, ADC model LU6424) that harbors a BRAF mutation (LU6424);
  • mice are inoculated with a human pancreatic tumor model (adenosquamous carcinoma model PA6258) with a K-Ras G12D mutation (PA6258).
  • mice When mean tumor volume reaches approximately 150- 200 mm 3 , animals are randomly allocated to appropriate treatment groups. Mice are treated with one of the following: (1) Vehicle control, (2) Exemplary MEK inhibitor alone, (3) Second anticancer agent alone, or (4) Combination of MEK inhibitor and second anti-cancer agent. Tumors are measured twice per week using calipers.
  • Human AsPc-1 cells or HCT-116 cells are seeded in 384-well culture plates and grown overnight. Cells are pretreated with compound (10-pt titration) for 4 hrs. Then, cell lysates are prepared and assayed for levels of phosphorylated ERK1/2 using a homogeneous TR-FRET assay.
  • CellTiter-Glo 3D cell viability assay is intended for determining cell viability in 3D cell spheroids.
  • the assay reagent penetrates large spheroids and has increased lytic capacity. It measures ATP as an indicator of viability and generates a luminescent readout.
  • Cell Titer-Glo 3D cell viability assay kit Promega G9683 was used.
  • the protein protein interaction of MEK1 and BRAF, MEK1 and CRAF, MEK1 and KSR1, and MEK1 and KSR2 are evaluated using a NANOBRET assay (Promega, Inc. Madison, Wisconsin).
  • the full length open reading frames of each gene pair are either N-terminally or C- terminally fused with the open reading frames of either the NANOLUC® or HALOTAG® coding sequences. Once the vectors are synthesized, empiric evaluation of tag location for each pair determines the optimum signal window.
  • NANOLUC® and HALOTAG® chimeric gene fusions are transfected into HEK293 cells (or other cell lines) and cultured in white 96- or 384-well plates suitable for tissue culture and signal evaluation. Ikena compounds are dispensed to the transfected, live cells along with the necessary positive and negative controls. At discrete times the NANOBRETTM NANOLUC® substrate is added and donor and acceptor signals are measured on the Envision Multimode (or other capable instrument). Protein: protein interaction is evaluated by calculating the NANOBRETTM ratio by subtracting the NANOBRETTM ratios of the control samples from the experimental samples. Additionally, expression of these chimeric gene fusions in mammalian, bacterial or yeast protein expression systems can yield recombinant protein that can be used in an in vitro biochemical assay.
  • the In-Cell Western (ICW) Assay is a quantitative immunofluorescence assay performed in microplates (optimized for 96- or 384-well format) that combines the specificity of Western blotting with the replicability and throughput of ELISA.
  • In-Cell Western Assays are also called cytoblots, cell-based ELISA, In-Cell ELISA (ICE), and FACE (Fast Activated Cell-based ELISA). With In-Cell Western Assays, you can:
  • Tables 2 and 3 show the activity of selected compounds in the assays described above.
  • the compound numbers correspond to the compound numbers in Table 1.
  • the activity is classified as A-D, wherein A represents IC50 ⁇ 100 nM; B represents 100 nM ⁇ IC50 ⁇ 1 uM; C represents 1 ⁇ IC50 ⁇ 10 uM; and D represents IC50 >10 uM.
  • Table 4 shows the activity of selected compounds in the assays described above.
  • the compound numbers correspond to the compound numbers in Table 1.
  • the activity is classified as A-D, wherein A represents IC50 ⁇ 100 nM; B represents 100 nM ⁇ IC50 ⁇ 1 uM; C represents 1 ⁇ IC50 ⁇ 10 uM; and D represents IC50 >10 uM.
  • the CRaf/MEK SPR: KD Ratio is classified as A- D, wherein A represents KD Ratio ⁇ 0.5; B represents 0.5 ⁇ KD Ratio ⁇ 1; C represents 1 ⁇ KD Ratio ⁇ 5; and D represents KD Ratio >5.
  • Step 1 /V-[2-(Dimethylamino)ethyl
  • Step 2 3-Cyclopropyl-l-[3-[2-(dimethylamino)ethylsulfamoylamino]phenyl]-5-(2-fluoro-4- iodo-anilino)-6,8-dimethyl-pyrido[4,3-d]pyrimidine-2,4,7-trione
  • Step 1 tert- Butyl /V-[2-(chlorosulfonylamino)ethyl]carbamate
  • Step 2 tert- Butyl /V-[2-[[3-[3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7- trioxo-pyrido[4,3-d]pyrimidin-l-yl]phenyl]sulfamoylamino]ethyl]carbamate
  • Step 3 l-[3-(2-Aminoethylsulfamoylamino)phenyl]-3-cyclopropyl-5-(2-fluoro-4-iodo- anilino)-6, 8-dim ethyl-pyrido [4, 3-d] pyrimidine-2, 4, 7-trione
  • Step 1 3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-l-(3-hydroxyphenyl)-6,8- dimethylpyrido[4,3- ⁇ /
  • reaction mixture was stirred at 100 °C for 2 h.
  • the reaction mixture was concentrated under reduced pressure to remove most acetic acid.
  • the residue was added addition sat aq NaHCO 3 until pH 7 and extracted with EtOAc (20 mL x 3).
  • Step 2 3-(3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl methylsulfamate
  • reaction mixture was acidified by the addition of 0.1 N HCl and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (20 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 3 5-(3-Amino-2-methyl-anilino)-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8- dimethyl-pyrido[2,3-d]pyrimidine-2,4,7-trione [00377] To a solution of [3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7- trioxo-pyrido[2,3-d]pyrimidin-5-yl] 4-methylbenzenesulfonate (220 mg, 327.89 ⁇ mol, 95.0% purity, 1 eq) in DMA (2 mL) was added 2-methylbenzene-1,3-diamine (123.89 mg, 983.66 ⁇ mol, 97.0% purity, 3 eq) and 2,6-LUTIDINE (105.40 mg, 983.66 ⁇ mol, 114.56 ⁇ L, 3 eq).
  • Step 4 3-Cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-5-[2-methyl-3- (methylsulfamoylamino)anilino]pyrido[2,3-d]pyrimidine-2,4,7-trione
  • 5-(3-a -cyclopropyl-1-(2-fluoro-4-iodo- phenyl)-6,8-dimethyl-pyrido[2,3-d]pyrimidine-2,4,7-trione 50 mg, 76.42 ⁇ mol, 95.4% purity, 1 eq, HCl) in DCM (1 mL) was added N-methylsulfamoyl chloride (8.91 mg, 68.78 ⁇ mol, 0.9 eq) and TEA (38.66 mg, 382.11 ⁇ mol, 53.18 ⁇ L, 5 eq).
  • Step 5 3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[2-methyl-3- (methylsulfamoylamino)phenyl]pyrido[4,3-d]pyrimidine-2,4,7-trione [00379] To a solution of 3-c enyl)-6,8-dimethyl-5-[2-methyl- 3-(methylsulfamoylamino)anilino]pyrido[2,3-d]pyrimidine-2,4,7-trione (30 mg, 42.11 ⁇ mol, 95.5% purity, 1 eq) in THF (1 mL) was added a drop of NaOMe/MeOH (28 wt %, 42.11 ⁇ mol, 1 eq).
  • reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere.
  • the reaction mixture was quenched by addition sat. aq. NaHCO 3 (15 mL) at 0 °C and extracted with DCM (20 mL x 3).
  • Step 3 Ethyl 3-[(2E)-2-[2-ethoxy-1-(3-nitrophenyl)-2-oxo-ethylidene]hydrazino]-3-oxo- propanoate O O O N [00384] To a solution of et e (22.5 g, 90.73 mmol, 1 eq) in EtOH (120 mL) was added H 2 SO 4 (2.29 g, 23.33 mmol, 1.24 mL, 0.25 eq) and ethyl 3- hydrazino-3-oxo-propanoate (13.79 g, 94.36 mmol, 1.04 eq). The mixture was stirred at 90 °C for 2 h.
  • Step 4 Ethyl 4-hydroxy-3-(3-nitrophenyl)-6-oxo-1H-pyridazine-5-carboxylate H N O N [00385] To a solution of eth ophenyl)-2-oxo- ethylidene]hydrazino]-3-oxo-propanoate (30 g, 85.39 mmol, E/Z mixture, 1 eq) in DMF (300 mL) was added K 2 CO 3 (6.49 g, 46.97 mmol, 0.55 eq). The mixture was stirred at 80 °C for 3 h. The mixture was cooled to ambient temperature and poured into 3N HCl (600 mL).
  • Step 5 Ethyl 2-allyl-5-hydroxy-6-(3-nitrophenyl)-3-oxo-pyridazine-4-carboxylate [00386] To a solution of ethy 6-oxo-1H-pyridazine-5- carboxylate (3 g, 8.85 mmol, 1 eq) in DMF (40 mL) was added NaH (707.63 mg, 17.69 mmol, 60.0% purity, 2 eq) and stirred at 20 °C for 30 min. The solution was cooled to -10 °C, 3- bromoprop-1-ene (1.12 g, 9.29 mmol, 1.05 eq) was added dropwise.
  • reaction temperature was slowly warmed up to 20 °C and stirred at 20 °C for 1 h.
  • the reaction mixture was quenched by addition water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield ethyl 2-allyl-5-hydroxy-6-(3-nitrophenyl)-3-oxo-pyridazine-4-carboxylate (3 g, 7.82 mmol, 88.4% yield, 90.0% purity) as a yellow oil.
  • Step 6 Ethyl 2-allyl-5-chloro-6-(3-nitrophenyl)-3-oxo-pyridazine-4-carboxylate [00387] To a solution of ethy henyl)-3-oxo-pyridazine-4- carboxylate (3 g, 7.82 mmol, 1 eq) in DCM (40 mL) was added (COCl)2 (9.92 g, 78.19 mmol, 6.84 mL, 10 eq). The mixture was stirred at 35 °C for 3 h.
  • Step 7 Ethyl 2-allyl-5-(methylamino)-6-(3-nitrophenyl)-3-oxo-pyridazine-4-carboxylate [00388] To a solution of ethy enyl)-3-oxo-pyridazine-4- carboxylate (3 g, 6.60 mmol, 1 eq) in DCM (30 mL) was added MeNH2 (13.66 g, 131.96 mmol, 30.0% purity, 20 eq) at 0 °C. The mixture was stirred at 0 °C for 5 h. The reaction mixture was quenched by addition water (50 mL) and extracted with EtOAc (60 mL x 3).
  • Step 8 2-Allyl-5-(methylamino)-6-(3-nitrophenyl)pyridazin-3-one [00389] To a solution of ethyl 2-allyl-5-(methylamino)-6-(3-nitrophenyl)-3-oxo-pyridazine-4- carboxylate (1.5 g, 3.77 mmol, 1 eq) in DMSO (20 mL) was added LiCl (3.19 g, 75.35 mmol, 20 eq). The mixture was stirred at 180 °C for 6 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (60 mL x 3).
  • Step 9 6-Allyl-4-hydroxy-1,3-dimethyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5-dione [00390] To a solution of 2-allyl- itrophenyl)pyridazin-3-one (1.2 g, 3.35 mmol, 1 eq) in Ac2O (20 mL) was added 2-methylpropanedioic acid (1.19 g, 10.06 mmol, 3 eq). The mixture was stirred at 110 °C for 2 h.
  • Step 10 [6-Allyl-1,3-dimethyl-8-(3-nitrophenyl)-2,5-dioxo-pyrido[2,3-d]pyridazin-4-yl] 4- methylbenzenesulfonate
  • 6-allyl- l-8-(3-nitrophenyl)pyrido[2,3- d]pyridazine-2,5-dione 1.1 g, 2.45 mmol, 1 eq
  • DIEA (1.58 g, 12.24 mmol, 2.13 mL, 5 eq
  • 4-methylbenzenesulfonyl chloride 933.71 mg, 4.90 mmol, 2 eq).
  • Step 11 6-Allyl-4-(2-fluoro-4-iodo-anilino)-1,3-dimethyl-8-(3-nitrophenyl)pyrido[2,3- d]pyridazine-2,5-dione [00392] To a solution of 2-flu g, 2.73 mmol, 2.49 eq) in THF (10 mL) was added NaH (175.74 mg, 4.39 mmol, 60.0% purity, 4 eq) and stirred at 0 °C for 30 min, [6-allyl-1,3-dimethyl-8-(3-nitrophenyl)-2,5-dioxo-pyrido[2,3-d]pyridazin-4-yl] 4- methylbenzenesulfonate (700 mg, 1.10 mmol, 1 eq) was added at 0 °C.
  • Step 10 6-Allyl-8-(3-aminophenyl)-4-(2-fluoro-4-iodo-anilino)-1,3-dimethyl-pyrido[2,3- d]pyridazine-2,5-dione [00393] To a solution of 6-all )-1,3-dimethyl-8-(3- nitrophenyl)pyrido[2,3-d]pyridazine-2,5-dione (130 mg, 188.14 ⁇ mol, 1 eq) in EtOH (1.5 mL) and H 2 O (1.5 mL) was added NH 4 Cl (100.64 mg, 1.88 mmol, 10 eq) and Fe (52.53 mg, 940.68 ⁇ mol, 5 eq).
  • Step 2 1-(3-Aminophenyl)-N-methylmethanesulfonamide [00395] To a solution of 4-methylb N-methyl-1-(3- nitrophenyl)methanesulfonamide (200 mg, 861.19 ⁇ mol, 99.1%, 1 eq) in MeOH (2 mL) was added Pd/C (200 mg, 861.19 ⁇ mol, 10.0%, 1 eq) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 1 h.
  • Step 3 1-(3-((3-Cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8- hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)-N-methylmethanesulfonamide [00396] To a solution of 1-(3-aminophenyl)-N-methyl-methanesulfonamide (150 mg, 711.58 ⁇ mol, 95.0%, 1.91 eq) in DMA (3 mL) was added 2,6-lutidine (119.77 mg, 1.12 mmol, 130.19 ⁇ L, 3 eq) and [3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-pyrido[2,3- d]pyrimi
  • Step 4 1-(3-(3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-methylmethanesulfonamide 7- trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)-N- methylmethanesulfonamide (45 mg, 58.15 ⁇ mol, 86.0%, 1 eq) in THF (1 mL) was added a drop of NaOMe/MeOH (20 wt%, 58.15 ⁇ mol, 1 eq).
  • reaction mixture was stirred at 0 °C for 5 h under N2 atmosphere.
  • the reaction mixture was quenched by addition sat. aq. NaHCO3 (30 mL) at 0 °C and extracted with DCM (30 mL x 3).
  • Step 2 (S)-N-[3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo- pyrido[4,3-d]pyrimidin-1-yl]phenyl]methanesulfinamide and (R)-N-[3-[3-cyclopropyl-5-(2- fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo-pyrido[4,3-d]pyrimidin-1- yl]phenyl]methanesulfinamide [00400] To -anilino)-6,8- dimethyl-pyrido[4,3-d]pyrimidine-2,4,7-trione (200 mg, 348.82 ⁇ mol, 100% purity, 1 eq) and Et3N (363.50 mg, 3.59 mmol, 0.5 mL, 10.
  • the product (160 mg) was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water ( NH 4 HCO 3 )-ACN]; B%: 40%-70%, 10 min) to give desired compound as a white solid, which was further separated by SFC (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: [0.1% NH3H2O EtOH]; B%: 45%- 45%) to yield peak 1 and peak 2.
  • Step 2 Ethyl 5-chloro-2-cyclopropyl-6-(3-nitrophenyl)-3-oxo-pyridazine-4-carboxylate
  • Step 3 Ethyl 2-cyclopropyl-5-(methylamino)-6-(3-nitrophenyl)-3-oxo-pyridazine-4- carboxylate [00403] To a solution of eth nitrophenyl)-3-oxo-pyridazine-4- carboxylate (400 mg, 989.69 ⁇ mol, 1 eq) in DCM (3 mL) was added MeNH2 (1.02 g, 9.90 mmol, 30.0% purity, 10 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h.
  • Step 4 2-Cyclopropyl-5-(methylamino)-6-(3-nitrophenyl)pyridazin-3-one [00404] To a solution of ethyl 2- mino)-6-(3-nitrophenyl)-3-oxo- pyridazine-4-carboxylate (300 mg, 669.74 ⁇ mol, 1 eq) in DMSO (5 mL) was added LiCl (283.93 mg, 6.70 mmol, 10 eq). The mixture was stirred at 150 °C for 8 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3).
  • Step 6 [6-Cyclopropyl-1,3-dimethyl-8-(3-nitrophenyl)-2,5-dioxo-pyrido[2,3-d]pyridazin-4- yl] 4-methylbenzenesulfonate [00406] To a solution of 6-cyclo dimethyl-8-(3-nitrophenyl)pyrido[2,3- d]pyridazine-2,5-dione (200 mg, 434.38 ⁇ mol, 1 eq) in DCM (8 mL) was added DIEA (561.40 mg, 4.34 mmol, 756.61 ⁇ L, 10 eq) and 4-methylbenzenesulfonyl chloride (414.06 mg, 2.17 mmol, 5 eq).
  • Step 7 6-Cyclopropyl-4-(2-fluoro-4-iodo-anilino)-1,3-dimethyl-8-(3-nitrophenyl)pyrido[2,3- d]pyridazine-2,5-dione [00407] To a solution of 2-fluo mg, 1.11 mmol, 3 eq) in THF (3 mL) was added NaH (89.10 mg, 2.23 mmol, 60.0% purity, 6 eq) and stirred at 0 °C for 30 min, then [6-cyclopropyl-1,3-dimethyl-8-(3-nitrophenyl)-2,5-dioxo-pyrido[2,3-d]pyridazin-4-yl] 4- methylbenzenesulfonate (200 mg, 371.27 ⁇ mol, 1 eq) was added at 0 °C.
  • Step 8 8-(3-Aminophenyl)-6-cyclopropyl-4-(2-fluoro-4-iodo-anilino)-1,3-dimethyl- pyrido[2,3-d]pyridazine-2,5-dione
  • Step 2 3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-1-(1H-indol-4-yl)-6,8- dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
  • Step 3 1-(1-Acetyl-1H-indol-4-yl)-3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8- dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
  • the mixture was stirred at 130 °C for 6 h.
  • the mixture was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um;mobile phase: [water (HCl)-ACN];B%: 44%-64%, 10 min) and lyophilized to yield 3-cyclopropyl-1-(1,1-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)-5-((2-fluoro-4- iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (6.74 mg, 9.69 ⁇ mol, 3.15% yield, 95.4% purity) as a yellow solid.
  • Step 2 3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[5- (methylsulfamoylamino)-3-pyridyl]pyrido[4,3-d]pyrimidine-2,4,7-trione [00417]
  • 1-( opyl-5-((2-fluoro-4- iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione 95 mg, 165.41 ⁇ mol, 100.0%, 1 eq
  • DCM 5 mL
  • N-methylsulfamoyl chloride 32.15 mg, 248.11 ⁇ mol, N/A, 1.5 eq
  • TEA 50.21 mg, 496.22 ⁇ mol, 69.07 ⁇ L, 3 eq).
  • Step 2 tert-Butyl N-[2-[[3-[3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7- trioxo-pyrido[4,3-d]pyrimidin-1-yl]phenyl]sulfamoylamino]ethyl]carbamate
  • Step 3 1-[3-(2-Aminoethylsulfamoylamino)phenyl]-3-cyclopropyl-5-(2-fluoro-4-iodo- anilino)-6,8-dimethyl-pyrido[4,3-d]pyrimidine-2,4,7-trione
  • reaction mixture was concentrated under reduced pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (0.05%NH 3 H 2 O+10mM NH 4 HCO 3 )- ACN]; B%: 45%-75%, 10 min) and lyophilized to yield 1-[3-(2- aminoethylsulfamoylamino)phenyl]-3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl- pyrido[4,3-d]pyrimidine-2,4,7-trione (16.78 mg, 23.94 umol, 38.09% yield, 99.223% purity) was obtained as a white solid.
  • Step 2 (S)-N-[3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo- pyrido[4,3-d]pyrimidin-1-yl]phenyl]methanesulfinamide and (R)-N-[3-[3-cyclopropyl-5-(2- fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo-pyrido[4,3-d]pyrimidin-1- yl]phenyl]methanesulfinamide [00422] To -anilino)-6,8- dimethyl-pyrido[4,3-d]pyrimidine-2,4,7-trione (200 mg, 348.82 ⁇ mol, 100% purity, 1 eq) and Et 3 N (363.50 mg, 3.59 mmol, 0.5 mL,
  • the product (160 mg) was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water ( NH4HCO3)-ACN]; B%: 40%-70%, 10 min) to give desired compound as a white solid, which was further separated by SFC (column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5um); mobile phase: [0.1% NH 3 H 2 O EtOH]; B%: 45%- 45%) to yield peak 1 and peak 2.
  • Step 2 3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[3- [methyl(methylsulfamoyl)amino]phenyl]-2,4,7-trioxo-pyrido[4,3-d]pyrimidine [00424]
  • 3-cycl -anilino)-6,8-dimethyl-1-[3- (methylamino)phenyl]pyrido[4,3-d]pyrimidine-2,4,7-trione 5 mg, 8.22 ⁇ mol, 96.6% purity, 1 eq
  • DIEA 22.26 mg, 172.23 ⁇ mol, 30 ⁇ L, 20.95 eq
  • N- methylsulfamoyl chloride 10 mg, 77.18 ⁇ mol, 9.39 eq
  • Step 2 tert-Butyl 1-(4-aminophenyl)-3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl- pyrido[4,3-d]pyrimidine-2,4,7-trione
  • Step 3 tert-Butyl 3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[4- (methylsulfamoylamino)phenyl]pyrido[4,3-d]pyrimidine-2,4,7-trione
  • Step 2 Methyl 2-chlorosulfonyl-5-nitro-benzoate [00429] To a solution of methyl 2-am enzoate (5 g, 25.49 mmol, 1 eq) in HCl (12 M, 80 mL, 37.66 eq) was added a solution of NaNO 2 (1.76 g, 25.49 mmol, 1 eq) in H 2 O (5 mL) dropwise at 0 °C.
  • Step 4 5-Amino-1,1-dioxo-1,2-benzothiazol-3-one [00431] To a solution of Pd/C (3 g, 1 % purity, 1 eq) in THF (50 mL) was added 5-nitro-1,1-dioxo-1,2-benzothiazol-3-one (3.7 g, 14.59 mmol, 90.0%, 1 eq) under N 2 . The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h.
  • Step 5 3-Cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-5-[(1,1,3-trioxo-1,2- benzothiazol-5-yl)amino]pyrido[2,3-d]pyrimidine-2,4,7-trione
  • Step 6 3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-(1,1,3-trioxo-1,2- benzothiazol-5-yl)pyrido[4,3-d]pyrimidine-2,4,7-trione
  • Step 1 tert-Butyl N-[3-[[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo- pyrido[2,3-d]pyrimidin-5-yl]amino]-1-bicyclo[1.1.1]pentanyl]carbamate [00435] To a solution of N-[3 do-phenyl)-6,8-dimethyl-2,4,7- trioxo-pyrido[2,3-d]pyrimidin-5-yl] trifluoromethanes ⁇ Lfonate (300 mg, 482.70 ⁇ mol, 99.0%, 1 eq) in DMF (8 mL) was added 2,6-lutidine (155.17 mg, 1.45 mmol, 168.66 ⁇ L, 3 eq) and tert- butyl N-(3-amino-1-bicyclo[1.1.1]pentanyl
  • Step 2 tert-Butyl N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo- pyrido[4,3-d]pyrimidin-1-yl]-1-bicyclo[1.1.1]pentanyl]carbamate [00436] A mixture of N-[3-[[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7- trioxo-pyrido[2,3-d]pyrimidin-5-yl]amino]-1-bicyclo[1.1.1]pentanyl]carbamate (100 mg, 146.20 ⁇ mol, 97.0%, 1 eq) and NaOMe/MeOH (19.40 mg, 20 ⁇ L, 30.0%, 1.00 eq) in THF (3 mL) was degassed and p
  • Step 3 tert-Butyl 1-(3-amino-1-bicyclo[1.1.1]pentanyl)-3-cyclopropyl-5-(2-fluoro-4-iodo- anilino)-6,8-dimethyl-pyrido[4,3-d]pyrimidine-2,4,7-trione [00437] To a solution of tert-b .1.1]pentanyl)-3-cyclopropyl-5-(2- fluoro-4-iodo-anilino)-6,8-dimethyl-pyrido[4,3-d]pyrimidine-2,4,7-trione (50 mg, 67.82 ⁇ mol, 90.0%, 1 eq) in DCM (1 mL) was added TFA (462.00 mg, 4.05 mmol, 0.3 mL, 59.74 eq).
  • Step 3 tert-Butyl 3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[3- (methyls ⁇ Lfamoylamino)-1-bicyclo[1.1.1]pentanyl]pyrido[4,3-d]pyrimidine-2,4,7-trione
  • reaction mixture was concentrated to yield a residue pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 51%-71%, 12 min), followed by lyophilization to yield product, followed by lyophilization to yield tert-butyl 3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8- dimethyl-1-[3-(methylsulfamoylamino)-1-bicyclo[1.1.1]pentanyl]pyrido[4,3-d]pyrimidine-2,4,7- trione (12.23 mg, 18.63 ⁇ mol, 42.1% yield, 100.0% purity) as a white solid.
  • Step 2 tert-Butyl 3-[[3-(cyclopropylcarbamoyl)-2-(2-fluoro-4-iodo-anilino)-1,5-dimethyl-6- oxo-4-pyridyl]amino]azetidine-1-carboxylate and tert-butyl 3-[3-cyclopropyl-5-(2-fluoro-4- iodo-anilino)-6,8-dimethyl-2,4,7-trioxo-pyrido[4,3-d]pyrimidin-1-yl]azetidine-1-carboxylate [00440] To a s o ut on o NaO e ( 3.
  • Step 3 1-(Azetidin-3-yl)-3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-pyrido[4,3- d]pyrimidine-2,4,7-trione [00441] To a solution of tert-bu -fluoro-4-iodo-anilino)-6,8-dimethyl- 2,4,7-trioxo-pyrido[4,3-d]pyrimidin-1-yl]azetidine-1-carboxylate (20 mg, 29.81 ⁇ mol, 95.0% purity, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL).
  • Step 4 3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo-pyrido[4,3- d]pyrimidin-1-yl]-N-methyl-azetidine-1-sulfonamide
  • Step 2 tert-Butyl (3-((3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo- 1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)cyclobutyl)carbamate
  • a mixture of 3-cyclo nyl)-6,8-dimethyl-2,4,7-trioxo- 1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate 350 mg, 563.15 ⁇ mol, 99.0%, 1 eq
  • tert-butyl N-(3-aminocyclobutyl)carbamate 115.38 mg, 619.46 ⁇ mol, 1.1 eq
  • Cs2CO3 550.45 mg, 1.69 mmol
  • Step 3 tert-Butyl (3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)cyclobutyl)carbamate
  • Step 4 1-(3-Aminocyclobutyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)- 6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
  • Step 5 3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[3- (methylsulfamoylamino)cyclobutyl]pyrido[4,3-d]pyrimidine-2,4,7-trione
  • reaction mixture was diluted with H2O (20 mL), extracted with DCM (20 mL x 3).
  • the organic layer was concentrated under reduced pressure, which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(NH4HCO3)-ACN]; B%: 45%-70%, 11 min) and lyophilized to yield 3-cyclopropyl-5-(2- fluoro-4-iodo-anilino)-6,8-dimethyl-1-[3-(methylsulfamoylamino)cyclobutyl]pyrido[4,3- d]pyrimidine-2,4,7-trione (3.13 mg, 4.81 ⁇ mol, 15.3% yield, 99.1% purity) as a yellow solid.
  • Step 2 3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(1-oxoisoindolin-5- yl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
  • Step 1 3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-l-[3- (methylamino)phenyl]pyrido[4,3-d]pyrimidine-2,4,7-trione
  • Step 2 3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-l-[3- [methyl(methylsulfamoyl)amino]phenyl]-2,4,7-trioxo-pyrido[4,3-d]pyrimidine
  • Step 1 tert- Butyl /V-[3-[[3-cyclopropyl-l-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo- pyrido[2,3-d]pyrimidin-5-yl]amino]-l-bicyclo[l.l.l]pentanyl]carbamate
  • Step 2 tert-Butyl N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-2,4,7-trioxo- pyrido[4,3-d]pyrimidin-1-yl]-1-bicyclo[1.1.1]pentanyl]carbamate
  • Step 3 tert-Butyl 1-(3-amino-1-bicyclo[1.1.1]pentanyl)-3-cyclopropyl-5-(2-fluoro-4-iodo- anilino)-6,8-dimethyl-pyrido[4,3-d]pyrimidine-2,4,7-trione
  • Step 3 tert-Butyl 3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[3- (methyls ⁇ Lfamoylamino)-1-bicyclo[1.1.1]pentanyl]pyrido[4,3-d]pyrimidine-2,4,7-trione
  • reaction mixture was concentrated to yield a residue pressure to yield a residue which was purified by preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 51%-71%, 12 min), followed by lyophilization to yield product, followed by lyophilization to yield tert-butyl 3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8- dimethyl-1-[3-(methylsulfamoylamino)-1-bicyclo[1.1.1]pentanyl]pyrido[4,3-d]pyrimidine-2,4,7- trione (12.23 mg, 18.63 ⁇ mol, 42.1% yield, 100.0% purity) as a white solid.
  • Step 2 tert-Butyl (3-((3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo- 1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)cyclobutyl)carbamate [00459] A mixture of 3-cyclo nyl)-6,8-dimethyl-2,4,7-trioxo- 1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (350 mg, 563.15 ⁇ mol, 99.0%, 1 eq), tert-butyl N-(3-aminocyclobutyl)carbamate (115.38 mg, 619.46 ⁇ mol, 1.1 eq) and Cs 2 CO 3 (550.45 mg, 1.69 mmol
  • Step 3 tert-Butyl (3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)cyclobutyl)carbamate I F [00460] To a solution of tert-bu 2-fluoro-4-iodophenyl)-6,8- dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5- yl)amino)cyclobutyl)carbamate (150 mg, 191.57 ⁇ mol, 83.2%, 1 eq) in THF (30 mL) was added NaOMe/MeOH (191.57 ⁇ mol, 0.25 mL, 30%, 1 eq) at 0 °C under
  • Step 4 1-(3-Aminocyclobutyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8- dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione [00461] To a solution of tert-bu 2-fluoro-4-iodophenyl)amino)-6,8- dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)cyclobutyl)carbamate (30 mg, 32.56 ⁇ mol, 70.7%, 1 eq) in DCM (2 mL) was added TFA (616.00 mg, 5.40 mmol, 0.4 mL, 165.94 eq).
  • Step 5 3-Cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[3- (methylsulfamoylamino)cyclobutyl]pyrido[4,3-d]pyrimidine-2,4,7-trione
  • reaction mixture was diluted with H 2 O (20 mL), extracted with DCM (20 mL x 3).
  • the organic layer was concentrated under reduced pressure, which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(NH 4 HCO 3 )-ACN]; B%: 45%-70%, 11 min) and lyophilized to yield 3-cyclopropyl-5-(2- fluoro-4-iodo-anilino)-6,8-dimethyl-1-[3-(methylsulfamoylamino)cyclobutyl]pyrido[4,3- d]pyrimidine-2,4,7-trione (3.13 mg, 4.81 ⁇ mol, 15.3% yield, 99.1% purity) as a yellow solid.
  • Step 1 3-Cyclo y y , y indolin-5- yl)amino)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione [00463] To a solution of [3-c -phenyl)-6,8-dimethyl-2,4,7- trioxo-pyrido[2,3-d]pyrimidin-5-yl] trifluoromethanesulfonate (200 mg, 321.80 ⁇ mol, 99.0%, 1 eq) in DMF (3 mL) was added 5-aminoisoindolin-1-one (47.68 mg, 321.80 ⁇ mol, 1 eq) and Cs2CO3 (314.54 mg, 965.39 ⁇ mol, 3 eq).
  • Step 2 3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(1-oxoisoindolin-5- yl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione [00464] To a solution of 3-cycl ophenyl)-6,8-dimethyl-5-((1- oxoisoindolin-5-yl)amino)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (30 mg, 48.27 ⁇ mol, 98.7%, 1 eq) in THF (30 mL) was added MeONa/MeOH (48.27 ⁇ mol, 0.1 mL, 30%, 1 eq) at 0°C under N2 atmosphere.
  • Step 2 1-(3-Aminophenyl)-N-methylmethanesulfonamide [00466] To a solution of 4-methylb N-methyl-1-(3- nitrophenyl)methanesulfonamide (200 mg, 861.19 ⁇ mol, 99.1%, 1 eq) in MeOH (2 mL) was added Pd/C (200 mg, 861.19 ⁇ mol, 10.0%, 1 eq) under N 2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 1 h.
  • Step 3 1-(3-((3-Cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8- hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)-N-methylmethanesulfonamide
  • Step 4 1-(3-(3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-methylmethanesulfonamide 7- trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)-N- methylmethanesulfonamide (45 mg, 58.15 ⁇ mol, 86.0%, 1 eq) in THF (1 mL) was added a drop Page 211 of 262 396661-032WO (190374) of NaOMe/MeOH (20 wt%, 58.15 ⁇ mol, 1 eq).
  • reaction mixture was stirred at 0 °C for 5 h under N2 atmosphere.
  • the reaction mixture was quenched by addition sat. aq. NaHCO3 (30 mL) at 0 °C and extracted with DCM (30 mL x 3).
  • Step 2 tert-Butyl 1-(4-aminophenyl)-3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl- pyrido[4,3-d]pyrimidine-2,4,7-trione
  • Step 3 tert-Butyl 3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8-dimethyl-1-[4- (methylsulfamoylamino)phenyl]pyrido[4,3-d]pyrimidine-2,4,7-trione I F [00472] To a solution of 1-(4-aminophenyl)-3-cyclopropyl-5-(2-fluoro-4-iodo-anilino)-6,8- dimethyl-pyrido[4,3-d]pyrimidine-2,4,7-trione (43.00 mg, 75.00 ⁇ mol, 1 eq) in DCM (1 mL) was added TEA (15.18 mg, 149.99 ⁇ mol, 20.88 ⁇ L, 2 eq) and N-methylsulfamoyl chloride (9.72 mg, 75.00 ⁇ mol,
  • Step 2 3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-1-(1H-indol-4-yl)-6,8- dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione
  • Step 3 4-(3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-1H-indole-1-sulfonyl fluoride
  • Step 4 4-(3-Cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-methyl-1H-indole-1-sulfonamide [00476] To a solution of 4-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-1H-indole-1-sulfonyl fluoride (20 mg, 29.44 ⁇ mol, N/A, 1 eq) in DMF (2 m
  • the mixture was stirred at 80 °C for 12 h.
  • the reaction mixture was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: [water(HCl)-ACN]; B%: 60%-80%, 10min) and lyophilized to yield 4-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-methyl-1H-indole-1-sulfonamide (2.51 mg, 3.64 ⁇ mol, 12.4% yield, 100.0% purity) as a white solid.
  • Step 2 Ethyl 2-(3-nitrophenyl)-2-oxo-acetate O O 2 N O [00478] To a solution of 2-(3-n cid (66 g, 338.24 mmol, 1 eq) in DMF (700 mL) was added K 2 CO 3 (121.54 g, 879.42 mmol, 2.6 eq). After stirred at 20 °C for 2h, iodoethane (263.77 g, 1.69 mol, 135.26 mL, 5 eq) was added dropwise. The mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water (800 mL), extracted with EtOAc (500 mL x 3).
  • Step 3 Ethyl 3-[(2E)-2-[2-ethoxy-1-(3-nitrophenyl)-2-oxo-ethylidene]hydrazino]-3-oxo- propanoate O O O N [00479] To a solution of et e (22.5 g, 90.73 mmol, 1 eq) in EtOH (120 mL) was added H 2 SO 4 (2.29 g, 23.33 mmol, 1.24 mL, 0.25 eq) and ethyl 3- hydrazino-3-oxo-propanoate (13.79 g, 94.36 mmol, 1.04 eq). The mixture was stirred at 90 °C for 2 h.
  • Step 4 Ethyl 4-hydroxy-3-(3-nitrophenyl)-6-oxo-1H-pyridazine-5-carboxylate [00480] To a solution of eth ophenyl)-2-oxo- ethylidene]hydrazino]-3-oxo-propanoate (30 g, 85.39 mmol, E/Z mixture, 1 eq) in DMF (300 mL) was added K 2 CO 3 (6.49 g, 46.97 mmol, 0.55 eq). The mixture was stirred at 80 °C for 3 h. The mixture was cooled to ambient temperature and poured into 3N HCl (600 mL).
  • Step 5 Ethyl 4-chloro-3-(3-nitrophenyl)-6-oxo-1H-pyridazine-5-carboxylate [00481] To a solution of eth 6-oxo-1H-pyridazine-5- carboxylate (2.5 g, 7.37 mmol, 1 eq) in DCM (30 mL) was added (COCl) 2 (935.60 mg, 7.37 mmol, 645.24 ⁇ L, 1 eq). The mixture was stirred at 35 °C for 3 h. The reaction mixture was quenched by addition water (30 mL) and extracted with DCM (40 mL x 3).
  • Step 6 Ethyl 5-chloro-2-cyclopropyl-6-(3-nitrophenyl)-3-oxo-pyridazine-4-carboxylate
  • Step 7 Ethyl 2-cyclopropyl-5-(methylamino)-6-(3-nitrophenyl)-3-oxo-pyridazine-4- carboxylate [00483] To a solution of ethy nitrophenyl)-3-oxo-pyridazine-4- carboxylate (400 mg, 989.69 ⁇ mol, 1 eq) in DCM (3 mL) was added MeNH2 (1.02 g, 9.90 mmol, 30.0% purity, 10 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h.
  • Step 8 2-Cyclopropyl-5-(methylamino)-6-(3-nitrophenyl)pyridazin-3-one [00484] To a solution of ethyl 2 mino)-6-(3-nitrophenyl)-3-oxo- pyridazine-4-carboxylate (300 mg, 669.74 ⁇ mol, 1 eq) in DMSO (5 mL) was added LiCl (283.93 mg, 6.70 mmol, 10 eq). The mixture was stirred at 150 °C for 8 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL x 3).
  • Step 9 6-Cyclopropyl-4-hydroxy-1,3-dimethyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine- 2,5-dione [00485] To a solution of 2-cyclop o)-6-(3-nitrophenyl)pyridazin-3-one (200 mg, 628.74 ⁇ mol, 1 eq) in Ac 2 O (3 mL) was added 2-methylpropanedioic acid (222.74 mg, 1.89 mmol, 152.56 ⁇ L, 3 eq). The mixture was stirred at 110 °C for 2 h.
  • Step 10 [6-Cyclopropyl-1,3-dimethyl-8-(3-nitrophenyl)-2,5-dioxo-pyrido[2,3-d]pyridazin- 4-yl] 4-methylbenzenesulfonate [00486] To a solution of 6-cyclopropyl-4-hydroxy-1,3-dimethyl-8-(3-nitrophenyl)pyrido[2,3- d]pyridazine-2,5-dione (200 mg, 434.38 ⁇ mol, 1 eq) in DCM (8 mL) was added DIEA (561.40 mg, 4.34 mmol, 756.61 ⁇ L, 10 eq) and 4-methylbenzenesulfonyl chloride (414.06 mg, 2.17 mmol, 5 eq).
  • Step 11 6-Cyclopropyl-4-(2-fluoro-4-iodo-anilino)-1,3-dimethyl-8-(3- nitrophenyl)pyrido[2,3-d]pyridazine-2,5-dione [00487] To a solution of 2-fluo mg, 1.11 mmol, 3 eq) in THF (3 mL) was added NaH (89.10 mg, 2.23 mmol, 60.0% purity, 6 eq) and stirred at 0 °C for 30 min, then [6-cyclopropyl-1,3-dimethyl-8-(3-nitrophenyl)-2,5-dioxo-pyrido[2,3-d]pyridazin-4-yl] 4- methylbenzenesulfonate (200 mg, 371.27 ⁇ mol, 1 eq) was added at 0 °C.
  • Step 12 8-(3-Aminophenyl)-6-cyclopropyl-4-(2-fluoro-4-iodo-anilino)-l,3-dimethyl- pyrido [2, 3-d] pyridazine-2,5-dione
  • the reaction mixture was filtered to remove the insoluble.
  • the filter liquor was concentrated under reduced pressure to give a residue.
  • the residue was purified by preparative HPLC (column: Boston Prime Cl 8 150*30mm*5um; mobile phase: [water(NH 3 H 2 0+NH 4 HC0 3 )-ACN]; B%: 64%-94%,10min), followed by lyophilization to yield 8-(3-aminophenyl)-6-cyclopropyl-4-(2-fluoro-4-iodo- anilino)-l,3-dimethyl-pyrido[2,3-d]pyridazine-2,5-dione (55.23 mg, 99.09 pmol, 63.3% yield, 100.0% purity) as a yellow solid.
  • Step 14 A-[3-[6-Cyclopropyl-4-(2-fluoro-4-iodo-anilino)-l,3-dimethyl-2,5-dioxo-pyrido[2,3- d]pyridazin-8-yl]phenyl]methanesulfinamide
  • Step 15 6-Cyclopropyl-4-(2-fluoro-4-iodo-anilino)-l,3-dimethyl-8-[3-[[methyl- (methylamino)-oxo-L6-sulfanylidene] amino] phenyl] pyrido [2, 3-d] pyridazine-2,5-dione
  • Step 16 (A)-A'-(3-(6-Cyclopropyl-4-((2-fluoro-4-iodophenyl)amino)-l,3-dimethyl-2,5-dioxo- l,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylmethanesulfonimidamide & (/?)-A'-(3-(6-Cyclopropyl-4-((2-fluoro-4-iodophenyl)amino)-l,3-dimethyl-2,5-dioxo- l,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylmethanesulfonimidamide
  • Step 1 Eth 5-dioxo- pyrido[2,3-d]pyridazin-8-yl]phenyl]carbamothioyl]carbamate
  • Step 2 Ethyl /V-[(Z)-/V-[3-[6-cyclopropyl-4-(2-fluoro-4-iodo-anilino)-l,3-dimethyl-2,5- dioxo-pyrido[2,3-d]pyridazin-8-yl]phenyl]-/V-methyl-carbamimidoyl]carbamate
  • Step 3 l-[3-[6-Cyclopropyl-4-(2-fluoro-4-iodo-anilino)-l,3-dimethyl-2,5-dioxo-pyrido[2,3- d]pyridazin-8-yl]phenyl]-3-methyl-guanidine [00495] To a solution of ethyl N-[(Z)-N-[3-[6-cyclopropyl-4-(2-fluoro-4-iodo-anilino)-1,3- dimethyl-2,5-dioxo-pyrido[2,3-d]pyridazin-8-yl]phenyl]-N'-methyl-carbamimidoyl]carbamate (100 mg, 142.96 ⁇ mol, 98.0% purity, 1 eq) in EtOH (4 mL) was added KOH (2 M, 1.14 mL, 16 eq).
  • Step 1 To a solution of DIPA (10.55 g, 104.26 mmol, 6.00 equiv) in THF (20.00 mL) was added n-BuLi (41.70 mL, 104.26 mmol, 6.00 equiv) dropwised at -78 °C under N2 atmosphere. The reaction mixture was stirred at -50 °C for 0.5 hr. A solution of tert-butyl propionate (6.79 g, 52.13 mmol, 3.00 equiv) in THF (20.00 mL) was added dropwise to previous reaction mixture at -78 °C and stirred for another 1 hr at -78 °C.
  • Step 2 [00500] n a -m roun ottom as , a so ut on o tert- uty -[ -cyc opropyl-5-hydroxy- 6-(3-nitrophenyl)-3-oxopyridazin-4-yl]-2-methyl-3-oxopropanoate (6.00 g, 13.97 mmol, 1.00 equiv) in TFA (50.00 mL) was stirred at 60 °C for 3 hrs.
  • Step 4 To a so ut on o - uoro- -o oan ne ( . g, . mmo , . equiv) in THF (30.00 mL) was added LiHMDS (10.01 mL, 10.01 mmol, 3.00 equiv) dropwise at -78 °C and stirred at -78 °C for 0.5 hrs.
  • Step 5 To a so ut on o -cyc opropy - -[( - uoro- -o op eny )am no]- -methyl-8-(3- nitrophenyl)pyrano[2,3-d]pyridazine-2,5-dione (1.06 g, 1.85 mmol, 1.00 equiv) in AcOH (20.00 mL) was added Fe (1.03 g, 18.5 mmol, 10.00 equiv) at 25 °C and stirred at 50 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure.
  • oxopyridazine -4-carboxylate (3.5 g, 1.45 mmol, 1.0 equiv) in DCM (30 mL) was added (COCl) 2 (12.9 g, 14.48 mmol, 10 equiv) and DMF (0.7 mL, 1.30 mmol, 0.9 equiv) dropwise at room temperature. The resulting mixture was stirred for 1 h at 40°C. The solvent and excess oxalyl dichloride were removed under reduced pressure. The residue was layered with DCM (50 mL) and H2O (30mL), the water layer was extracted with DCM (2*30 mL).
  • Step 6 To a stirred solution of ethy -3-fluoro-1-methyl-8-(3-nitrophenyl)- 2,4,5- trioxopyrido[2,3-d] pyridazine-3-carboxylate (2.4 g, 5.45 mmol, 1.0 equiv) in THF (25 mL) was added H2SO4 (24 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 3 h at 90°C. Then THF was removed, the residue was diluted with water (10 mL) and extracted with DCM (3 x 20mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4.
  • Step 7 To a stirred solution of 6-cy oro-4-hydroxy-1-methyl-8-(3-nitrophenyl) pyrido[2,3-d] pyridazine-2,5-dione (1.1 g, 2.96 mmol, 1.0 equiv) and pyridine (0.7 g, 8.87 mmol, 3.0 equiv) in DCM (10 mL), Tf 2 O (1.7 g, 5.91 mmol, 2.0 equiv) in DCM (2 mL) was added dropwise at 0°C. The resulting mixture was stirred for 0.5 h at room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20mL).
  • Step 8 I F NH O 2 [00514] To a stirred solution of 2-f e (648 mg, 2.74 mmol, 3.0 equiv) in THF (2 mL) were added LDA (2M in THF) (1.82ml, 3.65 mmol, 4.0 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0°C under nitrogen atmosphere.
  • Step 9 To a stirred solution of 6-cyclopropyl-3-fluoro-4-[(2-fluoro-4- iodophenyl)amino]-1- methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5-dione (240 mg, 0.40 mmol, 1.0 equiv) in AcOH (5 mL) was added Fe (226 mg, 4.06 mmol, 10 equiv) in portions at rt. The resulting mixture was stirred for 30 min at 60°C under nitrogen atmosphere. The reaction was monitored by LCMS.
  • Step 10 To a stirred solution of 8 yclopropyl-3-fluoro -4-[(2-fluoro-4- iodophenyl)amino]-1-methylpyrido[2,3-d]pyridazine-2,5-dione (150 mg, 0.27 mmol, 1.0 equiv) and Et3N (81 mg, 0.80 mmol, 3.0 equiv) in DCM (1.5 mL) was added N-methylsulfamoyl chloride (69 mg, 0.53 mmol, 2.0 equiv) in DCM (0.5 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature.
  • the reaction was monitored by LCMS. The reaction was quenched by the addition of water (20 mL) at 0°C, extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product (200 mg) was purified by Prep-HPLC with the following conditions (Complete Non-WJ SC Hardware 50 mm x 40 cm, 7 ⁇ m, 40 - 60 % 18 min, NH3 H 2 O+NH 4 HCO 3 /CAN, 80 mL/min flash) to afford 6-cyclopropyl-3-fluoro-4-[(2-fluoro-4- iodophenyl)amino]-1-methyl-8- ⁇ 3-[(methylsulfamoyl)amino]phenyl ⁇ pyrido[2,3-d]pyridazine- 2,5-dione (68.4 mg, 39%) as a white solid.

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Abstract

La présente invention concerne des inhibiteurs de MEK de formule (I'), des compositions de ceux-ci, et des méthodes d'utilisation de ceux-ci.
EP22720905.3A 2021-04-16 2022-04-15 Inhibiteurs de mek et leurs utilisations Withdrawn EP4323066A1 (fr)

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