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WO2024123966A1 - Compounds and compositions as c-kit kinase inhibitors - Google Patents

Compounds and compositions as c-kit kinase inhibitors Download PDF

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Publication number
WO2024123966A1
WO2024123966A1 PCT/US2023/082833 US2023082833W WO2024123966A1 WO 2024123966 A1 WO2024123966 A1 WO 2024123966A1 US 2023082833 W US2023082833 W US 2023082833W WO 2024123966 A1 WO2024123966 A1 WO 2024123966A1
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Prior art keywords
compound
nitrogen
sulfur
oxygen
independently selected
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PCT/US2023/082833
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French (fr)
Inventor
Gregg F. Keaney
Brian T. CHAMBERLAIN
Caitlin Nicole KENT
John A. Lowe Iii
Matthew Charles Lucas
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Third Harmonic Bio, Inc.
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Publication of WO2024123966A1 publication Critical patent/WO2024123966A1/en

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the present disclosure relates generally to various compounds and compositions useful as a selective inhibitor of c-kit kinase and uses of the same in the treatment of c-kit kinase associated diseases, disorders, and conditions.
  • Compounds of the present disclosure are selective inhibitors of c-kit kinase, useful for the depletion of mast cells and thus is useful for treating mast-cell associated diseases including, inter alia, asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn’
  • the present disclosure provides compounds, compositions, and methods of treating c- kit kinase mediated diseases comprising administering to a patient in need thereof a compound of the present disclosure, or a pharmaceutical salt or composition thereof.
  • the compounds and methods disclosed herein are useful for treating mast-cell associated diseases as described herein.
  • a compound of the present disclosure is represented by Formula I:
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • a compound of the present disclosure is represented by Formula 1-1 :
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • the invention provides methods of inhibiting c-kit kinase activity. Some such methods comprise contacting c-kit kinase with an effective amount of a compound described herein, such as a compound of Formula I, to inhibit c-kit kinase activity, as further described in the detailed description. Other such methods comprise contacting c-kit kinase with an effective amount of a compound described herein, such as a compound of Formula 1-1, to inhibit c-kit kinase activity, as further described in the detailed description.
  • the present disclosure is based at least in part on the identification of novel compounds that modulate c-kit kinase and methods of using the same to treat c-kit kinase associated diseases.
  • Disclosed herein are compounds represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein:
  • R A is of either of the following structures: each of which is substituted by n occurrences of R 3 ;
  • R A is of either of the following structures: each of which is substituted by n occurrences of R 3 ;
  • R 3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCRs, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(R) 2 OR, -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 ,
  • novel compounds that modulate c-kit kinase and methods of using the same to treat c-kit kinase associated diseases, wherein the compound is of Formula II: or a pharmaceutically acceptable salt thereof; wherein each of R A , X, R 1 , and m are as defined above and described herein for Formula I.
  • novel compounds that modulate c-kit kinase and methods of using the same to treat c-kit kinase associated diseases, wherein the compound is of Formula II:
  • 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 “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • 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” 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.
  • 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:
  • 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 C1-4 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-2/f-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • Ci-8 saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent Ci-8 (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., -(CH2) n - wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • 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.
  • phenylene refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group aryl group.
  • 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 > 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 unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4// quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • a 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.
  • heteroarylene refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it.
  • heteroarylene is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.
  • pyridinylene refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it.
  • pyridinylene is a bivalent pyridine radical when it has two groups
  • 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- 2/7 pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in A 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, 2-oxa-6- azaspiro[3.3]heptane, 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, 3/7-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono- or bicyclic.
  • heterocyclyl alkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • oxo-heterocyclyl refers to a heterocyclyl substituted by an oxo group.
  • heterocyclylene refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • R * is C 1–6 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 – NO2, wherein each R ⁇ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, 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)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 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, lower alkyl 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.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • a compound described herein may exist as an atropisomer (e.g., substituted biaryls)
  • all forms of such atropisomers are considered part of this invention.
  • Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. [0049]
  • the terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and Ci-Ce alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 -methyl -1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.
  • haloalkylene refers to a bivalent haloalkyl group.
  • hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl.
  • exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH 2 C(H)(OH)CH 2 CH 2 OH, and the like.
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • carbocyclylene refers to a multivalent carbocyclyl group having the appropriate number of open valences to account for groups attached to it.
  • carbocyclylene is a bivalent carbocyclyl group when it has two groups attached to it; “carbocyclylene” is a trivalent carbocyclyl group when it has three groups attached to it.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, terZ-butoxy and the like.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • exemplary haloalkoxyl groups include - OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.
  • hydroxyalkoxyl refers to an alkoxyl group that is substituted with at least one hydroxyl.
  • Exemplary hydroxyalkoxyl groups include -OCH2CH2OH, -OCH 2 C(H)(OH)CH 2 CH2OH, and the like.
  • alkoxyl ene refers to a bivalent alkoxyl group.
  • a cyclopentane susbsituted with an oxo group is cyclopentanone.
  • the substituent may be attached at any available position on the ring.
  • the chemical structure encompasses
  • the one or more substituent(s) may be independently attached to any of the rings crossed by the bond.
  • the chemical structure encompasses, for example,
  • any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solidvate encompasses both solution-phase and isolatable solvates.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H2O.
  • 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, includes humans.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • the terms “inhibitor” or “c-kit inhibitor” are defined as a compound that binds to and/or inhibits c-kit kinase with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner. In some embodiments, 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
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change or inhibition in c-kit kinase activity between a sample comprising a compound of the present invention, or composition thereof an equivalent sample comprising c-kit kinase, 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.
  • 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]
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed.
  • acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts.
  • Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified.
  • the present disclosure provides compounds and pharmaceutically acceptable salts thereof that may be used in pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds.
  • the present disclosure provides a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof; wherein:
  • R A is of either of the following structures: each of which is substituted by n occurrences of R 3 ;
  • R 3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(R) 2 OR, -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 ,
  • L 2 represents independently for each occurrence a Ci-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R) 2 -, -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 - or -Cy-;
  • Cy represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 3 represents independently for each occurrence hydrogen, OR, Ci-6 aliphatic, Ci-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • X is O or S
  • R 1 represents independently for each occurrence halogen, -CN, -OR, -NR 2 , -C(O)R, - C(O)OR, -C(O)NR 2 , CI-6 alkyl, or Ci-ehaloalkyl;
  • L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O) 2 -
  • R B is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R B is substituted with q occurrences of R 2 ;
  • R 2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms
  • L 1 represents independently for each occurrence a C1.2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 - , -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -;
  • R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCRs, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(R) 2 OR, -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -
  • R 7 is hydrogen or C1-6 alkyl; each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from Ci-6 aliphatic; C1-6 haloaliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen,
  • the present invention provides a compound represented by
  • Formula II or a pharmaceutically acceptable salt thereof; wherein each of R A , X, R 1 , and m are as defined above and described herein for Formula I.
  • variables in Formula I or II above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I.
  • the compound is a compound of Formula II.
  • a compound of the present invention does not significantly penetrate the brain or minimally penetrate the brain, wherein the extent of brain penetration is measured by measuring “Kp,” i.e., the ratio of compound concentration in the brain and blood (Cbrain/C piasma ) as demonstrated by certain assays described herein in Example 30.
  • Kp the ratio of compound concentration in the brain and blood
  • a compound of the present invention is characterized as having a Kp (brain) of less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, or less than about 0.1.
  • a compound of the present invention is characterized as having a Kp of less than about 0.7.
  • a compound of the present invention is characterized by having a Kp of less than about 0.6. In some embodiments, a compound of the present invention is characterized by having a K p of less than about 0.5. In some embodiments, a compound of the present invention is characterized by having a K p of less than about 0.4. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.3. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.2. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.1.
  • Various methods of assessing brain exposure are known to those of skill in the art and/or are described herein.
  • determination of from the unbound compounds plasma, brain and testes concentrations also supports peripheral restriction of the compounds.
  • BCRP Breast Cancer Resistance Protein
  • the human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP -binding cassette (ABC) efflux transporter.
  • BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, testis, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure.
  • BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition.
  • a compound of the present invention exhibits an efflux ratio (ER) of about 1-fold, indicating substantially no efflux. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 1.5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 2.0-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 3.5-fold.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 4.0-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 4.5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 6-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 7-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 8-fold.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 9-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 10-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 15-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 20-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 25-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 30-fold.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 35-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 40-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 45-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 50-fold.
  • compounds of the present invention have a BCRP inhibition IC50 of about 400 nM, or about 500 nM, or about 600 nM, or about 700 nM, or about 800 nM, or about 900 nM.
  • compounds of the present invention have a BCRP inhibition IC50 of about ImM, about 2 mM, about 3mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM.
  • compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 5 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 1 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 1 mM and 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 1 mM and 5 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 5 mM and 10 mM. Exemplary compounds of the present invention are described further herein.
  • PGP P-glycoprotein
  • an efflux membrane transporter is also referred to in the art as multi-drug resistance protein 1 ((MDR1), permeability glycoprotein, P-gp, or Pgp, encoded by MDR1/ABCB1 and belonging to the family of ATP- binding cassette transporters), and is widely distributed throughout the body and responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances.
  • MDR1 multi-drug resistance protein 1
  • PGP is one of the most important transporters at the blood-brain barrier (BBB), where it is highly expressed in the vessel walls of the brain capillaries functioning as an efflux pump.
  • BBB blood-brain barrier
  • PGP is also located throughout the human body in organs or tissues with an excretory and/or barrier function, such as the liver, kidney, placenta, and testes.
  • PGP has been found to have a role in the regulation of drug disposition to the fetus and has been extensively studied. Expression of PGP in the placental trophoblast layer has been confirmed at the mRNA and protein levels in all phases of pregnancy. Several in vitro and in vivo studies have demonstrated functional activity of the transporter in matemo-fetal drug transport. PGP is able to actively pump drugs and other xenobiotics from trophoblast cells back to the maternal circulation, thus providing protection to the fetus.
  • compounds of the present invention are efflux substrates of BRCP. In some embodiments, compounds of the present invention are efflux substrates of PGP. In some embodiments, compounds of the present invention are efflux substrates of one or both of BCRP and PGP.
  • lower testes exposure is meant a compound measured as having a K,> (testes) of less than about 1.0, or less than about 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, or less than about 0.5, or less than about 0.4, or less than about 0.3, or less than about 0.2, or less than about 0.1, or less than about 0.09, or less than about 0.08, or less than about 0.07, or less than about 0.06, or less than about 0.05, or less than about 0.04, or 0.03, or less than about 0.02, or less than about 0.01.
  • K,> testes
  • a compound of the present invention is not an inducer of CYP3A4, as measured by, for instance, Example 31.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
  • a compound of the present invention is not an inducer of CYP1A2, as measured by, for instance, Example 31.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
  • a compound of the present invention is not an inducer of CYP2C19.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3 -fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
  • a compound of Formula I is administered orally, as described further herein. In some embodiments, a compound of Formula I is administered by a means other than oral administration, as described further herein.
  • a compound of Formula II is administered orally, as described further herein. In some embodiments, a compound of Formula II is administered by a means other than oral administration, as described further herein. [0097] In some embodiments, it has been unexpectedly found that certain compounds of Formula II exhibit improved solubility as compared to c-KIT inhibitors known in the art when measured according to the procedure set forth in Example 32.
  • compounds of the present invention have a solubility greater than 2.0 ⁇ M. and less than or equal to 10.0 ⁇ M.. In some embodiments, compounds of the present invention have a solubility of about 2.5 ⁇ M, about 3.0 ⁇ M, about 3.5 ⁇ M, about 4.0 ⁇ M, about 4.5 ⁇ M, about 5.0 ⁇ M, about 5.5 ⁇ M, about 6.0 ⁇ M, about 6.5 ⁇ M, about 7.0 ⁇ M.. about 7.5 ⁇ M, about 8.0 ⁇ M, about 9.0 ⁇ M, about 9.5 ⁇ M, or about 10.0 ⁇ M.. In some embodiments, compounds of the present invention have a solubility greater than 10 ⁇ M.
  • compounds of the present invention have a solubility of about 15 ⁇ M, about 20 ⁇ M, about 25 ⁇ M, about 30 ⁇ M, about 35 ⁇ M.. about 40 ⁇ M, about 45 ⁇ M, or about 50 ⁇ M.. In some embodiments, compounds of the present invention have a solubility greater than 50 ⁇ M..
  • compounds of the present invention have a solubility of about 60 ⁇ M, about 70 ⁇ M, about 80 ⁇ M, about 90 ⁇ M, about 100 ⁇ M, about 200 ⁇ M, about 300 ⁇ M, about 400 ⁇ M, 500 ⁇ M, about 600 ⁇ M, about 700 ⁇ M, about 800 ⁇ M, about 900 ⁇ M, about 1000 ⁇ M, about 1500 ⁇ M. or about 2000 ⁇ M...
  • R 1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C1-6 alkyl, or C1-6 haloalkyl.
  • R 1 represents independently for each occurrence halogen.
  • R 1 represents independently for each occurrence fluoro, chloro, or bromo.
  • R 1 represents independently for each occurrence -CN.
  • R 1 represents independently for each occurrence -OR.
  • R 1 represents independently for each occurrence -OCH3.
  • R 1 represents independently for each occurrence -NR2.
  • R 1 represents independently for each occurrence -NH2. In some embodiments, R 1 represents independently for each occurrence -C(O)R. In some embodiments, R 1 represents independently for each occurrence -C(O)CH3. In some embodiments, R 1 represents independently for each occurrence -C(O)OR. In some embodiments, R 1 represents independently for each occurrence -C(0)0CH3. In some embodiments, R 1 represents independently for each occurrence -C(0)NR2. In some embodiments, R 1 represents independently for each occurrence -C(0)NH2. In some embodiments, R 1 represents independently for each occurrence -C(0)NHCH3. In some embodiments, R 1 represents independently for each occurrence -C(O)N(CH3)2.
  • R 1 represents independently for each occurrence Ci-6 alkyl or Ci-6 haloalkyl. In some embodiments, R 1 represents independently for each occurrence Ci-6 alkyl. In some such embodiments, R 1 represents independently for each occurrence methyl. In some embodiments, R 1 represents independently for each occurrence Ci-6 haloalkyl. In some such embodiments, R 1 represents independently for each occurrence -CF3, -CF2H, or -CFH2. In some embodiments, at least one R 1 is fluoro. In some embodiments, at least one R 1 is chloro. In some embodiments, at least one R 1 is bromo. In some embodiments, at least one R 1 is -CN. In some embodiments, at least one R 1 is -OR.
  • At least one R 1 is -OMe. In some embodiments, at least one R 1 is methyl. In some embodiments, at least one R 1 is -CF3. In some embodiments, at least one R 1 is -CF2H. In some embodiments, at least one R 1 is -CFH2.
  • R 1 is halogen, -CN, -OR, -NR2, C1-6 alkyl, or Ci-6 haloalkyl. In some embodiments, R 1 is halogen. In some embodiments, R 1 is fluoro, chloro, or bromo. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -NR2. In some embodiments, R 1 is -NH2. In some embodiments, R 1 is Ci-6 alkyl or Ci-6 haloalkyl. In some embodiments, R 1 is Ci-6 alkyl. In some such embodiments, R 1 is methyl. In some embodiments, R 1 is C 1-6 haloalkyl. In some such embodiments, R 1 is -CF3, -CF2H, or -CFH2.
  • R 1 is as depicted in Table 1, below.
  • R 1 is as described above and herein, wherein m is 0 or 1. In some such embodiments, m is 0. In some such embodiments, m is 1.
  • R 2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic hetero
  • R 2 represents independently for each occurrence halogen. In some embodiments, R 2 represents independently for each occurrence chloro flouro, or bromo. In some embodiments, R 2 represents independently for each occurrence chloro or flouro.
  • R 2 represents independently for each occurrence Ci-6 aliphatic. In some such embodiments, R 2 represents independently for each occurrence Ci-6 alkyl. In some such embodiments, R 2 represents independently for each occurrence methyl, ethyl, or propyl.
  • R 2 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 7-membered saturated monocyclic carbocyclic ring.
  • R 2 represents independently for each occurrence a 3-4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 represents independently for each occurrence a 3 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 represents independently for each occurrence a 4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 represents independently for each occurrence a 3-4 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R 6 . In some such embodiments, at least one R 6 is fluoro. In some such embodiments, two R 6 are fluoro. In some such embodiments, at least one R 6 is methyl. In some such embodiments, at least one R 6 is -CN.
  • R 2 represents independently for each occurrence a 5 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 represents independently for each occurrence a 5 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R 6 . In some such embodiments, at least one R 6 is fluoro. In some such embodiments, two R 6 are fluoro. In some such embodiments, at least one R 6 is methyl. In some such embodiments, at least one R 6 is -CN.
  • R 2 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 3 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. In some embodiments, R 2 represents independently for each occurrence a 5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of R 6 .
  • R 2 represents independently for each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 occurrences of R 6 .
  • at least one R 6 is fluoro.
  • two R 6 are fluoro.
  • at least one R 6 is methyl.
  • at least one R 6 is -CN.
  • R 2 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence an 8- 10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence an 8 membered bicyclic heteroaryl ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 9 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00115] In some embodiments, R 2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0 heteroatoms. In some embodiments, R 2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00117] In some embodiments, R 2 represents independently for each occurrence L 1 -R 4 . [00118] In some embodiments, R 2 is C1-6 aliphatic. In some such embodiments, R 2 is C1-6 alkyl. In some such embodiments, R 2 is methyl, ethyl, or propyl. In some embodiments, R 2 is - CH 2 CH(OH)CH 3 . [00119] In some embodiments, R 2 is halogen. In some embodiments, R 2 is flouro or chloro. In some embodiments, R 2 is flouro. [00120] In some embodiments, R 2 is oxo. In some embodiments, R 2 is phenyl.
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 7-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 3-4 membered saturated monocyclic carbocyclic ring.
  • R 2 is a 3-4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 is a 3 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 is a 4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 is a 3-4 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R 6 . In some such embodiments, at least one R 6 is fluoro. In some such embodiments, two R 6 are fluoro. In some such embodiments, at least one R 6 is methyl. In some such embodiments, at least one R 6 is -CN.
  • R 2 is a 5 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 is a 5 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R 6 . In some such embodiments, at least one R 6 is fluoro. In some such embodiments, two R 6 are fluoro. In some such embodiments, at least one R 6 is methyl. In some such embodiments, at least one R 6 is -CN.
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 3 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 4 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. In some embodiments, R 2 is a 5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of R 6 .
  • R 2 is a 4-5 membered monocyclic heterocyclic ring having 1 nitrogen atom.
  • R 2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 occurrences of R 6 .
  • at least one R 6 is fluoro.
  • two R 6 are fluoro.
  • at least one R 6 is methyl.
  • at least one R 6 is -CN.
  • R 2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is an 8 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 9 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0 heteroatoms. In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 6-1 1 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is I?-R 4 .
  • each L 1 represents independently for each occurrence a Ci-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -.
  • L 1 is a Ci- 2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)- , -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -.
  • L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -
  • L is a bond.
  • L is -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O) 2 - , -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -.
  • L 1 is -O-, -C(O)-, -OC(O)-, or -C(O)O-.
  • R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence oxo, halogen, -CN, -NO 2 , -OR, -OCR 3 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , - C(R) 2 OR, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R,
  • R 6 represents independently for each occurrence oxo, halogen, -CN, -NO 2 , -OR, -OCR 3 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , - C(R) 2 OR, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R, -N(R)S(O) 2
  • R 6 represents independently for each occurrence halogen, -CN, -OR, or -S(O)2R. In some embodiments, R 6 represents independently for each occurrence fluoro, -CN, or -OH.
  • At least one R 6 is halogen. In some embodiments, at least one R 6 is fluoro. In some embodiments, at least two R 6 are fluoro. In some embodiments, at least one R 6 is methyl. In some embodiments, at least one R 6 is cyano.
  • R 7 is hydrogen or C1-3 alkyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is C1-3 alkyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is as depicted in Table 1, below.
  • R 2 is selected from:
  • R 2 is selected from:
  • R 2 is selected from:
  • R 2 is as described above and herein, wherein R 2 is substituted with p occurrences of R 6 .
  • p is 0.
  • p is 1.
  • p is 2.
  • p is 3.
  • p is 4.
  • p is 5.
  • R 2 is as depicted in Table 1, below.
  • R A is of either of the following structures: each of which is substituted by n occurrences of R 3 .
  • R A is . In some embodiments, R A is
  • R A is any of those depicted in Table 1 below. [00150] As described above and herein, each R A is substituted by n occurrences of R 3 . In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.
  • R B is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R B is substituted with q occurrences of R 2 .
  • R B is phenyl. In some embodiments, R B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with q occurrences of R 2 . In some embodiments, R B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q occurrences of R 2 . In some embodiments, R B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q occurrences of R 2 .
  • R B is selected from: [00154] As described above and herein, R 3 represents independently for each occurrence oxo, halogen, -CN, -NO 2 , -OR, -OCR3, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , - C(R) 2 OR, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , ,
  • R 3 represents independently for each occurrence oxo, halogen, -CN, -NO 2 , -OR, -OCR3, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , - C(R) 2 OR, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R, -N
  • R 3 represents independently for each occurrence halogen. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, at least one R 3 is fluoro. In some embodiments, at least one R 3 is chloro. In some embodiments, at least one R 3 is bromo. In some embodiments, at least one R 3 is -CN. In some embodiments, at least one R 3 is -OR. In some embodiments, wherein at least one R 3 is -OR, wherein R is C1-6 alkyl. In some embodiments, at least one R 3 is -OR, wherein R is methyl, ethyl, or propyl.
  • At least one R 3 is -OR, wherein R is methyl. In some embodiments, at least one R 3 is -OR, wherein R is ethyl. In some embodiments, at least one R 3 is -OR, wherein R is propyl. In some embodiments, at least one R 3 is -OCR3, wherein at least one R is fluoro. In some embodiments, at least one R 3 is -NR2. In some embodiments, wherein at least one R 3 is -NR2, at least one R is hydrogen. In some embodiments, wherein at least one R 3 is -NR2, at least one R is methyl or ethyl.
  • At least one R 3 is -L 2 -R 5 .
  • one, two, or three methylene units of L 2 are independently replaced by -O- or -Cy-.
  • one, two, or three methylene units of L 2 are independently replaced by -N(R)- or - Cy-.
  • At least one R 3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, at least one R 3 is oxetane.
  • At least one R 3 is -CF3, -CF2H, or -CFH2.
  • R 3 represents independently for each occurrence C1-6 aliphatic or Ci-6 haloaliphatic.
  • R 3 represents independently for each occurrence phenyl or naphthalenyl.
  • R 3 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. [00163] In some embodiments, R 3 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two R 3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 5 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having one heteroatom independently selected from oxygen.
  • R 3 represents independently for each occurrence -L 2 -R 5 .
  • each L 2 represents independently for each occurrence a Ci-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)- , -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- , -S(O) 2 - or -Cy-.
  • each L 2 represents independently for each occurrence a Ci-6 bivalent saturated straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 - or -Cy-.
  • -Cy- represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • -Cy- represents independently for each occurrence phenyl.
  • -Cy- represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated monocyclic carbocyclic ring. In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence hydrogen, OR, Ci-6 aliphatic, Ci-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence hydrogen.
  • R 5 represents independently for each occurrence OR.
  • R 5 represents independently for each occurrence OH or OMe.
  • R 5 represents independently for each occurrence Ci-6 aliphatic or Ci-6 haloaliphatic.
  • R ? represents independently for each occurrence phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R 3 group is independently substituted with r instances of R.
  • r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5.
  • R 3 is independently for each occurrence selected from:
  • R 3 is -OMe or -OiPr.
  • R 3 is as depicted in Table 1 below.
  • X is O. In some embodiments, X is S.
  • R is independently for each occurrence, hydrogen, -CN, halogen, or an optionally substituted group selected from Ci-6 aliphatic; Ci-6 haloaliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from Ci-6 aliphatic; Ci-6
  • R is independently for each occurrence hydrogen, -CN, halogen, or an optionally substituted Ci-6 aliphatic. In some embodiments, R is independently for each occurrence hydrogen. In some embodiments, R is fluoro. In some embodiments, R is independently for each occurrence an optionally substituted Ci-6 alkyl. In some such embodiments, R is methyl.
  • R is independently for each occurrence an optionally substituted group selected from phenyl or naphthalenyl. In some embodiments, R is Ci-6 haloaliphatic.
  • R is independently for each occurrence an optionally substituted group selected from a a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10
  • two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a compound of the present disclosure is represented by any of the following or a pharmaceutically acceptable salt thereof:
  • R A , R 1 , X, L, and R B are as defined above and described herein.
  • a compound of the present disclosure is represented by the following or a pharmaceutically acceptable salt thereof:
  • R A , R 1 , X, L, and R B are as defined above and described herein.
  • a compound of the present disclosure is represented by either of the following or a pharmaceutically acceptable salt thereof:
  • R A , R 1 , L, and R B are as defined above and described herein.
  • a compound of the present disclosure is represented by any of the following or a pharmaceutically acceptable salt thereof wherein R 1 , R 3 , L, and R B are as defined above and described herein. In some such embodiments,
  • R 3 is -OiPr, -CH 2 O(CH 2 )2OH, or -CH 2 OCH 2 C(CH3)2OH, and R 2 is selected from F A-/ [00190]
  • a compound of the present disclosure is represented by the following, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , and R A are as defined above and described herein.
  • a compound is of any of formulae I-a - I-m above, wherein n is 0. In some embodiments, a compound is of any of formulae I-a - I-m above, wherein n is i.
  • the present disclosure provides a compound represented by Formula (1-1):
  • R A is of either of the following structures: each of which is substituted by n occurrences of R 3 ;
  • R 1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, - C(O)OR, -C(0)NR2, CI-6 alkyl, or Ci-ehaloalkyl;
  • L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O) 2 - , -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -;
  • R B is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R B is substituted with q occurrences of R 2 ;
  • R 2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms
  • L 1 represents independently for each occurrence a C1.2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -;
  • R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(R) 2 OR, -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , --
  • each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from C1-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic
  • variables in Formula 1-1 or II-l above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula 1-1.
  • the compound is a compound of Formula II-l.
  • a compound of the present invention does not significantly penetrate the brain or minimally penetrate the brain, wherein the extent of brain penetration is measured by measuring “K p ,” i.e., the ratio of compound concentration in the brain and blood (Cbrain/Cpiasma) as demonstrated by certain assays described herein in Example 30.
  • K p the ratio of compound concentration in the brain and blood
  • a compound of the present invention is characterized as having a K /; (brain) of less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, or less than about 0.1.
  • a compound of the present invention is characterized as having a K p of less than about 0.7.
  • a compound of the present invention is characterized by having a K p of less than about 0.6. In some embodiments, a compound of the present invention is characterized by having a I ⁇ ; > of less than about 0.5. In some embodiments, a compound of the present invention is characterized by having a I ⁇ ; > of less than about 0.4. In some embodiments, a compound of the present invention is characterized by having a K p of less than about 0.3. In some embodiments, a compound of the present invention is characterized by having a K p of less than about 0.2. In some embodiments, a compound of the present invention is characterized by having a K /; of less than about 0.1.
  • a compound of the present invention is characterized by having a K P of less than about 0.09. In some embodiments, a compound of the present invention is characterized by having a K p of less than about 0.08. In some embodiments, a compound of the present invention is characterized by having a K p of less than about 0.05. In some embodiments, a compound of the present invention is characterized by having a K p of less than about 0.04. In some embodiments, a compound of the present invention is characterized by having a K p of less than about 0.03. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.02. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.01. Various methods of assessing brain exposure are known to those of skill in the art and/or are described herein.
  • BCRP Breast Cancer Resistance Protein
  • the human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter.
  • BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, testis, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure.
  • BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition.
  • a compound of the present invention exhibits an efflux ratio (ER) of about 1-fold, indicating substantially no efflux.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 1 .5-fold.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 2.0-fold.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 3.5-fold.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 4.0-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 4.5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 6-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 7-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 8-fold.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 9-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 10-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 15-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 20-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 25-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 30-fold.
  • a compound of the present invention exhibits an efflux ratio (ER) of at least about 35-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 40-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 45-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 50-fold.
  • compounds of the present invention have a BCRP inhibition IC50 of about 400 nM, or about 500 nM, or about 600 nM, or about 700 nM, or about 800 nM, or about 900 nM.
  • compounds of the present invention have a BCRP inhibition IC50 of about ImM, about 2 mM, about 3mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM.
  • compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 5 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 1 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 1 mM and 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 1 mM and 5 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 5 mM and 10 mM. Exemplary compounds of the present invention are described further herein.
  • PGP P-glycoprotein
  • an efflux membrane transporter is also referred to in the art as multi-drug resistance protein 1 ((MDR1), permeability glycoprotein, P-gp, or Pgp, encoded by MDR1/ABCB1 and belonging to the family of ATP- binding cassette transporters), and is widely distributed throughout the body and responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances.
  • MDR1 multi-drug resistance protein 1
  • PGP is one of the most important transporters at the blood-brain barrier (BBB), where it is highly expressed in the vessel walls of the brain capillaries functioning as an efflux pump.
  • BBB blood-brain barrier
  • PGP is also located throughout the human body in organs or tissues with an excretory and/or barrier function, such as the liver, kidney, placenta, and testes.
  • PGP has been found to have a role in the regulation of drug disposition to the fetus and has been extensively studied. Expression of PGP in the placental trophoblast layer has been confirmed at the mRNA and protein levels in all phases of pregnancy. Several in vitro and in vivo studies have demonstrated functional activity of the transporter in matemo-fetal drug transport. PGP is able to actively pump drugs and other xenobiotics from trophoblast cells back to the maternal circulation, thus providing protection to the fetus.
  • compounds of the present invention are efflux substrates of BRCP. In some embodiments, compounds of the present invention are efflux substrates of PGP. In some embodiments, compounds of the present invention are efflux substrates of one or both of BCRP and PGP. [00207] It has been further surprisingly discovered that certain compounds of the present invention afford lower testes exposure, which may lead to better spermatogonia survival and/or spermatogonia maturation. Various methods of assessing whether a compound affords lower testes exposure are known to those of skill in the art and/or are described herein, for instance in Example 30.
  • lower testes exposure is meant a compound measured as having a K,, (testes) of less than about 1.0, or less than about 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, or less than about 0.5, or less than about 0.4, or less than about 0.3, or less than about 0.2, or less than about 0.1, or less than about 0.09, or less than about 0.08, or less than about 0.07, or less than about 0.06, or less than about 0.05, or less than about 0.04, or 0.03, or less than about 0.02, or less than about 0.01.
  • a compound of the present invention is not an inducer of CYP3A4, as measured by, for instance, Example 31.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
  • a compound of the present invention is not an inducer of CYP1A2, as measured by, for instance, Example 31.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
  • a compound of the present invention is not an inducer of CYP2C19.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold.
  • a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3 -fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold. [00211] In some embodiments, a compound of Formula 1-1 is administered orally, as described further herein. In some embodiments, a compound of Formula 1-1 is administered by a means other than oral administration, as described further herein.
  • a compound of Formula II- 1 is administered orally, as described further herein.
  • a compound of Formula II-l is administered by a means other than oral administration, as described further herein.
  • compounds of the present invention have a solubility greater than 2.0 ⁇ M. and less than or equal to 10.0 ⁇ M.. In some embodiments, compounds of the present invention have a solubility of about 2.5 ⁇ M, about 3.0 ⁇ M, about 3.5 ⁇ M, about 4.0 ⁇ M, about 4.5 ⁇ M, about 5.0 ⁇ M, about 5.5 ⁇ M, about 6.0 ⁇ M, about 6.5 ⁇ M, about 7.0 ⁇ M, about 7.5 ⁇ M, about 8.0 ⁇ M, about 9.0 ⁇ M, about 9.5 ⁇ M, or about 10.0 ⁇ M. In some embodiments, compounds of the present invention have a solubility greater than 10 ⁇ M.
  • compounds of the present invention have a solubility of about 15 ⁇ M, about 20 ⁇ M, about 25 ⁇ M, about 30 ⁇ M, about 35 ⁇ M, about 40 ⁇ M, about 45 ⁇ M, or about 50 ⁇ M.. In some embodiments, compounds of the present invention have a solubility greater than 50 ⁇ M..
  • compounds of the present invention have a solubility of about 60 ⁇ M, about 70 ⁇ M, about 80 ⁇ M, about 90 ⁇ M, about 100 ⁇ M, about 200 ⁇ M, about 300 ⁇ M, about 400 ⁇ M, 500 ⁇ M, about 600 ⁇ M, about 700 ⁇ M, about 800 ⁇ M, about 900 ⁇ M, about 1000 ⁇ M, about 1500 ⁇ M. or about 2000 ⁇ M.. [00216J
  • when L is a bond and R B is X is S. In some embodiments, when R B is X is S.
  • R 1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C1-6 alkyl, or C1-6 haloalkyl.
  • R 1 represents independently for each occurrence halogen.
  • R 1 represents independently for each occurrence fluoro, chloro, or bromo.
  • R 1 represents independently for each occurrence -CN.
  • R 1 represents independently for each occurrence -OR.
  • R 1 represents independently for each occurrence -OCH3.
  • R 1 represents independently for each occurrence -NR2.
  • R 1 represents independently for each occurrence -NH2. In some embodiments, R 1 represents independently for each occurrence -C(O)R. In some embodiments, R 1 represents independently for each occurrence -C(O)CH3. In some embodiments, R 1 represents independently for each occurrence -C(O)OR. In some embodiments, R 1 represents independently for each occurrence -C(O)OCH3. In some embodiments, R 1 represents independently for each occurrence -C(O)NR2. In some embodiments, R 1 represents independently for each occurrence -C(O)NH2. In some embodiments, R 1 represents independently for each occurrence -C(O)NHCH3. In some embodiments, R 1 represents independently for each occurrence -C(O)N(CH3)2.
  • R 1 represents independently for each occurrence C1-6 alkyl or C1-6 haloalkyl. In some embodiments, R 1 represents independently for each occurrence Cue alkyl. In some such embodiments, R 1 represents independently for each occurrence methyl. In some embodiments, R 1 represents independently for each occurrence C1-6 haloalkyl. In some such embodiments, R 1 represents independently for each occurrence -CF3, -CF2H, or -CFH2. In some embodiments, at least one R 1 is fluoro. In some embodiments, at least one R 1 is chloro. In some embodiments, at least one R 1 is bromo. In some embodiments, at least one R 1 is -CN. In some embodiments, at least one R 1 is -OR.
  • At least one R 1 is -OMe. In some embodiments, at least one R 1 is methyl. In some embodiments, at least one R 1 is -CF3. In some embodiments, at least one R 1 is -CF2H. In some embodiments, at least one R 1 is -CFH2. [00218] In some embodiments, R 1 is halogen, -CN, -OR, -NR 2 , C 1-6 alkyl, or C 1-6 haloalkyl. In some embodiments, R 1 is halogen. In some embodiments, R 1 is fluoro, chloro, or bromo. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -OR.
  • R 1 is -NR2. In some embodiments, R 1 is -NH 2 . In some embodiments, R 1 is C 1-6 alkyl or C 1-6 haloalkyl. In some embodiments, R 1 is C1-6 alkyl. In some such embodiments, R 1 is methyl. In some embodiments, R 1 is C1-6 haloalkyl. In some such embodiments, R 1 is -CF3, -CF2H, or -CFH2. [00219] In some embodiments, R 1 is as depicted in Table 1, below. [00220] In some embodiments, R 1 is as described above and herein, wherein m is 0, 1, 2, 3, or 4. In some such embodiments, m is 0. In some such embodiments, m is 1.
  • R 2 represents independently for each occurrence halogen, oxo, C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0- 3
  • R 2 represents independently for each occurrence halogen. In some embodiments, R 2 represents independently for each occurrence chloro flouro, or bromo. In some embodiments, R 2 represents independently for each occurrence chloro or flouro. [00223] In some embodiments, R 2 represents independently for each occurrence C 1-6 aliphatic. In some such embodiments, R 2 represents independently for each occurrence C1-6 alkyl. In some such embodiments, R 2 represents independently for each occurrence methyl, ethyl, or propyl. [00224] In some embodiments, R 2 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R 2 represents independently for each occurrence a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 represents independently for each occurrence a 7-membered saturated monocyclic carbocyclic ring.
  • R 2 represents independently for each occurrence a 3-4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 represents independently for each occurrence a 3 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 represents independently for each occurrence a 4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 represents independently for each occurrence a 3-4 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R 6 . In some such embodiments, at least one R 6 is fluoro. In some such embodiments, two R 6 are fluoro. In some such embodiments, at least one R 6 is methyl. In some such embodiments, at least one R 6 is -CN.
  • R 2 represents independently for each occurrence a 5 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 represents independently for each occurrence a 5 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R 6 . In some such embodiments, at least one R 6 is fluoro. In some such embodiments, two R 6 are fluoro. In some such embodiments, at least one R 6 is methyl. In some such embodiments, at least one R 6 is -CN.
  • R 2 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 3 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. In some embodiments, R 2 represents independently for each occurrence a 5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of R 6 .
  • R 2 represents independently for each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 occurrences of R 6 .
  • at least one R 6 is fluoro.
  • two R 6 are fluoro.
  • at least one R 6 is methyl.
  • at least one R 6 is -CN.
  • R 2 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00230] In some embodiments, R 2 represents independently for each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence an 8- 10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence an 8 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 9 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00232] In some embodiments, R 2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0 heteroatoms. In some embodiments, R 2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 represents independently for each occurrence L x -R 4 .
  • R 2 is Ci-6 aliphatic. In some such embodiments, R 2 is Ci-6 alkyl. In some such embodiments, R 2 is methyl, ethyl, or propyl. In some embodiments, R 2 is - CH 2 CH(OH)CH 3 .
  • R 2 is halogen. In some embodiments, R 2 is flouro or chloro. In some embodiments, R 2 is flouro.
  • R 2 is oxo. In some embodiments, R 2 is phenyl.
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 7-membered saturated monocyclic carbocyclic ring. In some embodiments, R 2 is a 3-4 membered saturated monocyclic carbocyclic ring.
  • R 2 is a 3-4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 is a 3 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 is a 4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 is a 3-4 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R 6 . In some such embodiments, at least one R 6 is fluoro. In some such embodiments, two R 6 are fluoro. In some such embodiments, at least one R 6 is methyl. In some such embodiments, at least one R 6 is -CN.
  • R 2 is a 5 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R 6 . In some embodiments, R 2 is a 5 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R 6 In some such embodiments, at least one R 6 is fluoro. In some such embodiments, two R 6 are fluoro. In some such embodiments, at least one R 6 is methyl. In some such embodiments, at least one R 6 is -CN.
  • R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 3 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 4 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. In some embodiments, R 2 is a 5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of R 6 .
  • R 2 is a 4-5 membered monocyclic heterocyclic ring having 1 nitrogen atom.
  • R 2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 occurrences of R 6 .
  • at least one R 6 is fluoro.
  • two R 6 are fluoro.
  • at least one R 6 is methyl.
  • at least one R 6 is -CN.
  • R 2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is an 8 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 9 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00245] In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00246] In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0 heteroatoms. In some embodiments, R 2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2 is I?-R 4 .
  • each L 1 represents independently for each occurrence a Ci-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or - S(O) 2 -.
  • L 1 is a C1-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)- , -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.
  • L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.
  • L is a bond.
  • L is -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O) 2 - , -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -.
  • L 1 is -O-, -C(O)-, -OC(O)-, or -C(O)O-.
  • R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 6 represents independently for each occurrence oxo, halogen, -CN, -NO 2 , -OR, -OCR 3 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , - C(R) 2 OR, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R,
  • R 6 represents independently for each occurrence halogen, -CN, -OR, or -S(O) 2 R. In some embodiments, R 6 represents independently for each occurrence fluoro, -CN, or -OH.
  • At least one R 6 is halogen. In some embodiments, at least one R 6 is fluoro. In some embodiments, at least two R 6 are fluoro. In some embodiments, at least one R 6 is methyl. In some embodiments, at least one R 6 is cyano.
  • R 2 is selected from:
  • R 2 is selected from:
  • R 2 is selected from:
  • R 2 is as described above and herein, wherein R 2 is substituted with p occurrences of R 6 .
  • p is 0.
  • p is 1.
  • p is 2.
  • p is 3.
  • p is 4.
  • p is 5.
  • R 2 is as depicted in Table 1, below.
  • R A is of either of the following structures: each of which is substituted by n occurrences of R 3 .
  • R A is In some embodiments, R A is
  • R A is any of those depicted in Table 1 below.
  • each R A is substituted by n occurrences of R 3 .
  • n is 0.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • n is 5.
  • R B is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R B is substituted with q occurrences of R 2 .
  • R B is phenyl. In some embodiments, R B is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with q occurrences of R 2 . In some embodiments, R B is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q occurrences of R 2 . In some embodiments, R B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q occurrences of R 2 .
  • R B is selected from:
  • R 3 represents independently for each occurrence oxo, halogen, -CN, -NO 2 , -OR, -OCR 3 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , - C(R) 2 OR, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)NR 2 , -N(R)S(O) 2 NR 2 , - N(R)S(O) 2 R, - -SR, -NR 2
  • R 3 represents independently for each occurrence halogen. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, at least one R 3 is fluoro. In some embodiments, at least one R 3 is chloro. In some embodiments, at least one R 3 is bromo. In some embodiments, at least one R 3 is -CN. In some embodiments, at least one R 3 is -OR. In some embodiments, wherein at least one R 3 is -OR, wherein R is Ci-6 alkyl. In some embodiments, at least one R 3 is -OR, wherein R is methyl, ethyl, or propyl.
  • At least one R 3 is -OR, wherein R is methyl. In some embodiments, at least one R 3 is -OR, wherein R is ethyl. In some embodiments, at least one R 3 is -OR, wherein R is propyl. In some embodiments, at least one R 3 is -OCRs, wherein at least one R is fluoro. In some embodiments, at least one R 3 is -NR 2 . In some embodiments, wherein at least one R 3 is -NR 2 , at least one R is hydrogen. In some embodiments, wherein at least one R 3 is -NR 2 , at least one R is methyl or ethyl.
  • At least one R 3 is -NR 2
  • at least one R is optionally substituted phenyl.
  • the two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • at least one R 3 is - N(R)S(O) 2 R.
  • each R is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, naphthalenyl, or a 5-membered heteroaryl ring having one, two, or three heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • At least one R 3 is -L 2 -R 5
  • one, two, or three methylene units of L 2 are independently replaced by -O- or -Cy-.
  • one, two, or three methylene units of L 2 are independently replaced by -N(R)- or - Cy-.
  • At least one R 3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, at least one R 3 is oxetane.
  • At least one R 3 is -CF3, -CF2H, or -CFH2.
  • R 3 represents independently for each occurrence C1-6 aliphatic or C1-6 haloaliphatic.
  • R 3 represents independently for each occurrence phenyl or naphthal enyl.
  • R 3 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R 3 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00283] In some embodiments, R 3 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 3 represents independently for each occurrence or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two R 3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 5 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having one heteroatom independently selected from oxygen.
  • R 3 represents independently for each occurrence -L 2 -R 5 .
  • each L 2 represents independently for each occurrence a Ci-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R) 2 -, -N(R)- , -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- , -S(O) 2 - or -Cy-.
  • each L 2 represents independently for each occurrence a Ci-6 bivalent saturated straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R) 2 -, -N(R)-, - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 - or -Cy-.
  • -Cy- represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • -Cy- represents independently for each occurrence phenyl.
  • -Cy- represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated monocyclic carbocyclic ring. In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence hydrogen, OR, C1-6 aliphatic, C1-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 5 represents independently for each occurrence hydrogen.
  • R 5 represents independently for each occurrence OR.
  • R 5 represents independently for each occurrence OH or OMe.
  • R 5 represents independently for each occurrence C1-6 aliphatic or C1-6 haloaliphatic.
  • R 5 represents independently for each occurrence phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R 3 group is independently substituted with r instances of R.
  • r is 0.
  • r is 1.
  • r is 2.
  • r is 3.
  • r is 4.
  • r is 5.
  • R 3 is independently for each occurrence selected from: O H S N HO O ,
  • R is -OMe or -OiPr.
  • R 3 is as depicted in Table 1 below.
  • X is O.
  • X is S.
  • R is independently for each occurrence, hydrogen, -CN, halogen, or an optionally substituted group selected from C 1-6 aliphatic; phenyl; naphthalenyl; a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
  • R is independently for each occurrence hydrogen, -CN, halogen, or an optionally substituted Ci-6 aliphatic. In some embodiments, R is independently for each occurrence hydrogen. In some embodiments, R is fluoro. In some embodiments, R is independently for each occurrence an optionally substituted Ci-6 alkyl. In some such embodiments, R is methyl.
  • R is independently for each occurrence an optionally substituted group selected from phenyl or naphthal enyl.
  • R is independently for each occurrence an optionally substituted group selected from a a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10
  • two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • a compound of the present disclosure is represented by any of the following or a pharmaceutically acceptable salt thereof: I-c-1 I-d-1 wherein R A , R 1 , X, L, and R B are as defined above and described herein.
  • a compound of the present disclosure is represented by the following or a pharmaceutically acceptable salt thereof
  • R A , R 1 , X, L, and R B are as defined above and described herein.
  • a compound of the present disclosure is represented by either of the following or a pharmaceutically acceptable salt thereof
  • a compound of the present disclosure is represented by any of the following or a pharmaceutically acceptable salt thereof
  • a compound of the present disclosure is represented by the following, or a pharmaceutically acceptable salt thereof:
  • a compound is of any of formulae I-a-1 - I-m-1 above, wherein n is 0. In some embodiments, a compound is of any of formulae I-a-1 - I-m-1 above, wherein n is 1.
  • the compound is a compound in Table 1. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from Compound II- 1 to II- 70 of Table 1, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from Compound II- 1 to 11-70 of Table 1.
  • one aspect of the invention provides a method of treating a disorder associated with c-kit kinase in a subject.
  • the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to a subject in need thereof to treat the disorder.
  • the compound is a compound of any of Formulae I, II, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, or I-m defined by one of the embodiments described above.
  • one aspect of the invention provides a method of treating a disorder associated with c-kit kinase in a subject.
  • the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula 1-1, to a subject in need thereof to treat the disorder.
  • the compound is a compound of any of Formulae 1-1, 11-1, I-a-1, I-b- 1, 1-c-1, 1-d-1, 1-e-1, 1-f-1, 1-g-1, 1-h-1, 1-i-1, 1- j-1, I-k- 1 , 1-1-1, or I-m-1 defined by one of the embodiments described above.
  • the c-kit kinase-mediated disease, disorder or condition is associated with wild-type c-kit kinase. In some embodiments, the c-kit kinase-mediated disease, disorder or condition is associated with mutant c-kit kinase.
  • the kit mutation is selected from D419, D816Y, D816F, N822, V559, K558Q, I517P, Duplication 572-573, V559A, V559D, W557R, V560G, L576P, K642E, D820V, V560G, D52N, D816V, D816, V825A, E490K, W557R, V559A, V560Del, V560G, K642E, V654A, D816H, D820E, A829P, T417, Y418, D419, A502, K5091, V530I, F552C, A533D, V560, ITD, V559D, K704, N705, S715, 1748T, L773S, V8251, and D816N.
  • Non-limiting examples of the c-kit kinase-mediated disease include Acute Myeloid Leukemia, Mastocytosis, AMI-HMCI-cell line, GIST, Melanoma, Myeloproliferative Disease, Renal Cell Carcinoma, Papillary renal carcinoma, Sinonasal NK/Tcell Lymphoma, Thymic Carcinoma, Acute Lymphoblastic leukemia, Germ cell tumor, Acute Myelogenous Leukemia, and Extranodal NK/T cell lymphoma.
  • the method may be further characterized according to the c-kit kinase mediated disease or disorder that is to be treated in the patient.
  • the c-kit kinase mediated disease or disorder is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a dermatological disease, an allergic disease, a cardiovascular disease, or a neurological disorder.
  • the c-kit kinase mediated disease or disorder is a mast-cell associated disease.
  • the c-kit kinase mediated disease or disorder is an inflammatory disorder.
  • the c-kit kinase mediated disease or disorder is an autoimmune disorder. In some embodiments, the c-kit kinase mediated disease or disorder is a metabolic disease. In some embodiments, the c-kit kinase mediated disease or disorder is a fibrotic disease. In some embodiments, the c-kit kinase mediated disease or disorder is a dermatological disease. In some embodiments, the c-kit kinase mediated disease or disorder is an allergic disease. In some embodiments, the c-kit kinase mediated disease or disorder is a cardiovascular disease. In some embodiments, the c-kit kinase mediated disease or disorder is a neurological disorder.
  • the disease or disorder is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn’s disease, or systemic and cutaneous lupus erythematosus and dermatomyositis.
  • PAH pulmonary arterial hypertension
  • PPH primary pulmonary
  • the disease or disorder is asthma. In some embodiments, the disease or disorder is allergic rhinitis. In some embodiments, the disease or disorder is pulmonary arterial hypertension (PAH). In some embodiments, the disease or disorder is primary pulmonary hypertension (PPH). In some embodiments, the disease or disorder is pulmonary fibrosis. In some embodiments, the disease or disorder is hepatic fibrosis. In some embodiments, the disease or disorder is cardiac fibrosis. In some embodiments, the disease or disorder is scleroderma. In some embodiments, the disease or disorder is irritable bowel syndrome (IBS). In some embodiments, the disease or disorder is inflammatory bowel disease (IBD). In some embodiments, the disease or disorder is urticaria.
  • PAH pulmonary arterial hypertension
  • PPH primary pulmonary hypertension
  • the disease or disorder is pulmonary fibrosis.
  • the disease or disorder is hepatic fibrosis.
  • the disease or disorder is cardiac fibrosis.
  • the disease or disorder is
  • the disease or disorder is dermatosis. In some embodiments, the disease or disorder is atopic dermatitis. In some embodiments, the disease or disorder is allergic contact dermatitis. In some embodiments, the disease or disorder is rheumatoid arthritis. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is melanoma. In some embodiments, the disease or disorder is a gastrointestinal stromal tumor. In some embodiments, the disease or disorder is a mast cell tumor. In some embodiments, the disease or disorder is mastocytosis. In some embodiments, the disease or disorder is anaphylactic syndrome. In some embodiments, the disease or disorder is food allergy.
  • the disease or disorder is chronic rhinosinusitis. In some embodiments, the disease or disorder is type I diabetes. In some embodiments, the disease or disorder is type II diabetes. In some embodiments, the disease or disorder is systemic sclerosis. In some embodiments, the disease or disorder is allergic keratoconjunctivitis. In some embodiments, the disease or disorder is vernal keratoconjunctivitis. In some embodiments, the disease or disorder is Crohn’s disease. In some embodiments, the disease or disorder is systemic and cutaneous lupus erythematosus and dermatomyositis.
  • the c-kit mediated disease or disorder is urticaria.
  • the disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD), ulcerative colitis, eosinophilic gastritis (EG), or eosinophilic colitis (EC).
  • the disease or disorder is mast cell gastrointestinal disease.
  • the disease or disorder is prurigo nodularis.
  • the disease or disorder is allergic conjunctivitis.
  • the allergic conjunctivitis is seasonal conjunctivitis. In some such embodiments, the allergic conjunctivitis is perennial conjunctivitis. In some embodiments, the disease or disorder is eosinophilic esophagitis. In some embodiments, the disease or disorder is mast cell activation syndrome. In some embodiments, the disease or disorder is eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD). In some embodiments, the disease or disorder is ulcerative colitis.
  • the present invention provides a method for treating a c-kit kinase mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • kits kinase are provided herein.
  • 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 c- kit kinase 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 of c-kit kinase 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.
  • 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 subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a companion animal. In certain embodiments, the subject is a canine, feline, or equine.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament.
  • the medicament is for treating a disorder described herein, such as a c-kit kinase mediated disorder.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein (for example, a c-kit kinase mediated disorder).
  • a compound described herein such as a compound of Formula I, or other compounds in Section I
  • a medical disorder described herein for example, a c-kit kinase mediated disorder.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula 1-1, or other compounds in Section I) in the manufacture of a medicament.
  • the medicament is for treating a disorder described herein, such as a c-kit kinase mediated disorder.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula 1-1, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein (for example, a c-kit kinase mediated disorder).
  • a compound described herein such as a compound of Formula 1-1, or other compounds in Section I
  • a medical disorder described herein for example, a c-kit kinase mediated disorder.
  • the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a described compound may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present disclosure provides a single unit dosage form comprising a described compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • Two or more agents are typically considered to be administered “in combination” when a patient or individual is simultaneously exposed to both agents.
  • two or more agents are considered to be administered “in combination” when a patient or individual simultaneously shows therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in brain, in serum, etc.).
  • compositions according to this disclosure may comprise a combination of a compound of Formula I and another therapeutic or prophylactic agent.
  • pharmaceutical or prophylactic compositions according to this disclosure may comprise a combination of a compound of Formula 1-1 and another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as “agents appropriate for the disease, or condition, being treated.”
  • the subject method includes administering a therapeutically effective amount of one or more additional active agents.
  • combination therapy is meant that a c-kit inhibiting compound can be used in a combination with another therapeutic agent to treat a single disease or condition.
  • a compound of the present disclosure is administered concurrently with the administration of another therapeutic agent, which can be administered as a component of a composition including the compound of the present disclosure or as a component of a different composition.
  • the subject compounds can be administered in combination with other therapeutic agents in a variety of therapeutic applications.
  • Therapeutic applications of interest for combination therapy include those applications in which activity of a target c-kit kinase is the cause or a compounding factor in disease progression.
  • the subject compounds find use in combination therapies in which the inhibition of a target c-kit kinase in the subject is desired.
  • the compounds utilized in the compositions and methods of this disclosure may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those, which increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and/or alter rate of excretion.
  • treatment is used interchangeably herein with the term “therapeutic method” and refers to both 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions, disease or disorder, and 2) and prophylactic/preventative measures.
  • Those in need of treatment may include individuals already having a particular medical disease or disorder as well as those who may ultimately acquire the disorder (i.e., those at risk or needing preventive measures).
  • subject refers to any individual or patient to which the subject methods are performed. Generally, the subject is human, although as will be appreciated by those in the art, the subject may be an animal.
  • terapéuticaally effective amount refers to the amount of a subject compound that will elicit the biological or medical response in a tissue, system, animal or human that is being sought by administering said compound. Generally, the response is either amelioration of symptoms in a patient or a desired biological outcome. In some embodiments, such amount should be sufficient to inhibit a c-kit kinase.
  • the term “about” refers to within ⁇ 10% of the stated value.
  • an effective amount of a c-kit inhibiting compound is an amount that ranges from about 50 ng/ml to 50 pg/ml (e.g., from about 50 ng/ml to 40 pg/ml, from about 30 ng/ml to 20 pg/ml, from about 50 ng/ml to 10 ⁇ g/ml, from about 50 ng/ml to 1 ⁇ g/ml, from about 50 ng/ml to 800 ng/ml, from about 50 ng/ml to 700 ng/ml, from about 50 ng/ml to 600 ng/ml, from about 50 ng/ml to 500 ng/ml, from about 50 ng/ml to 400 ng/ml, from about 60
  • an effective amount of a c-kit inhibiting compound is an amount that ranges from about 10 pg to 100 mg, e.g., from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1 ng, from about 1 ng to 10 ng, from about 10 ng to 50 ng, from about 50 ng to 150 ng, from about 150 ng to 250 ng, from about 250 ng to 500 ng, from about 500 ng to 750 ng, from about 750 ng to 1 mg, from about 1 pg to 10 pg, from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 100 mg, from about 1 p
  • compositions including compounds as disclosed herein e.g., compounds of Formula I and pharmaceutically acceptable salts thereof. Also disclosed herein are pharmaceutical compositions including compounds as disclosed herein e.g., compounds of Formula 1-1 and pharmaceutically acceptable salts thereof.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat
  • compositions comprising only the compounds described herein as the active component
  • methods for administering these compositions may additionally comprise the step of administering to the subject an additional agent or therapy.
  • Such therapies include, but are not limited to, an anemia therapy, a diabetes therapy, a hypertension therapy, a cholesterol therapy, neuropharmacologic drugs, drugs modulating cardiovascular function, drugs modulating inflammation, immune function, production of blood cells, hormones and antagonists, drugs affecting gastrointestinal function, chemotherapeutics of microbial diseases, and/or chemotherapeutics of neoplastic disease.
  • Other pharmacological therapies can include any other drug or biologic found in any drug class.
  • other drug classes can comprise allergy/cold/ENT therapies, analgesics, anesthetics, anti-inflammatories, antimicrobials, antivirals, asthma/pulmonary therapies, cardiovascular therapies, dermatology therapies, endocrine/metabolic therapies, gastrointestinal therapies, cancer therapies, immunology therapies, neurologic therapies, ophthalmic therapies, psychiatric therapies or rheumatologic therapies.
  • agents or therapies that can be administered with the compounds described herein include a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) Preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/
  • the compounds and compositions, according to the method of the present disclosure are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided above.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • 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 disclosure 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.
  • compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the disclosure are 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, dimethyl formamide, 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
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure 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, cety
  • 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 pol ethylene 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. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this disclosure 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 disclosure. Additionally, the present disclosure 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.
  • Embodiment 1 A compound represented by Formula 1-1 :
  • R A is of either of the following structures: each of which is substituted by n occurrences of R 3 ;
  • R 3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(R) 2 OR, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)C(NR 2 , -N(R)NR 2 , -N(R)S(
  • L 2 represents independently for each occurrence a C1-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2- or - Cy-; Cy represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 represents independently for each occurrence hydrogen, OR, Ci-6 aliphatic, Ci-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • X is O or S
  • R 1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, - C(0)NR2, C1-6 alkyl, or C 1-6 haloalky 1;
  • L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or-S(O)2-;
  • R B is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R B is substituted with q occurrences of R 2 ;
  • R 2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms
  • L 1 represents independently for each occurrence a Ci- 2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -S-, -S(O)-, or-S(O) 2 -;
  • R 4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 6 represents independently for each occurrence oxo, halogen, -CN, -NO 2 , -OR, -OCRs, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(R) 2 OR, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)C(NR 2 , -N(R)NR 2 , -N(R
  • Embodiment 2 The compound of embodiment 1, wherein the compound is a compound of Formula 1-1.
  • Embodiment 3 The compound of either of embodiments 1-2 wherein when L is a bond
  • Embodiment 4 The compound of either of embodiment 1 or 2, wherein X is O.
  • Embodiment 5 The compound of either of embodiment 1 or 2, wherein X is S.
  • Embodiment 6 The compound of any one of embodiments 1-5, wherein R 1 is halogen.
  • Embodiment 7 The compound of any one of embodiments 1-5, wherein R 1 is Ci-6 alkyl.
  • Embodiment 8 The compound of any one of embodiments 1-5, wherein R 1 is methyl.
  • Embodiment 9 The compound of any one of embodiments 1-5, wherein R 1 is Ci-6 haloalkyl.
  • Embodiment 10 The compound of any one of embodiments 1-5, wherein R 1 is -OR, - NR 2 , -C(O)R, -C(O)OR, -or C(O)NR 2 .
  • Embodiment 11 The compound of embodiment 10, wherein R 1 is -OH, -OCH 3 , -NH2, -N(CH 3 ) 2 , -C(O)CH 3 , -C(O)OCH 3 , -C(O)NH 2 , -C(O)NHCH 3 , or -C(O)N(CH 3 ) 2 .
  • Embodiment 12 The compound of any one of embodiments 1-5, wherein m is 0.
  • Embodiment 13 The compound of any one of embodiments 1-11, wherein m is 1.
  • Embodiment 14 The compound of any one of embodiments 1-11, wherein the compound is represented by the following or a pharmaceutically acceptable salt thereof:
  • Embodiment 17 The compound of embodiment 1, wherein the compound is represented by one of the following or a pharmaceutically acceptable salt thereof:
  • Embodiment 18 The compound of any one of embodiments 1-14, wherein n is 0.
  • Embodiment 19 The compound of any one of embodiments 1-14, wherein n is 1.
  • Embodiment 20 The compound of any one of embodiments 1-14, wherein n is 2.
  • Embodiment 21 The compound of any one of embodiments 1-14, wherein n is 3.
  • Embodiment 22 The compound of any one of embodiments 1-14, wherein n is 4.
  • Embodiment 23 The compound of any one of embodiments 1-14, wherein n is 5.
  • Embodiment 24 The compound of any one of embodiments 1-2 or 4-23, wherein R B is selected from:
  • Embodiment 25 The compound of any one of embodiments 1-20 or 19-24, wherein at least one R 3 is halogen.
  • Embodiment 26 The compound of any one of embodiments 1-20 or 19-24, wherein at least one R 3 is bromo.
  • Embodiment 27 The compound of any one of embodiments 1-20 or 19-24, wherein at least one R 3 is -CN.
  • Embodiment 28 The compound of any one of embodiments 1-27, wherein at least one R 2 is Ci-6 alkyl.
  • Embodiment 29 The compound of any one of embodiments 1-27, wherein at least one R 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Embodiment 30 The compound of embodiment 29, wherein at least one R 2 is a 3-4 membered saturated monocyclic carbocyclic ring.
  • Embodiment 31 The compound of any one of embodiments 1-27, wherein at least one R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Embodiment 32 The compound of embodiment 31, wherein at least one R 2 is a 4-5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 nitrogen atom.
  • Embodiment 33 The compound of any one of embodiments 1-27, wherein at least one R 2 is L’-R 4
  • Embodiment 34 The compound of embodiment 33, wherein L 1 is a C1-2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, - S(O)-, or -S(O) 2 -.
  • Embodiment 35 The compound of embodiment 33, wherein R 4 is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • Embodiment 37 The compound of any one of embodiments 1-36, wherein R 6 represents independently for each occurrence oxo, halogen, -CN, -OR, -OCR3, -SR, -NR2, or -S(O) 2 R.
  • Embodiment 38 The compound of any one of embodiments 1-37, wherein R 6 represents independently for each occurrence halogen, -CN, -OR, or -S(O)2R.
  • Embodiment 39 The compound of any one of embodiments 1-437, wherein R 6 represents independently for each occurrence fluoro, -CN, or -OH.
  • Embodiment 40 The compound of any one of embodiments 1-27, wherein each R 2 is independently selected from:
  • Embodiment 41 The compound embodiment 40, wherein each R 2 is independently selected from wherein each of R A , X, R 1 , and m are as defined above in embodiment 1.
  • Embodiment 43 The compound of any one of those depicted in Table 1 herein, or a pharmaceutically acceptable salt thereof.
  • Embodiment 44 A pharmaceutical composition comprising a compound of any one of embodiments 1-43 and a pharmaceutically acceptable carrier.
  • Embodiment 45. A method of inhibiting the activity of a c-kit kinase in a patient, comprising administering to said patient a compound of any one of embodiments 1-43.
  • Embodiment 46 A method of treating a c-kit kinase mediated disease or disorder in a patient, comprising administering to said patient a compound of any one of embodiments 1-43.
  • Embodiment 47 The method according to embodiment 46, wherein the c-kit kinase mediated disease or disorder is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a dermatological disease, an allergic disease, a cardiovascular disease, or a neurological disorder.
  • Embodiment 48 The method according to embodiment 46, wherein the c-kit kinase mediated disease or disorder is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn’s disease, or systemic and cutaneous lupus erythe
  • Embodiment 49 The method according to embodiment 46, wherein the c-kit kinase mediated disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD), ulcerative colitis, eosinophilic gastritis (EG), or eosinophilic colitis (EC).
  • the c-kit kinase mediated disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD), ulcerative colitis, eosinophilic gastritis (EG), or eos
  • Embodiment 50 The method of embodiment 46, wherein the c-kit kinase mediated disease or disorder is urticaria.
  • Embodiment 51 The method of any one of embodiments 46-50, wherein the patient is a human.
  • stereochemical representation introduces three types of identifiers that can be attached to a stereogenic center.
  • a stereochemical group label is composed from an identifier and a group number.
  • Each stereogenic center marked with wedge bonds belongs to one (and only one) stereochemical group. Grouping allows to specify relative relationships among stereogenic centers.
  • ABS denotes a stereogenic center where the absolute configuration is known.
  • “or” denotes a stereogenic center where the relative configuration is known, but the absolute configuration is not known.
  • the structure represents one stereoisomer that is either the structure as drawn (R,S) or the epimer in which the stereogenic centers have the opposite configuration (S,R).
  • R,S structure as drawn
  • S,R epimer in which the stereogenic centers have the opposite configuration
  • One of skill in the art would understand that if a single stereogenic center is present, the designation “or” represents a single isomer for which the absolute configuration is not known. In some such instances, two compounds may be depicted identically with “or” at the single stereogenic center, one of which has a single stereogenic center which is in the R configuration, the other of which is in the S configuration.
  • the designations “and” are used interchangeably and denote a mixture of stereoisomers. It can be a pair of enantiomers or all the diastereomers.
  • reaction mixture was quenched with saturated aqueous NH4CI (5 mL), extracted with di chloromethane (200 mL), and fdtered. The fdtrate was washed with brine (100 mL x 3), then the organic phase was dried over ISfeSCL, filtered and concentrated in vacuo.
  • Step 1 To a stirred solution of (1R,2S)-2-fluorocyclopropanecarboxamide (5 g, 1.0 eq) in dichloromethane (80 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (13.87 g, 1.2 eq), at 25°C.
  • Step 2 To a stirred solution of (1R,2S)-2-fluorocyclopropanecarbonitrile (3.5 g, 1.0 eq) in ethanol (30 mL) was added hydroxylamine (10.87 g, 50% purity, 4.0 eq), and the reaction mixture warmed to 80°C. After 3 hours, the reaction mixture was concentrated in vacuum below 35°C to give a residue. The residue was further lyophilized to give (1R,2S)-2-fluoro-N'-hydroxy- cyclopropanecarboxamidine (3 g, crude) as a yellow oil.
  • Step 3 To a solution of 3-amino-4-chloro-benzoic acid (4.07 g, 1.0 eq) in NMP (50 mL) was added CDI (4.61 g, 1.2 eq), the mixture was stirred at 25°C for 0.5 hours, then (1R,2S)- 2-fluoro-N'-hydroxy-cyclopropanecarboxamidine (2.8 g, 1.0 eq) was added, the reaction mixture was heated to 120°C.
  • Step 4 To a stirred solution of 2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4- oxadiazol-5-yl]aniline (500 mg, 1.0 eq) and ethyl 7-(2-tetrahydropyran-2- yloxyethoxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (686 mg, 1.0 eq) in toluene (10 mL) was added trimethylaluminium in toluene (2 M, 2.5 eq) at 0°C, then the reaction mixture was warmed at 80°C for 12 hours under N 2 .
  • Step 5 To a solution of N-[2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4- oxadiazol-5-yl]phenyl]-7-(2-tetrahydropyran-2-yloxyethoxymethyl)imidazo[1,2-a]pyridine-3- carboxamide (900 mg, 1.0 eq) in methanol (10 mL) was added 4-methylbenzenesulfonic acid, pyridine (81 mg, 0.2 eq), and the reaction mixture was stirred at 25°C for 12 h.
  • reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL), extracted with dichloromethane (200 mL), then the mixture was filtered and the filtrate washed with brine (100 mL x 3). The organic phase was dried (Na2SO4) filtered and concentrated in vacuum.
  • Step 2 To a solution of ethyl 7-(isopropoxymethyl)imidazo[1,2-a]pyridine-3- carboxylate (70.0 mg, 0.267 mmol, 1.00 eq) and 5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4- oxadiazol-5-yl]-2-methyl-aniline (62 mg, 0.267 ⁇ mol, 1.00 eq) in toluene (2 mL) was added a 2M solution of trimethylaluminum in toluene (333.58 ⁇ L, 2.50 eq) under an N2 atmosphere. The mixture was stirred at 80 °C for 2 h.
  • reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 1 To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutanoic acid (5 g, 1.0 eq) in DMF (50 mL) was added saturated aqueous ammonium chloride (1.06 g, 1.5 eq), HATU (7.53 g, 1.5 eq), and DIPEA (5.12 g, 3 eq).
  • Step 2 To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutanamide (2.40 g, 1.0 eq) in dichloromethane (25 mL) was added Burgess reagent (1.82 g, 1.2 eq). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL x 2).
  • Step 3 To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutanenitrile (2.3 g, 1.0 eq) in ethanol (30 mL) was added hydroxylamine (845 mg, 50% purity, 2.0 eq). The mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give (Z)-3-((tert-butyldiphenylsilyl)oxy)-4,4-difluoro-N'-hydroxybutanimidamide (2.3 g, crude) as a colorless oil.
  • Step 4 To a solution of 3-amino-4-methylbenzoic acid (0.85 g, 1.0 eq) in NMP (8 mL) was added di(imidazol-1-yl)methanone (1.00 g, 1.1 eq). The mixture was stirred at 25 °C for 0.5 hour.
  • Step 5 To a solution of 7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (160 mg, 1.6 eq), then reaction mixture was stirred at 25 °C for 0.5 hours. Then 5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4- oxadiazol-5-yl)-2-methylaniline (291 mg, 1.1 eq) was added and the reaction mixture was stirred at 60 °C for 2 hours.
  • reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL ⁇ 2). The combined organic layers were washed with brine (20 mL ⁇ 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 6 To a solution of N-(5-(3-(2-((tert-butyldimethylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide (85 mg, 1.0 eq) in THF (2 mL) was added TBAF (1 M, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 2 To a solution of NH 3 •water (9.1 g, 10 mL, 28% purity, 6.6 eq) was added the mixture of 4-methyl-3-nitro-benzoyl chloride (2.2 g, 1.0 eq) in dichloromethane (20 mL) and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and the filter cake was washed with water (100 mL), and dried under vacuum to give 4-methyl-3- nitrobenzamide (1.9 g, crude) as a white solid.
  • Step 3 A mixture of 4-methyl-3-nitrobenzamide (0.7 g, 1.0 eq) in DMF-DMA (1:1, 10 mL) was stirred at 110 °C for 1 hour. The reaction mixture was concentrated in vacuum.
  • Step 4 To a solution of hydroxylamine hydrochloride (222 mg, 1.5 eq) and NaOH (5 M, 2.50 mL, 5.88 eq) in dioxane (20 mL) and acetic acid (25 mL) was added N- (dimethylaminomethylene)-4-methyl-3-nitro-benzamide (500 mg, 1.0 eq), and the reaction mixture was stirred at 25°C for 0.5 hour.
  • Step 5 To a solution of 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (100 mg, 1.0 eq) and 4-(4-pyridyl)pyridine (2.00 mg, 0.03 eq) in DMF (2 mL) was added hypoboric acid (131 mg, 3.0 eq), and the reaction mixture was stirred at 25°C for 1 hour.
  • Step 6 To a solution of imidazo[1,2-a]pyridine-3-carboxylic acid (79 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (149 mg, 1.6 eq), the mixture was stirred at 25 °C for 0.5 hour, then 2-methyl-5-(1,2,4-oxadiazol-5-yl)aniline (85 mg, 1.0 eq) was added, and the reaction mixture stirred at 60°C for 2 hours. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL), the organic layer was washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuum.
  • EDCI 149 mg, 1.6 eq
  • Step 2 To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) and 2-methyl-5-(1H-1,2,4-triazol-3-yl)aniline (110 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (130 mg, 1.2 eq). The mixture was stirred at 60°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • EDCI 130 mg, 1.2 eq
  • EXAMPLE 8 Preparation of 6-(difluoromethyl)-N-(2-methyl-5-(3-methyl-1,2,4-oxadiazol- 5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-77) , mg, 1.0 eq) in DMSO (5 mL) was added Pd(OAc) 2 (33 mg, 0.2 eq) and DPPP (31 mg, 0.1 eq), Et3SiH (173 mg, 2.0 eq), and triethylamine (226 mg, 3.0 eq). The mixture was stirred at 80 °C for 12 hours under CO at 45 psi.
  • Step 2 To a solution of ethyl 6-formylpyrazolo[1,5-a]pyridine-3-carboxylate (50 mg, 1.0 eq) in dichloromethane (1 mL) was added DAST (37 mg, 1.0 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 3 To a solution of 2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)aniline (26 mg, 1.1 eq) in toluene (1 mL) was added trimethylaluminium in toluene (2 M, 2.5 eq) at 25 °C, then the reaction mixture was stirred at 25 °C for 0.5 hour. Ethyl 6-(difluoromethyl)pyrazolo[1,5- a]pyridine-3-carboxylate (30 mg, 1.0 eq) was added, then the reaction mixture was stirred at 80 °C for 2 hours.
  • reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) then was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was stirred at 25 °C for 0.5 hours, then ethyl 6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 1 eq) was added.
  • the reaction mixture was stirred at 80 °C for 12 hours.
  • the reaction mixture was quenched with a saturated aqueous ammonium chloride solution (20 mL) then extracted with ethyl acetate (50 mL x 3).
  • the combined organic layers were washed with brine (25 mL x 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (100 mg, 1.0 eq) in THF (2 mL) was added TBAF (1 M, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL x 3).
  • Step 2 To a solution of (1H-imidazol-1-yl)(4-methyl-3-nitrophenyl)methanone (9.45 g, 1.0 eq) in THF (100 mL) was added NH 3 •water (11.24 mL, 28% purity, 2.0 eq). The mixture was stirred at 25°C for 12 hours.
  • Step 3 A mixture of 4-methyl-3-nitro-benzamide (3.2 g, 1.0 eq) and DMF-DMA (32 mL, 13.56 eq) was heated to 110°C for 1 hour. The mixture was cooled then concentrated to give a residue.
  • Step 4 To a solution of N-((dimethylamino)methylene)-4-methyl-3-nitrobenzamide (3.0 g, 1.0 eq) in acetic acid (30 mL) was added hydrazine hydrate (977 mg,, 98% purity, 1.5 eq).
  • Step 5 To a mixture of 3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (500 mg, 1.0 eq) and cyclopropylboronic acid (2.10 g, 10.0 eq) in dichloroethane (10 mL) was added Cu(OAc)2 (667 mg, 1.5 eq), 2-(2- pyridyl)pyridine (573 mg, 1.5 eq) and Na2CO3 (1.3 g, 5.0 eq) under O2 (15 psi). The mixture was stirred at 80 °C for 12 hours under O 2 , then cooled to room temperature and filtered. The filtrate was concentrated to give a residue.
  • Step 6 To a solution of 1-cyclopropyl-3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (200 mg, 1.0 eq) in DMF (6 mL) was added 4-(4-pyridyl)pyridine (1.48 mg, 0.01 eq) slowly. To the mixture was added hypoboric acid (220 mg, 3.0 eq) slowly. The mixture was stirred at 25 °C for 0.5 hours. The mixture was diluted with water (10 mL) then extracted with ethyl acetate (30 mL x 3).
  • Step 7 To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) and 5-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methylaniline (190 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (163 mg, 1.5 eq). The mixture was stirred at 60 °C for 2 hours. The mixture was concentrated to give a residue.
  • Step 2 To a solution of 1-(3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)propan-2- ol (200 mg, 1.0 eq) in THF (5 mL) and ethanol (5 mL) was added Pd/C (100 mg, 10% purity, 0.1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H 2 (15psi) at 25°C for 12 hours.
  • Step 3 To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (120 mg, 1.0 eq) and 1-(3-(3-amino-4-methylphenyl)-1H-1,2,4-triazol-1-yl)propan-2-ol (180 mg, 1.02 eq) in pyridine (2 mL) was added EDCI (157 mg, 1.2 eq). The mixture was stirred at 60 °C for 2 hours. The mixture was concentrated to give a residue.
  • Step 2 To a solution of 5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylaniline (183 mg, 1.1 eq) in toluene (2 mL) was added trimethylaluminium in toluene (2 M, 2.5 eq), the reaction mixture was stirred at 25 °C for 0.5 hour, then ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 1 eq) was added, and the reaction mixture was stirred at 80 °C for 2 hours.
  • reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) then was extracted with dichloromethane (25 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step 3 To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2- a]pyridine-3-carboxamide (83 mg, 1.0 eq) in THF (1 mL) was added TBAF (1 M, 1.1 eq).
  • Step 2 To a solution of 2-methyl-4-(pyridin-3-ylmethoxy)butan-2-ol (1.8 g, 1.0 eq) in acetonitrile (20 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (1.84 g, 1.0 eq). The mixture was stirred at 40°C for 16 hours. The mixture was concentrated to give 1-amino-3-((3- hydroxy-3-methylbutoxy)methyl)pyridin-1-ium (1.95 g, crude) as a yellow oil.
  • Step 3 To a solution of 1-amino-3-((3-hydroxy-3-methylbutoxy)methyl)pyridin-1-ium (1.95 g, 1.0 eq) and ethyl prop-2-ynoate (905 mg, 1.0 eq) in DMF (20 mL) was added K 2 CO 3 (3.19 g, 2.5 eq). The mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 4 To a solution of ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2- a]pyridine-3-carboxylate (200 mg, 1 eq) in toluene (2 mL) was added Al(CH3)3 (2 M, 492 ⁇ L, 2.5 eq) under N 2 . The mixture was stirred at 25°C for 0.5 hour. To the mixture was added ethyl 6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (121 mg, 1.0 eq) and the mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature.
  • Step 5 To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide (170 mg, 1 eq) in THF (3 mL) was added TBAF (1 M, 265 ⁇ L, 1.2 eq). The mixture was stirred at 25°C for 12 hours. The mixture was concentrated to give a residue.
  • Step 3 To a solution of ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2- a]pyridine-3-carboxylate (110 mg, 1.0 eq) in toluene (2 mL) was added Al(CH3)3 (3 M, 314 ⁇ L, 2.5 eq).
  • reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure and was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water( NH4HCO3)-acetonitrile]; gradient:28%-58% B over 20 min) to give ethyl 7-((2-((tetrahydro-2H- pyran-2-yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (220 mg) as a yellow oil.
  • Step 2 To a solution of 5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2- methylaniline (76 mg, 1.0 eq) in toluene (2 mL) was added trimethylaluminium in toluene (2 M, 359 ⁇ L, 2.5 eq) and stirred at 25°C for 0.5h.
  • Step 3 To a solution N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2- methylphenyl)-7-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3- carboxamide (40 mg, 1.0 eq) in dichloromethane (2 mL) was added TFA (614 mg, 0.4 mL, 76 eq) and the mixture was stirred at 25°C for 1 hour.
  • reaction mixture was concentrated under reduced pressure and was purified by prep-HPLC (column: C18150 ⁇ 30mm;mobile phase: [water(formic acid)- acetonitrile];gradient: 28%-58% B over 7 min) to give N-(5-(3-(3,3- difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2- hydroxyethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-84, 19 mg) as a yellow gum.
  • Step 2 To a solution of N-cyano-4-methyl-3-nitro-benzamide (800 mg, 1 eq) in pyridine (8 mL) was added NH2OH.HCl (271 mg, 1 eq), then the reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (80 mL x 3), then the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 3 To a solution of 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazol-3-amine (110 mg, 1.0 eq) in water (0.4 mL) was added the solution of NaNO 2 (62.05 mg, 1.8 eq) in HBr (1 mL) at 0 °C, the mixture was stirred at 0.1 hour, then CuBr (72 mg, 1 eq) was added, and then the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (30 mL), and the organic layer was concentrated in vacuum.
  • Step 4 To a solution of 3-bromo-5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (100 mg, 1.0 eq) and 4-(4-pyridyl)pyridine (1.4 mg) in DMF (1 mL) was added hypoboric acid (95 mg, 3.0 eq), then the reaction mixture was stirred at 25 °C for 0.5 hour.
  • Step 5 To a solution of 5-(3-bromo-1,2,4-oxadiazol-5-yl)-2-methyl-aniline (60 mg, 1.0 eq) in toluene (1 mL) was added trimethylaluminium in toluene (2 M, 295 ⁇ L, 2.5 eq) at 0 °C and the mixture was stirred at 25 °C for 0.5 hour under N 2 . Then ethyl 7-methylimidazo[1,2- a]pyridine-3-carboxylate (48 mg, 1.0 eq) was added and the reaction mixture was stirred at 80 °C for 2 hours under N2.
  • reaction mixture was quenched with a saturated aqueous NH4Cl solution (1 mL), extracted with dichloromethane (50 mL), washed with brine (10 mL x 2), and then the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • Step 2 To a solution of N-cyano-4-methyl-3-nitro-benzamide (800 mg, 1.0 eq) in pyridine (8 mL) was added NH2OH.HCl (271 mg, 1 eq), the reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (80 mL x 3), and the organic layer was dried over Na2SO4, filtered and concentrated in vacuum.
  • Step 3 To a solution of 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazol-3-amine (220 mg, 1.0 eq) in water (0.8 mL) was added a solution of NaNO2 (124 mg, 1.8 eq) in HCl (2 mL) at 0 °C. The mixture was stirred for 0.1 hour, then CuCl (297 mg, 1.0 eq) was added, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (40 mL), and the organic layer was concentrated in vacuum.
  • Step 4 To a solution of 3-chloro-5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (130 mg, 1.0 eq) and 4-(4-pyridyl)pyridine (2.2 mg, 2.63e-2 eq) in DMF (2 mL) was added hypoboric acid (146 mg, 3.0 eq), the reaction mixture was stirred at 25 °C for 0.5 hours.
  • Step 5 To a solution of 5-(3-chloro-1,2,4-oxadiazol-5-yl)-2-methyl-aniline (83 mg, 1.1 eq) in pyridine (2 mL) was added EDCI (132 mg, 1.6 eq). The mixture was stirred at 25 °C for 0.5 hours, then 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (90 mg, 1.0 eq) was added. The reaction mixture was stirred at 60 °C for 3.5 hours, then cooled and concentrated in vacuum.
  • EXAMPLE 19 Preparation of 6-Fluoro-N-(2-methyl-5-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-88) (60 mg, 0.319 mmol, 1.0 eq) in toluene (1 mL) was added a solution of 2 M trimethylaluminum in toluene (2 M, 319 ⁇ L, 2.0 eq) under nitrogen. The mixture was stirred at 25 °C for 0.5 h.
  • Ethyl 6- fluoropyrazolo[1,5-a]pyridine-3-carboxylate (66 mg, 0.319 mmol, 1.0 eq) was added into the mixture and stirred at 80 °C for 2 h.
  • the mixture was cooled to room temperature and quenched with ice water (10 mL).
  • the solution was extracted with dichloromethane (20 mL x 3).
  • the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of 1-methyl-3-(4-methyl-3-nitro-phenyl)-1,2,4-triazole (280 mg, 1.28 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL) was added 4-(4-pyridyl)pyridine (10 mg, 0.64 mmol, 0.05 eq) and hypoboric acid (345 mg, 3.85 mmol, 3.0 eq). The mixture was stirred at 25 °C for 10 minutes. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3).
  • Step 3 To a solution of 2-methyl-5-(1-methyl-1,2,4-triazol-3-yl)aniline (60 mg, 3.19 mmol, 1.0 eq) in toluene (1 mL) was added a solution of 2M trimethylaluminum in toluene (2 M, 319 ⁇ L, 2.0 eq) under nitrogen. The mixture was stirred at 25 °C for 0.5 h. Ethyl 7-thiazol-4- ylimidazo[1,2-a]pyridine-3-carboxylate (87 mg, 3.19 mmol, 1.0 eq) was added into the mixture and stirred at 80 °C for 2 h.
  • EXAMPLE 22 Preparation of 7-(1,1-Difluoroethyl)-N-(2-methyl-5-(1-methyl-1H-1,2,4- triazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (II-91) mg, 3.19 mmol, 1.0 eq) in toluene (2 mL) was added a solution of 2M trimethylaluminum in toluene (2 M, 319 ⁇ L, 2.0 eq) under nitrogen. The mixture was stirred at 25°C for 0.5 h.
  • the mixture was stirred at 25 °C for 1 hour.
  • the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of 5-(5-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-3-yl)-N,2-dimethylaniline (80 mg, 0.153 mmol, 1.0 eq) in dichloromethane (2 mL) was added diisopropylethylamine (50 mg, 0.383 mmol, 2.5 eq) and imidazo[1,2-a]pyridine- 3-carbonyl chloride (33 mg, 0.153 mmol, 1.0 eq, HCl) at 0 °C.
  • Step 3 To a solution of N-(5-(5-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-3-yl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (75 mg, 0.113 mmol, 1.0 eq) in tetrahydrofuran (1 mL) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 0.135 mmol, 1.2 eq). The mixture was stirred at 25 °C for 1 h.
  • the crude product was purified by prep-HPLC (formic acid condition; column: YMC-Actus Triart C18150 ⁇ 30mm ⁇ 7um; mobile phase: [water(formic acid)- acetonitrile]; gradient:20%-50% B over 10 min) to give N-(5-(5-(3,3-difluoro-2-hydroxypropyl)- 1,2,4-oxadiazol-3-yl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (II-93, 17 mg, 0.035 mmol, 31%) as a white solid and as a formic acid salt.
  • EXAMPLE 25 Analytical Data for Compounds of the Present Invention
  • Table 2 The compounds listed in Table 2 below were prepared using experimental procedures analogous to those described in the Examples and Detailed Description. Table 2 also list each compound’s 1 H NMR characterization data and mass-to-charge ratio observed by high-resolution MS or LC/MS. Chemical structures are presented in Table 1 above. TABLE 2. Compound Mass Spec. Chemical Shift Data Compound Mass Spec. Chemical Shift Data No.
  • Peptide Substrate The substrate used in the CSF-1R and PDGFR ⁇ assay is FAM- KKKKEEIYFFF- CONH2 (FAM is carboxyfluorescein). Peptide should be >95% purity.
  • the substrate for the KIT assay is FAM-GEEPLYWSFPAKKK-NH 2 .
  • Assay Setup & Conditions 1. To a well of a 384-wellplate add 5 ⁇ L of 2X enzyme buffer (or control). 2. Add 100 nL of 100X compound. Enzyme and compound may be pre-incubated at this time if desired. 3. Add 5 ⁇ L of 2X substrate buffer. 4. Incubate plate at 25°C for 3 hours. 5.
  • Enzyme concentration may need to be adjusted to yield 10-20% conversion of substrate to product.
  • TABLE 3 Protein Lots and assay conditions Protein Assay Assay Vendor and [Enzyme], ATP Substr Incubat l Pl f l M i Part II – Results [00500] Experimental results are provided in Table 4, below. The symbol “****” indicates an IC50 less than or equal to 0.05 ⁇ M. The symbol “***” indicates an IC50 in the range of greater than 0.05 ⁇ M and less than or equal to 0.5 ⁇ M. The symbol “**” indicates an IC50 in the range of greater than 0.5 ⁇ M and less than or equal to 5 ⁇ M.
  • Peptide Substrate [00502]
  • the substrate used in the CSF-1R and PDGFR ⁇ assay is FAM- KKKKEEIYFFF- CONH2 (FAM is carboxyfluorescein). Peptide should be >95% purity.
  • the substrate for the KIT assay is FAM-GEEPLYWSFPAKKK-NH 2 .
  • Assay Setup & Conditions 1. To a well of a 384-well plate add 5 ⁇ L of2 X enzyme buffer(or control) 2. Add 100 nL of 100X compound. 3.
  • IC50 less than or equal to 0.05 ⁇ M indicates an IC50 in the range of greater than 0.05 ⁇ M. and less than or equal to 0.5 ⁇ M..
  • the symbol indicates an IC50 in the range of greater than 0.5 ⁇ M. and less than or equal to 5 ⁇ M.
  • the symbol “ t ” indicates an IC50 in the range of greater than 5 ⁇ M. to 30 ⁇ M..
  • M-07e cells are also represented as M-07E, M-07e, M07-e, M07e, Mo7e, M07e, M07E and M07E. Assay procedures and results are described below.
  • RPMI medium ATCC® RPMI- 1640 Medium, Cat# 30-2001
  • FBS Fetal Bovine Serum, certified, United States Gibco
  • Thermo-Fisher 16000044 GM-CSF: Recombinant Human GM-CSF Protein, R&D cat# 215-GM SCF: Recombinant Human SCF Protein, R&D cat# 255-SC
  • the symbol “+++” indicates an IC50 in the range of greater than 0.05 qM and less than or equal to 0.5 qM.
  • the symbol “++” indicates an IC50 in the range of greater than 0.5 qM and less than or equal to 5 qM.
  • the symbol “+” indicates an IC50 in the range of greater than 5 qM to 30 qM.
  • Exemplary compounds were tested for cell permeability in Caco-2, MDCKII-MDR1 and MDCKII-BCRP cell lines with efflux transporter engagement inferred from the efflux ratios determined. Procedures and results are described below. As described above and herein, it has been surprisingly found that certain compounds of the present invention have reduced brain penetration. This feature of certain compounds is in part due to efflux transporter engagement. See, for instance, exemplary such compounds included in data tables below.
  • Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96-well Coming Insert plates at 1 x 105 cells/ cm 2 , and refreshed medium every 4 ⁇ 5 days until to the 21 st to 28 th day for confluent cell monolayer formation.
  • PET polyethylene membranes
  • the transport buffer in the study was HBSS with 10.0 mM HEPES at pH 7.40 ⁇ 0.05.
  • Test compound was tested at 2.00 ⁇ M. bi-directionally in duplicate.
  • Digoxin was tested at 10.0 ⁇ M. bi-directionally in duplicate, while nadolol and metoprolol were tested at 2.00 ⁇ M. in A to B direction in duplicate.
  • Final DMSO concentration was adjusted to less than 1%.
  • the plate was incubated for 2 hours in CO2 incubator at 37 ⁇ 1°C, with 5% CO2 at saturated humidity without shaking. And all samples after mixed with acetonitrile containing internal standard were centrifuged at 3200 xg for 10 min.
  • test and control compounds were quantified by LC-MS/MS methodologies, using peak area ratio of analyte/internal standard.
  • lucifer yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity.
  • Lucifer yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity. And permeation of lucifer yellow through the monolayer was measured to evaluate the cellular integrity.
  • P app (dCr/dt) x Vr / (A x Co), where dC r /dt is the cumulative concentration of compound in the receiver chamber as a function of time ( ⁇ M/.s); V r is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, i.e. 0.0804 cm 2 for the area of the monolayer; Co is the initial concentration in the donor chamber ( ⁇ M).
  • the transport assay can be performed between days 12 to day 15 using ready to use PreadyPortTM BCRP-MDCKII monolayer in 96 well plate.
  • PreadyPartTM plate was removed from the incubator and placed in the laminar flow hood. [00519] The medium was aspirated from the apical and basal compartments and 75 and 235 pL assay buffer was added to each of the 96 wells of apical and basal compartments of the PreadyPoRTTM plate.
  • the plates were pre-incubated for 15 min at 37°C with 5% CO2 in humidified atmosphere. After preincubation the assay buffer was removed from the apical and basal inserts of the plate.
  • the sandwich plate was incubated for 120 min in incubator at 5 % CO2 and 37°C.
  • V Volume of receiver chamber
  • MDR1-MDCKII cells obtained from Piet Borst at the Netherlands Cancer Institute were seeded onto polyethylene membranes (PET) in 96-well insert systems at 2.5 x 10 5 cells/ mL until to 4-7 days for confluent cell monolayer formation.
  • Test compounds were diluted with the transport buffer (HBSS with lOmM Hepes, pH7.4) from DMSO stock solution to a concentration of 2.00 ⁇ M. (DMSO ⁇ 1%) and applied to the apical or basolateral side of the cell monolayer. Permeation of the test compounds from A to B direction or B to A direction was determined in duplicate. Digoxin was tested at 10.0 ⁇ M.
  • test and reference compounds were quantified by LC-MS/MS analysis based on the peak area ratio of analyte/IS.
  • Lucifer yellow rejection assay are applied to determine the cell monolayer integrity. Buffers are removed from both apical and basolateral chambers, followed by the addition of 75 pL of 100 ⁇ M. lucifer yellow in transport buffer and 250 pL transport buffer in apical and basolateral chambers, respectively. The plate is incubated for 30 minutes at 37°C with 5% CO2 and saturated humidity without shaking. After 30 minutes incubation, 20 pL of lucifer yellow samples are taken from the apical sides, followed by the addition of 60 pL of Transport Buffer. And then 80 pL of lucifer yellow samples are taken from the basolateral sides. The relative fluorescence unit (RFU) of lucifer yellow is measured at 425/528 nm (excitation/emission) with an Envision plate reader.
  • REU relative fluorescence unit
  • dC r /dt is the cumulative concentration of compound in the receiver chamber as a function of time ( ⁇ M/.s);
  • V r is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side);
  • A is the surface area for the transport, i.e. 0.0804 cm 2 for the area of the monolayer;
  • Co is the initial concentration in the donor chamber ( ⁇ M).
  • Va the volume in the donor chambers (0.075 mb on the apical side, 0.25 mL on the basolateral side); Cd and C r are the final concentrations of transport compound in donor and receiver chambers, respectively.
  • EXAMPLE 30 Three Time Point Assay for Plasma, Brain and Testes Distribution [00530] Exemplary compounds were tested for distribution in plasma, brain and testes tissue following oral dosing of the compounds in rats. Procedures and results are described below.
  • test article was accurately weighed and mixed with an appropriate volume of vehicle to get a clear solution or a uniform suspension; vortexing or sonication in water bath may also be need. Animals were dosed within four hours after the formulation is prepared.
  • Formulation samples were removed from each of the formulation solutions or suspensions, transferred into 1.5 mb of polypropylene microcentrifuge tubes and run dose validation by LC/UV or LC-MS/MS.
  • the dose formulation was administered via oral gavage following facility SOPs.
  • the dose volume was determined by the animals’ body weight collected on the morning of dosing day. The dose was 10 mg/kg.
  • Each blood collection (about 1 mb per time point at one or more of 0.5h, 2h, 3h, 5.3h, and 7h) was performed from jugular vein or other suitable site of each animal into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifugation.
  • Plasma samples were processed for plasma by centrifugation at approximately 4°C, 3,200 g for 10 min. Plasma was collected respectively and transferred into pre-labeled 96 well plate or polypropylene tubes, quick frozen over dry ice and kept at -60°C or lower until LC- MS/MS analysis.
  • the brain homogenate was kept at -60°C or lower until LC-MS/MS analysis.
  • General sample processing procedure (brain homogenate & testis homogenate) using 96-well plate:
  • the concentrations of the test compound in dose formulation samples were determined by the LC-UV or LC-MS/MS method.
  • ⁇ Acceptance criteria for an analytical run at least of 5 of 6 calibration standards should be within ⁇ 20% of nominal values by using LC-UV method and ⁇ 30% of nominal values by using LC-MS/MS method.
  • a calibration curve with at least 6 non-zero calibration standards was applied for the method including LLOQ.
  • N in 1 cassette LC-MS/MS method was developed for samples coming from different studies and the interference among all cassette analytes was evaluated during the method development.
  • Sample analysis 1 . If sample number within a batch was ⁇ 12, at least one set of standard curve separated with two parts through begin and end of the sequence, was included in the run, and QCs were not required. The recommended injection order was C8, C6, C4, C2, study samples, C7, C5, C3, Cl.
  • sample number within a batch was > 12, one standard curve and two sets of QCs with low, middle and high concentrations were applied for bioanalysis. Meanwhile, QCs number should be more than 5% of study sample number.
  • the mean calculated concentration in the single blank matrix should be ⁇ 50% LLOQ.
  • Carryover evaluation should be estimated according to absolute carryover. Carryover contribution is calculated by the area ratio of the blank with the highest carryover (Area max of carryover blank) to the ULOQ with the minimum calculated value (Area min of ULOQ);
  • Carryover impact is calculated by the area ratio of one injection (Area of one injection) to the following injection (Area of the following injection); Absolute carryover is calculated by carryover contribution multiplies carryover impact, the value of absolute carryover should be below the acceptable accuracy of the studies (e.g., 20% or 25%).
  • Cryopreserved human hepatocytes were purchased from BioIVT (Baltimore, MD, USA), and they were stored in liquid nitrogen before using. The detailed information of hepatocytes is as follows:
  • Positive control was purchased from commercial vender.
  • QIAcube HT System Qiagen, QIAcube HT, USA
  • BIO-RAD CFX 384 Touch Real Time PCR System (BIO-RAD, CFX 384 Touch, USA)
  • NanoDrop ND-2000 Spectrophotometer Thermo, NanoDrop ND2000, USA
  • Microplate spectrophotometer (Molecular Devices, Spectra Max M2 e , USA)
  • Microplate Shaker (Thermo, 100-240V, 50-60Hz, China)
  • Cryopreserved hepatocytes were thawed and counted to determine yield, viability was measured. Hepatocytes at the concentrations of 0.7 million/mL were transferred to collagen-coated 96-well plates for attachment (0.1 mb viable cells/well). After allowing 4 to 5 hours for attachment of cells, the plating medium was replaced with Incubation Medium containing 2% (v/v) MatrigelTM (sandwich medium) and the hepatocytes were incubated until use.

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Abstract

The invention provides novel compounds, pharmaceutical compositions, and their use for inhibiting c-kit kinase activity.

Description

COMPOUNDS AND COMPOSITIONS AS c-Kit KINASE INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63/430,920, filed December 7, 2022; the contents of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present disclosure relates generally to various compounds and compositions useful as a selective inhibitor of c-kit kinase and uses of the same in the treatment of c-kit kinase associated diseases, disorders, and conditions.
BACKGROUND
[0003] Compounds of the present disclosure are selective inhibitors of c-kit kinase, useful for the depletion of mast cells and thus is useful for treating mast-cell associated diseases including, inter alia, asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn’s disease, or systemic and cutaneous lupus erythematosus and dermatomyositis. Exemplary other mast-cell diseases are described further herein.
[0004] There remains a need in the art for novel compounds, compositions and methods for treating mast-cell associated diseases.
SUMMARY
[0005] The present disclosure provides compounds, compositions, and methods of treating c- kit kinase mediated diseases comprising administering to a patient in need thereof a compound of the present disclosure, or a pharmaceutical salt or composition thereof. In general, the compounds and methods disclosed herein are useful for treating mast-cell associated diseases as described herein.
[0006] In some embodiments, a compound of the present disclosure is represented by Formula I:
Figure imgf000003_0001
[0007] or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of such compounds is described herein in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
[0008] In some embodiments, a compound of the present disclosure is represented by Formula 1-1 :
Figure imgf000003_0002
(1-1) or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of such compounds is described herein in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
[0009] In some embodiments, the invention provides a method of treating a disorder mediated by c-kit kinase in a subject. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to a subject in need thereof to treat the disorder, as further described in the detailed description. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I- 1 , to a subject in need thereof to treat the disorder, as further described in the detailed description.
[0010] In some embodiments, the invention provides methods of inhibiting c-kit kinase activity. Some such methods comprise contacting c-kit kinase with an effective amount of a compound described herein, such as a compound of Formula I, to inhibit c-kit kinase activity, as further described in the detailed description. Other such methods comprise contacting c-kit kinase with an effective amount of a compound described herein, such as a compound of Formula 1-1, to inhibit c-kit kinase activity, as further described in the detailed description.
DETAILED DESCRIPTION
[0011] The present disclosure is based at least in part on the identification of novel compounds that modulate c-kit kinase and methods of using the same to treat c-kit kinase associated diseases. Disclosed herein are compounds represented by Formula I:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof; wherein:
RA is of either of the following structures:
Figure imgf000004_0002
each of which is substituted by n occurrences of R3;
R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, –N(R)NR2, -N(R)S(O)2NR2, – N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, -L2-R5, or an optionally substituted group selected from C1-6 aliphatic, C1-6 haloaliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R; or: two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with r instances of R; L2 represents independently for each occurrence a C1-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by –C(R)2-, –N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, –S(O)2- or -Cy-; Cy represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5 represents independently for each occurrence hydrogen, OR, C1-6 aliphatic, C1-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X is O or S; R1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, - C(O)OR, -C(O)NR2, C1-6 alkyl, or C1-6 haloalkyl; L is a bond or –N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or –S(O)2-; RB is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RB is substituted with q occurrences of R2; R2 represents independently for each occurrence halogen, oxo, C1-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L1-R4; wherein R2 is substituted with p occurrences of R6; L1 represents independently for each occurrence a C1-2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by –C(R)2-, –N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or –S(O)2-; R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R6 represents independently for each occurrence oxo, halogen, –CN, –NO2, –OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, –N(R)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, or optionally substituted phenyl; R7 is hydrogen or C1-3 alkyl; each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from C1-6 aliphatic; phenyl; C1-6 haloaliphatic; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0 or 1; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, or 5.
[0012] Further disclosed herein are compounds of Formula 1-1:
Figure imgf000008_0001
(1-1) or a pharmaceutically acceptable salt thereof; wherein:
RA is of either of the following structures:
Figure imgf000008_0002
each of which is substituted by n occurrences of R3;
R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCRs, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2,
N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, N=S(O)R2, S(NR)(O)R, N(R)S(O)R, -N(R)CN, -L2-R5, or an optionally substituted group selected from C1-6 aliphatic, C1-6 haloaliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R; or: two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with r instances of R; L2 represents independently for each occurrence a C1-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by –C(R)2-, –N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, –S(O)2- or -Cy-; Cy represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5 represents independently for each occurrence hydrogen, OR, C1-6 aliphatic, C1-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X is O or S; R1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, - C(O)OR, -C(O)NR2, C1-6 alkyl, or C1-6 haloalkyl; L is a bond or –N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or –S(O)2-; RB is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RB is substituted with q occurrences of R2; R2 represents independently for each occurrence halogen, oxo, C1-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L1-R4; wherein R2 is substituted with p occurrences of R6; L1 represents independently for each occurrence a C1-2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by –C(R)2-, –N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or –S(O)2-; R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R6 represents independently for each occurrence oxo, halogen, –CN, –NO2, –OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, – C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, –N(R)NR2, -N(R)S(O)2NR2, –N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, or optionally substituted phenyl; each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from C1-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, or 5.
[0013] Further disclosed herein are novel compounds that modulate c-kit kinase and methods of using the same to treat c-kit kinase associated diseases, wherein the compound is of Formula II:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof; wherein each of RA, X, R1, and m are as defined above and described herein for Formula I.
[0014] Further disclosed herein are novel compounds that modulate c-kit kinase and methods of using the same to treat c-kit kinase associated diseases, wherein the compound is of Formula II:
Figure imgf000012_0001
(II-l) or a pharmaceutically acceptable salt thereof; wherein each of RA, X, R1, and m are as defined above and described herein for Formula 1-1.
[0015] The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991- 1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds ); “Current protocols in molecular biology” (F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.
[0016] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.
Definitions
[0017] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0018] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” 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.
[0019] As used herein, the term “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. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” 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. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:
Figure imgf000014_0001
[0021] The term “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. [0022] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
[0023] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2/f-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).
[0024] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.
[0025] As used herein, the term “bivalent Ci-8 (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
[0026] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n- wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
[0027] The term “-(Co alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-” encompasses a bond (i.e., Co) and a -(C1.3 alkylene)- group.
[0028] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
[0029] The term “halogen” means F, Cl, Br, or I.
[0030] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group
Figure imgf000016_0001
aryl group.
[0031] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 > electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4// quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0032] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it. The term “pyridinylene” refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it. For example, “pyridinylene” is a bivalent pyridine radical when it has two groups
Figure imgf000017_0001
[0033] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2/7 pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in A substituted pyrrolidinyl).
[0034] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3/7-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl alkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by an oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. [0035] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0036] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0037] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH2)0–4R ^; –(CH2)0–4OR ^; -O(CH2)0-4Ro, –O–(CH2)0– 4C(O)OR°; –(CH2)0–4CH(OR ^)2; –(CH2)0–4SR ^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; – N3; -(CH2)0–4N(R ^)2; –(CH2)0–4N(R ^)C(O)R ^; –N(R ^)C(S)R ^; –(CH2)0–4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^2; –(CH2)0–4N(R ^)C(O)OR ^; –N(R ^)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^2; -N(R ^)N(R ^)C(O)OR ^; –(CH2)0–4C(O)R ^; –C(S)R ^; –(CH2)0–4C(O)OR ^; –(CH2)0–4C(O)SR ^; -(CH2)o 4C(O)OSiR°3; -(CH2)O 4OC(O)R°; -OC(0)(CH2)O^SR- SC(S)SR°; -(CH2)O 4SC(O)RO; -(CH2)O 4C(O)NRO 2; -C(S)NRO 2; -C(S)SR°; -SC(S)SR°, -(CH2)O 4OC(O)NRO 2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0 4SSR°; -(CH2)0 4S(O)2R°; -(CH2)O 4S(0)20RO; -(CH2)O-4OS(0)2R°; -S(O)2NRO 2; -S(O)(NR°)R°; - S(O)2N=C(NR°2)2; -(CH2)O 4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; - C(NH)NR°2; -P(O)2RO; -P(0)RO 2; -0P(0)RO 2; -0P(0)(0RO)2; SiR°3; -(Ci 4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2.
[0038] Each R° is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =0 and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, - (CH2)0 2R*, -(haloR*), -(CH2)0 2OH, -(CH2)o-2OR*, -(CH2)o 2CH(OR’)2; -O(haloR’), -CN, -N3, -(CH2)0 2C(O)R*, -(CH2)O 2C(O)OH, -(CH2)O 2C(O)OR*, -(CH2)O 2SR*, -(CH2)O 2SH, -(CH2)O 2NH2, -(CH2)O 2NHR*, -(CH2)O 2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(Ci^t straight or branched alkylene)C(O)OR’, or -SSR*.
[0039] Each R* is independently selected from Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5- 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2 3O- or - S(C(R*2))2-3S-, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0040] When 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 – NO2, wherein each R ^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, 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. [0041] 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)2R†; wherein each R† is independently hydrogen, C1–6 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 unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when 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 –NO2, wherein each R ^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, 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. [0042] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et 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. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[0043] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al. , Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.
[0044] 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, lower alkyl sulfonate and aryl sulfonate.
[0045] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
[0046] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
[0047] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomers are considered part of this invention.
[0048] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. [0049] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.
[0050] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and Ci-Ce alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 -methyl -1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
[0051] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.
[0052] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group.
[0053] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.
[0054] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
[0055] The term “carbocyclylene” refers to a multivalent carbocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “carbocyclylene” is a bivalent carbocyclyl group when it has two groups attached to it; “carbocyclylene” is a trivalent carbocyclyl group when it has three groups attached to it. [0056] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, terZ-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include - OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. The term “hydroxyalkoxyl” refers to an alkoxyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkoxyl groups include -OCH2CH2OH, -OCH2C(H)(OH)CH2CH2OH, and the like. The term “alkoxyl ene” refers to a bivalent alkoxyl group.
[0057] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane susbsituted with an oxo group is cyclopentanone.
[0058] The symbol “•«««” indicates a point of attachment.
[0059] When a chemical structure containing a ring is depicted with a substituent having a bond that crosses a ring bond, the substituent may be attached at any available position on the ring. For example, the chemical structure
Figure imgf000024_0001
encompasses
Figure imgf000024_0002
Figure imgf000024_0003
In the context of a polycyclic fused ring, when a chemical structure containing a polycyclic fused ring is depicted with one or more substituent(s) having a bond that crosses multiple rings, the one or more substituent(s) may be independently attached to any of the rings crossed by the bond. To illustrate, the chemical structure
Figure imgf000024_0004
encompasses, for example,
Figure imgf000024_0005
[0060] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. [0061] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.
[0062] As used herein, 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, includes humans.
[0063] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target. The potency of an inhibitor is usually defined by its IC50 value. The lower the IC50 value the greater the potency of the antagonist and the lower the concentration that is required to inhibit the maximum biological response. In certain embodiments, an inhibitor has an IC50 and/or binding constant of less than about 100 μM, less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
[0064] As used herein, the terms “inhibitor” or “c-kit inhibitor” are defined as a compound that binds to and/or inhibits c-kit kinase with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner. In some embodiments, 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.
[0065] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change or inhibition in c-kit kinase activity between a sample comprising a compound of the present invention, or composition thereof an equivalent sample comprising c-kit kinase, in the absence of said compound, or composition thereof.
[0066] As used herein, the term “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.
[0067] As used herein, the term “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. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, 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.
[0068] As used herein, the term “pharmaceutical 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.
[0069] As used herein, 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. For examples of carriers, stabilizers and adjuvants, see e.g, Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975], [0070] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
[0071] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
[0072] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
[0073] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.
I. Compounds of the Present Disclosure
[0074] The present disclosure provides compounds and pharmaceutically acceptable salts thereof that may be used in pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds.
Formula I:
[0075] In some embodiments, the present disclosure provides a compound represented by Formula (I):
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof; wherein:
RA is of either of the following structures:
Figure imgf000028_0002
each of which is substituted by n occurrences of R3;
R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2,
N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L2-R5, or an optionally substituted group selected from C1-6 aliphatic, C1-6 haloaliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R; or: two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with r instances of R;
L2 represents independently for each occurrence a Ci-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2- or -Cy-;
Cy represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R3 represents independently for each occurrence hydrogen, OR, Ci-6 aliphatic, Ci-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
X is O or S;
R1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, - C(O)OR, -C(O)NR2, CI-6 alkyl, or Ci-ehaloalkyl;
L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-
, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;
RB is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RB is substituted with q occurrences of R2;
R2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L'-R4; wherein R2 is substituted with p occurrences of R6;
L1 represents independently for each occurrence a C1.2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;
R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCRs, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -
N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl;
R7 is hydrogen or C1-6 alkyl; each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from Ci-6 aliphatic; C1-6 haloaliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0 or 1; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, or 5.
[0076] In some embodiments, the present invention provides a compound represented by
Formula II:
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof; wherein each of RA, X, R1, and m are as defined above and described herein for Formula I.
[0077] The definitions of variables in Formula I or II above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
[0078] In certain embodiments, the compound is a compound of Formula I.
[0079] In certain embodiments, the compound is a compound of Formula II.
[0080] The description above describes multiple embodiments relating to compounds of Formula I and II. The patent application specifically contemplates all combinations of the embodiments.
[0081] It has been surprisingly discovered that certain compounds of the present invention do not significantly penetrate the brain or minimally penetrate the brain, wherein the extent of brain penetration is measured by measuring “Kp,” i.e., the ratio of compound concentration in the brain and blood (Cbrain/Cpiasma) as demonstrated by certain assays described herein in Example 30. In some such embodiments, a compound of the present invention is characterized as having a Kp (brain) of less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, or less than about 0.1. In some embodiments, a compound of the present invention is characterized as having a Kp of less than about 0.7. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.6. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.5. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.4. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.3. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.2. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.1. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.09. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.08. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.05. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.04. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.03. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.02. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.01 . Various methods of assessing brain exposure are known to those of skill in the art and/or are described herein.
[0082] In some embodiments, for compounds with low Kp values, determination of
Figure imgf000033_0001
from the unbound compounds plasma, brain and testes concentrations also supports peripheral restriction of the compounds.
[0083] In some embodiments, it has been surprisingly discovered that compounds of the present invention are Breast Cancer Resistance Protein (BCRP) efflux substrates. The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP -binding cassette (ABC) efflux transporter. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, testis, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition.
[0084] Various methods of assessing whether a compound is a BCRP efflux substrate are known to those of skill in the art and/or are described herein, for instance in Example 29. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of about 1-fold, indicating substantially no efflux. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 1.5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 2.0-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 3.5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 4.0-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 4.5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 6-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 7-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 8-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 9-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 10-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 15-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 20-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 25-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 30-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 35-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 40-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 45-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 50-fold.
[0085] In some embodiments, it has been surprisingly discovered that certain compounds of the present invention do not significantly inhibit BCRP.
[0086] Various methods of assessing whether a compound is a BCRP inhibitor are known to those of skill in the art and/or are described herein, for instance in Example 33. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of about 400 nM, or about 500 nM, or about 600 nM, or about 700 nM, or about 800 nM, or about 900 nM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of about ImM, about 2 mM, about 3mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 5 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 1 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 1 mM and 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 1 mM and 5 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 5 mM and 10 mM. Exemplary compounds of the present invention are described further herein.
[0087] In some embodiments, it has been surprising discovered that compounds of the present invention are P-glycoprotein (PGP) efflux substrates. P-glycoprotein (PGP), an efflux membrane transporter, is also referred to in the art as multi-drug resistance protein 1 ((MDR1), permeability glycoprotein, P-gp, or Pgp, encoded by MDR1/ABCB1 and belonging to the family of ATP- binding cassette transporters), and is widely distributed throughout the body and responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances. PGP is one of the most important transporters at the blood-brain barrier (BBB), where it is highly expressed in the vessel walls of the brain capillaries functioning as an efflux pump. PGP is also located throughout the human body in organs or tissues with an excretory and/or barrier function, such as the liver, kidney, placenta, and testes.
[0088] With respect to the placenta, PGP has been found to have a role in the regulation of drug disposition to the fetus and has been extensively studied. Expression of PGP in the placental trophoblast layer has been confirmed at the mRNA and protein levels in all phases of pregnancy. Several in vitro and in vivo studies have demonstrated functional activity of the transporter in matemo-fetal drug transport. PGP is able to actively pump drugs and other xenobiotics from trophoblast cells back to the maternal circulation, thus providing protection to the fetus.
[0089] In some embodiments, compounds of the present invention are efflux substrates of BRCP. In some embodiments, compounds of the present invention are efflux substrates of PGP. In some embodiments, compounds of the present invention are efflux substrates of one or both of BCRP and PGP.
[0090] It has been further surprisingly discovered that certain compounds of the present invention afford lower testes exposure, which may lead to better spermatogonia survival and/or spermatogonia maturation. Various methods of assessing whether a compound affords lower testes exposure are known to those of skill in the art and/or are described herein, for instance in Example 30. By lower testes exposure is meant a compound measured as having a K,> (testes) of less than about 1.0, or less than about 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, or less than about 0.5, or less than about 0.4, or less than about 0.3, or less than about 0.2, or less than about 0.1, or less than about 0.09, or less than about 0.08, or less than about 0.07, or less than about 0.06, or less than about 0.05, or less than about 0.04, or 0.03, or less than about 0.02, or less than about 0.01.
[0091] In some embodiments, a compound of the present invention is not an inducer of CYP3A4, as measured by, for instance, Example 31. For instance, in some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
[0092] In some embodiments, a compound of the present invention is not an inducer of CYP1A2, as measured by, for instance, Example 31. For instance, in some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
[0093] In some embodiments, a compound of the present invention is not an inducer of CYP2C19. For instance, in some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3 -fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
[0094] In some embodiments, a compound of Formula I is administered orally, as described further herein. In some embodiments, a compound of Formula I is administered by a means other than oral administration, as described further herein.
[0095] In some embodiments, it has been unexpectedly found that certain compounds of Formula I exhibit improved solubility as compared to c-KIT inhibitors known in the art when measured according to the procedure set forth in Example 32.
[0096] In some embodiments, a compound of Formula II is administered orally, as described further herein. In some embodiments, a compound of Formula II is administered by a means other than oral administration, as described further herein. [0097] In some embodiments, it has been unexpectedly found that certain compounds of Formula II exhibit improved solubility as compared to c-KIT inhibitors known in the art when measured according to the procedure set forth in Example 32.
[0098] In some embodiments, compounds of the present invention have a solubility greater than 2.0 μM. and less than or equal to 10.0 μM.. In some embodiments, compounds of the present invention have a solubility of about 2.5 μM, about 3.0 μM, about 3.5 μM, about 4.0 μM, about 4.5 μM, about 5.0 μM, about 5.5 μM, about 6.0 μM, about 6.5 μM, about 7.0 μM.. about 7.5 μM, about 8.0 μM, about 9.0 μM, about 9.5 μM, or about 10.0 μM.. In some embodiments, compounds of the present invention have a solubility greater than 10 μM. and less than or equal to 50 μM.. In some embodiments, compounds of the present invention have a solubility of about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM.. about 40 μM, about 45 μM, or about 50 μM.. In some embodiments, compounds of the present invention have a solubility greater than 50 μM.. In some embodiments, compounds of the present invention have a solubility of about 60 μM, about 70 μM, about 80 μM, about 90 μM, about 100 μM, about 200 μM, about 300 μM, about 400 μM, 500 μM, about 600 μM, about 700 μM, about 800 μM, about 900 μM, about 1000 μM, about 1500 μM. or about 2000 μM...
[0099] In some embodiments, when L is a bond and RB is
Figure imgf000038_0001
X is S. In some embodiments, when
Figure imgf000038_0002
[00100] As described above and herein, in some embodiments, R1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C1-6 alkyl, or C1-6 haloalkyl. In some embodiments, R1 represents independently for each occurrence halogen. In some embodiments, R1 represents independently for each occurrence fluoro, chloro, or bromo. In some embodiments, R1 represents independently for each occurrence -CN. In some embodiments, R1 represents independently for each occurrence -OR. In some embodiments, R1 represents independently for each occurrence -OCH3. In some embodiments, R1 represents independently for each occurrence -NR2. In some embodiments, R1 represents independently for each occurrence -NH2. In some embodiments, R1 represents independently for each occurrence -C(O)R. In some embodiments, R1 represents independently for each occurrence -C(O)CH3. In some embodiments, R1 represents independently for each occurrence -C(O)OR. In some embodiments, R1 represents independently for each occurrence -C(0)0CH3. In some embodiments, R1 represents independently for each occurrence -C(0)NR2. In some embodiments, R1 represents independently for each occurrence -C(0)NH2. In some embodiments, R1 represents independently for each occurrence -C(0)NHCH3. In some embodiments, R1 represents independently for each occurrence -C(O)N(CH3)2. In some embodiments, R1 represents independently for each occurrence Ci-6 alkyl or Ci-6 haloalkyl. In some embodiments, R1 represents independently for each occurrence Ci-6 alkyl. In some such embodiments, R1 represents independently for each occurrence methyl. In some embodiments, R1 represents independently for each occurrence Ci-6 haloalkyl. In some such embodiments, R1 represents independently for each occurrence -CF3, -CF2H, or -CFH2. In some embodiments, at least one R1 is fluoro. In some embodiments, at least one R1 is chloro. In some embodiments, at least one R1 is bromo. In some embodiments, at least one R1 is -CN. In some embodiments, at least one R1 is -OR. In some such embodiments, at least one R1 is -OMe. In some embodiments, at least one R1 is methyl. In some embodiments, at least one R1 is -CF3. In some embodiments, at least one R1 is -CF2H. In some embodiments, at least one R1 is -CFH2.
[00101] In some embodiments, R1 is halogen, -CN, -OR, -NR2, C1-6 alkyl, or Ci-6 haloalkyl. In some embodiments, R1 is halogen. In some embodiments, R1 is fluoro, chloro, or bromo. In some embodiments, R1 is -CN. In some embodiments, R1 is -OR. In some embodiments, R1 is -NR2. In some embodiments, R1 is -NH2. In some embodiments, R1 is Ci-6 alkyl or Ci-6 haloalkyl. In some embodiments, R1 is Ci-6 alkyl. In some such embodiments, R1 is methyl. In some embodiments, R1 is C 1-6 haloalkyl. In some such embodiments, R1 is -CF3, -CF2H, or -CFH2.
[00102] In some embodiments, R1 is as depicted in Table 1, below.
[00103] In some embodiments, R1 is as described above and herein, wherein m is 0 or 1. In some such embodiments, m is 0. In some such embodiments, m is 1.
[00104] As described above and herein, R2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L'-R4; wherein R2 is substituted with p occurrences ofR6.
[00105] In some embodiments, R2 represents independently for each occurrence halogen. In some embodiments, R2 represents independently for each occurrence chloro flouro, or bromo. In some embodiments, R2 represents independently for each occurrence chloro or flouro.
[00106] In some embodiments, R2 represents independently for each occurrence Ci-6 aliphatic. In some such embodiments, R2 represents independently for each occurrence Ci-6 alkyl. In some such embodiments, R2 represents independently for each occurrence methyl, ethyl, or propyl.
[00107] In some embodiments, R2 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 7-membered saturated monocyclic carbocyclic ring.
[00108] In some embodiments, R2 represents independently for each occurrence a 3-4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 3 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 3-4 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00109] In some embodiments, R2 represents independently for each occurrence a 5 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 5 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00110] In some embodiments, R2 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 3 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. In some embodiments, R2 represents independently for each occurrence a 5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00111] In some embodiments, R2 represents independently for each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00112] In some embodiments, R2 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00113] In some embodiments, R2 represents independently for each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence an 8- 10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence an 8 membered bicyclic heteroaryl ring having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 9 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00114] In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00115] In some embodiments, R2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0 heteroatoms. In some embodiments, R2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00116] In some embodiments, R2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00117] In some embodiments, R2 represents independently for each occurrence L1-R4. [00118] In some embodiments, R2 is C1-6 aliphatic. In some such embodiments, R2 is C1-6 alkyl. In some such embodiments, R2 is methyl, ethyl, or propyl. In some embodiments, R2 is - CH2CH(OH)CH3. [00119] In some embodiments, R2 is halogen. In some embodiments, R2 is flouro or chloro. In some embodiments, R2 is flouro. [00120] In some embodiments, R2 is oxo. In some embodiments, R2 is phenyl.
[00121] In some embodiments, R2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R2 is a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 7-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 3-4 membered saturated monocyclic carbocyclic ring.
[00122] In some embodiments, R2 is a 3-4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 3 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 3-4 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00123] In some embodiments, R2 is a 5 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 5 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00124] In some embodiments, R2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 3 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 4 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. In some embodiments, R2 is a 5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00125] In some embodiments, R2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 4-5 membered monocyclic heterocyclic ring having 1 nitrogen atom. In some embodiments, R2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00126] In some embodiments, R2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00127] In some embodiments, R2 is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an 8 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 9 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00128] In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00129] In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0 heteroatoms. In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00130] In some embodiments, R2 is a 6-1 1 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00131] In some embodiments, R2 is I?-R4.
[00132] As described above and herein, each L1 represents independently for each occurrence a Ci-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L1 is a Ci-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)- , -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. As described above and defined herein, L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2- In some embodiments, L is a bond. In some embodiments, L is -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.
[00133] In some embodiments, L1 is -O-, -C(O)-, -OC(O)-, or -C(O)O-.
[00134] As described above and defined herein, R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00135] In some embodiments, R4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00136] As described above and herein, R6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl. [00137] In some embodiments, R6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, or -N(R)CN. [00138] In some embodiments, R6 represents independently for each occurrence halogen, -CN, -OR, or -S(O)2R. In some embodiments, R6 represents independently for each occurrence fluoro, -CN, or -OH.
[00139] In some embodiments, at least one R6 is halogen. In some embodiments, at least one R6 is fluoro. In some embodiments, at least two R6 are fluoro. In some embodiments, at least one R6 is methyl. In some embodiments, at least one R6 is cyano.
[00140] As described above and herein, R7 is hydrogen or C1-3 alkyl. In some embodiments, R7 is hydrogen. In some embodiments, R7 is C1-3 alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is as depicted in Table 1, below.
[00141] In some embodiments, R2 is selected from:
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
[00143] In some embodiments, R2 is selected from:
Figure imgf000054_0002
[00144] In some embodiments, R2 is selected from:
Figure imgf000054_0003
[00145] In some embodiments, R2 is as described above and herein, wherein R2 is substituted with p occurrences of R6. In some such embodiments, p is 0. In some such embodiments, p is 1. In some such embodiments, p is 2. In some such embodiments, p is 3. In some such embodiments, p is 4. In some such embodiments, p is 5.
[00146] In some embodiments, R2 is as depicted in Table 1, below.
[00147] As described above and herein, RA is of either of the following structures:
Figure imgf000054_0004
each of which is substituted by n occurrences of R3.
[00148] In some embodiments, RA is
Figure imgf000054_0005
. In some embodiments, RA is
Figure imgf000054_0006
[00149] In some embodiments, RA is any of those depicted in Table 1 below. [00150] As described above and herein, each RA is substituted by n occurrences of R3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.
[00151] As descibed above and herein RB is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RB is substituted with q occurrences of R2.
[00152] In some embodiments, RB is phenyl. In some embodiments, RB is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with q occurrences of R2. In some embodiments, RB is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q occurrences of R2. In some embodiments, RB is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q occurrences of R2.
[00153] In some embodiments, RB is selected from:
Figure imgf000055_0001
[00154] As described above and herein, R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L2-R5, or an optionally substituted group selected from C1-6 aliphatic, C1-6 haloaliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R; or: two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is substituted with r instance of R.
[00155] In some embodiments, R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or -L2-R5.
[00156] In some embodiments, R3 represents independently for each occurrence halogen. In some embodiments, R3 is halogen. In some embodiments, R3 is -CN. In some embodiments, at least one R3 is fluoro. In some embodiments, at least one R3 is chloro. In some embodiments, at least one R3 is bromo. In some embodiments, at least one R3 is -CN. In some embodiments, at least one R3 is -OR. In some embodiments, wherein at least one R3 is -OR, wherein R is C1-6 alkyl. In some embodiments, at least one R3 is -OR, wherein R is methyl, ethyl, or propyl. In some embodiments, at least one R3 is -OR, wherein R is methyl. In some embodiments, at least one R3 is -OR, wherein R is ethyl. In some embodiments, at least one R3 is -OR, wherein R is propyl. In some embodiments, at least one R3 is -OCR3, wherein at least one R is fluoro. In some embodiments, at least one R3 is -NR2. In some embodiments, wherein at least one R3 is -NR2, at least one R is hydrogen. In some embodiments, wherein at least one R3 is -NR2, at least one R is methyl or ethyl. In some embodiments, wherein at least one R3 is -NR2, at least one R is optionally substituted phenyl. In some embodiments, wherein at least one R3 is -NR2, the two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R3 is - N(R)S(O)2R. In some such embodiments, each R is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, naphthalenyl, or a 5-membered heteroaryl ring having one, two, or three heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00157] In some embodiments, at least one R3 is -L2-R5. In some such embodiments, one, two, or three methylene units of L2 are independently replaced by -O- or -Cy-. In some such embodiments, one, two, or three methylene units of L2 are independently replaced by -N(R)- or - Cy-.
[00158] In some embodiments, at least one R3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, at least one R3 is oxetane.
[00159] In some embodiments, at least one R3 is -CF3, -CF2H, or -CFH2.
[00160] In some embodiments, R3 represents independently for each occurrence C1-6 aliphatic or Ci-6 haloaliphatic.
[00161] In some embodiments, R3 represents independently for each occurrence phenyl or naphthalenyl.
[00162] In some embodiments, R3 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. [00163] In some embodiments, R3 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00164] In some embodiments, R3 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00165] In some embodiments, R3 represents independently for each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00166] In some embodiments, R3 represents independently for each occurrence a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00167] In some embodiments, R3 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00168] In some embodiments, R3 represents independently for each occurrence or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00169] In some embodiments, two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 5 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having one heteroatom independently selected from oxygen.
[00170] In some embodiments, R3 represents independently for each occurrence -L2-R5.
[00171] As described above and herein, each L2 represents independently for each occurrence a Ci-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)- , -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- , -S(O)2- or -Cy-. In some embodiments, each L2 represents independently for each occurrence a Ci-6 bivalent saturated straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2- or -Cy-.
[00172] As described above and herein, -Cy- represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00173] In some embodiments, -Cy- represents independently for each occurrence phenyl.
[00174] In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated monocyclic carbocyclic ring. In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00175] As described above and herein, R5 represents independently for each occurrence hydrogen, OR, Ci-6 aliphatic, Ci-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 represents independently for each occurrence hydrogen. In some embodiments, R5 represents independently for each occurrence OR. In some such embodiments, R5 represents independently for each occurrence OH or OMe. In some embodiments, R5 represents independently for each occurrence Ci-6 aliphatic or Ci-6 haloaliphatic. In some embodiments, R? represents independently for each occurrence phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00176J In some embodiments, each R3 group is independently substituted with r instances of R. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5.
[00177] In some embodiments, R3 is independently for each occurrence selected from:
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
[00178] In some embodiments, R3 is -OMe or -OiPr.
[00179] In some embodiments, R3 is as depicted in Table 1 below.
[00180] In some embodiments X is O. In some embodiments, X is S.
[00181] As defined above and herein, R is independently for each occurrence, hydrogen, -CN, halogen, or an optionally substituted group selected from Ci-6 aliphatic; Ci-6 haloaliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00182] In some embodiments, R is independently for each occurrence hydrogen, -CN, halogen, or an optionally substituted Ci-6 aliphatic. In some embodiments, R is independently for each occurrence hydrogen. In some embodiments, R is fluoro. In some embodiments, R is independently for each occurrence an optionally substituted Ci-6 alkyl. In some such embodiments, R is methyl.
[00183] In some embodiments, R is independently for each occurrence an optionally substituted group selected from phenyl or naphthalenyl. In some embodiments, R is Ci-6 haloaliphatic.
[00184] In some embodiments, R is independently for each occurrence an optionally substituted group selected from a a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00185] In some embodiments, two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00186] In some embodiments, a compound of the present disclosure is represented by any of the following or a pharmaceutically acceptable salt thereof:
Figure imgf000064_0001
I-c I-d wherein RA, R1, X, L, and RB are as defined above and described herein.
[00187] In some embodiments, a compound of the present disclosure is represented by the following or a pharmaceutically acceptable salt thereof:
Figure imgf000064_0002
I-e wherein RA, R1, X, L, and RB are as defined above and described herein.
[00188] In some embodiments, a compound of the present disclosure is represented by either of the following or a pharmaceutically acceptable salt thereof:
Figure imgf000065_0001
wherein RA, R1, L, and RB are as defined above and described herein.
[00189] In some embodiments, a compound of the present disclosure is represented by any of the following or a pharmaceutically acceptable salt thereof
Figure imgf000065_0002
wherein R1, R3, L, and RB are as defined above and described herein. In some such embodiments,
R3 is -OiPr, -CH2O(CH2)2OH, or -CH2OCH2C(CH3)2OH, and R2 is selected from F A-/
Figure imgf000065_0003
[00190] In some embodiments, a compound of the present disclosure is represented by the following, or a pharmaceutically acceptable salt thereof:
Figure imgf000066_0001
I-m wherein R1, R2, and RA are as defined above and described herein.
[00191] In some embodiments, a compound is of any of formulae I-a - I-m above, wherein n is 0. In some embodiments, a compound is of any of formulae I-a - I-m above, wherein n is i.
Formula 1-1:
[00192] In some embodiments, the present disclosure provides a compound represented by Formula (1-1):
Figure imgf000066_0002
(1-1) or a pharmaceutically acceptable salt thereof; wherein:
RA is of either of the following structures:
Figure imgf000066_0003
each of which is substituted by n occurrences of R3;
R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, –N(R)NR2, -N(R)S(O)2NR2, – N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, -L2-R5, or an optionally substituted group selected from C1-6 aliphatic, C1-6 haloaliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R; or: two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with r instances of R; L2 represents independently for each occurrence a C1-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by –C(R)2-, –N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, –S(O)2- or -Cy-; Cy represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5 represents independently for each occurrence hydrogen, OR, C1-6 aliphatic, C1-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; X is O or S;
R1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, - C(O)OR, -C(0)NR2, CI-6 alkyl, or Ci-ehaloalkyl;
L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;
RB is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RB is substituted with q occurrences of R2;
R2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L'-R1; wherein R2 is substituted with p occurrences of R6;
L1 represents independently for each occurrence a C1.2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;
R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -
N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl; each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from C1-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, or 5. [00193] In some embodiments, the present invention provides a compound represented by
Formula II- 1 :
Figure imgf000070_0001
(II-l) or a pharmaceutically acceptable salt thereof; wherein each of RA, X, R1, and m are as defined above and described herein for Formula 1-1.
[00194] The definitions of variables in Formula 1-1 or II-l above encompass multiple chemical groups. The application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
[00195] In certain embodiments, the compound is a compound of Formula 1-1.
[00196] In certain embodiments, the compound is a compound of Formula II-l.
[00197] The description above describes multiple embodiments relating to compounds of Formula 1-1 and II-l. The patent application specifically contemplates all combinations of the embodiments.
[00198] It has been surprisingly discovered that certain compounds of the present invention do not significantly penetrate the brain or minimally penetrate the brain, wherein the extent of brain penetration is measured by measuring “Kp,” i.e., the ratio of compound concentration in the brain and blood (Cbrain/Cpiasma) as demonstrated by certain assays described herein in Example 30. In some such embodiments, a compound of the present invention is characterized as having a K/; (brain) of less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2, or less than about 0.1. In some embodiments, a compound of the present invention is characterized as having a Kp of less than about 0.7. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.6. In some embodiments, a compound of the present invention is characterized by having a I<;> of less than about 0.5. In some embodiments, a compound of the present invention is characterized by having a I<;> of less than about 0.4. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.3. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.2. In some embodiments, a compound of the present invention is characterized by having a K/; of less than about 0.1. In some embodiments, a compound of the present invention is characterized by having a KP of less than about 0.09. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.08. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.05. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.04. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.03. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.02. In some embodiments, a compound of the present invention is characterized by having a Kp of less than about 0.01. Various methods of assessing brain exposure are known to those of skill in the art and/or are described herein.
[00199] In some embodiments, for compounds with low Kp values, determination of Kp„„ from the unbound compounds plasma, brain and testes concentrations also supports peripheral restriction of the compounds.
[00200] In some embodiments, it has been surprisingly discovered that compounds of the present invention are Breast Cancer Resistance Protein (BCRP) efflux substrates. The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, testis, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition.
[00201] Various methods of assessing whether a compound is a BCRP efflux substrate are known to those of skill in the art and/or are described herein, for instance in Example 29. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of about 1-fold, indicating substantially no efflux. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 1 .5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 2.0-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 3.5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 4.0-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 4.5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 5-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 6-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 7-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 8-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 9-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 10-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 15-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 20-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 25-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 30-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 35-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 40-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 45-fold. In some embodiments, a compound of the present invention exhibits an efflux ratio (ER) of at least about 50-fold.
[00202] In some embodiments, it has been surprisingly discovered that certain compounds of the present invention do not significantly inhibit BCRP.
[00203] Various methods of assessing whether a compound is a BCRP inhibitor are known to those of skill in the art and/or are described herein, for instance in Example 33. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of about 400 nM, or about 500 nM, or about 600 nM, or about 700 nM, or about 800 nM, or about 900 nM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of about ImM, about 2 mM, about 3mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM. Tn some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 5 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 500 nM and 1 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 1 mM and 10 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 1 mM and 5 mM. In some embodiments, compounds of the present invention have a BCRP inhibition IC50 of between about 5 mM and 10 mM. Exemplary compounds of the present invention are described further herein.
[00204] In some embodiments, it has been surprising discovered that compounds of the present invention are P-glycoprotein (PGP) efflux substrates. P-glycoprotein (PGP), an efflux membrane transporter, is also referred to in the art as multi-drug resistance protein 1 ((MDR1), permeability glycoprotein, P-gp, or Pgp, encoded by MDR1/ABCB1 and belonging to the family of ATP- binding cassette transporters), and is widely distributed throughout the body and responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances. PGP is one of the most important transporters at the blood-brain barrier (BBB), where it is highly expressed in the vessel walls of the brain capillaries functioning as an efflux pump. PGP is also located throughout the human body in organs or tissues with an excretory and/or barrier function, such as the liver, kidney, placenta, and testes.
[00205] With respect to the placenta, PGP has been found to have a role in the regulation of drug disposition to the fetus and has been extensively studied. Expression of PGP in the placental trophoblast layer has been confirmed at the mRNA and protein levels in all phases of pregnancy. Several in vitro and in vivo studies have demonstrated functional activity of the transporter in matemo-fetal drug transport. PGP is able to actively pump drugs and other xenobiotics from trophoblast cells back to the maternal circulation, thus providing protection to the fetus.
[00206] In some embodiments, compounds of the present invention are efflux substrates of BRCP. In some embodiments, compounds of the present invention are efflux substrates of PGP. In some embodiments, compounds of the present invention are efflux substrates of one or both of BCRP and PGP. [00207] It has been further surprisingly discovered that certain compounds of the present invention afford lower testes exposure, which may lead to better spermatogonia survival and/or spermatogonia maturation. Various methods of assessing whether a compound affords lower testes exposure are known to those of skill in the art and/or are described herein, for instance in Example 30. By lower testes exposure is meant a compound measured as having a K,, (testes) of less than about 1.0, or less than about 0.9, or less than about 0.8, or less than about 0.7, or less than about 0.6, or less than about 0.5, or less than about 0.4, or less than about 0.3, or less than about 0.2, or less than about 0.1, or less than about 0.09, or less than about 0.08, or less than about 0.07, or less than about 0.06, or less than about 0.05, or less than about 0.04, or 0.03, or less than about 0.02, or less than about 0.01.
[00208] In some embodiments, a compound of the present invention is not an inducer of CYP3A4, as measured by, for instance, Example 31. For instance, in some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
[00209] In some embodiments, a compound of the present invention is not an inducer of CYP1A2, as measured by, for instance, Example 31. For instance, in some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold.
[00210] In some embodiments, a compound of the present invention is not an inducer of CYP2C19. For instance, in some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 10-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 9-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 8-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 7-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 6-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 5-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 4-fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 3 -fold. In some embodiments, a compound of the present invention when measured as described herein exhibits an induction fold of less than or equal to about 2-fold. [00211] In some embodiments, a compound of Formula 1-1 is administered orally, as described further herein. In some embodiments, a compound of Formula 1-1 is administered by a means other than oral administration, as described further herein.
[00212] In some embodiments, it has been unexpectedly found that certain compounds of Formula 1-1 exhibit improved solubility as compared to c-KIT inhibitors known in the art when measured according to the procedure set forth in Example 32.
[00213] In some embodiments, a compound of Formula II- 1 is administered orally, as described further herein. In some embodiments, a compound of Formula II-l is administered by a means other than oral administration, as described further herein.
[00214] In some embodiments, it has been unexpectedly found that certain compounds of Formula II- 1 exhibit improved solubility as compared to c-KIT inhibitors known in the art when measured according to the procedure set forth in Example 32.
[00215] In some embodiments, compounds of the present invention have a solubility greater than 2.0 μM. and less than or equal to 10.0 μM.. In some embodiments, compounds of the present invention have a solubility of about 2.5 μM, about 3.0 μM, about 3.5 μM, about 4.0 μM, about 4.5 μM, about 5.0 μM, about 5.5 μM, about 6.0 μM, about 6.5 μM, about 7.0 μM, about 7.5 μM, about 8.0 μM, about 9.0 μM, about 9.5 μM, or about 10.0 μM.. In some embodiments, compounds of the present invention have a solubility greater than 10 μM. and less than or equal to 50 μM.. In some embodiments, compounds of the present invention have a solubility of about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, or about 50 μM.. In some embodiments, compounds of the present invention have a solubility greater than 50 μM.. In some embodiments, compounds of the present invention have a solubility of about 60 μM, about 70 μM, about 80 μM, about 90 μM, about 100 μM, about 200 μM, about 300 μM, about 400 μM, 500 μM, about 600 μM, about 700 μM, about 800 μM, about 900 μM, about 1000 μM, about 1500 μM. or about 2000 μM.. [00216J In some embodiments, when L is a bond and RB is X is S. In some
Figure imgf000077_0001
embodiments, when RB is X is S.
Figure imgf000077_0002
[00217] As described above and herein, in some embodiments, R1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, C1-6 alkyl, or C1-6 haloalkyl. In some embodiments, R1 represents independently for each occurrence halogen. In some embodiments, R1 represents independently for each occurrence fluoro, chloro, or bromo. In some embodiments, R1 represents independently for each occurrence -CN. In some embodiments, R1 represents independently for each occurrence -OR. In some embodiments, R1 represents independently for each occurrence -OCH3. In some embodiments, R1 represents independently for each occurrence -NR2. In some embodiments, R1 represents independently for each occurrence -NH2. In some embodiments, R1 represents independently for each occurrence -C(O)R. In some embodiments, R1 represents independently for each occurrence -C(O)CH3. In some embodiments, R1 represents independently for each occurrence -C(O)OR. In some embodiments, R1 represents independently for each occurrence -C(O)OCH3. In some embodiments, R1 represents independently for each occurrence -C(O)NR2. In some embodiments, R1 represents independently for each occurrence -C(O)NH2. In some embodiments, R1 represents independently for each occurrence -C(O)NHCH3. In some embodiments, R1 represents independently for each occurrence -C(O)N(CH3)2. In some embodiments, R1 represents independently for each occurrence C1-6 alkyl or C1-6 haloalkyl. In some embodiments, R1 represents independently for each occurrence Cue alkyl. In some such embodiments, R1 represents independently for each occurrence methyl. In some embodiments, R1 represents independently for each occurrence C1-6 haloalkyl. In some such embodiments, R1 represents independently for each occurrence -CF3, -CF2H, or -CFH2. In some embodiments, at least one R1 is fluoro. In some embodiments, at least one R1 is chloro. In some embodiments, at least one R1 is bromo. In some embodiments, at least one R1 is -CN. In some embodiments, at least one R1 is -OR. In some such embodiments, at least one R1 is -OMe. In some embodiments, at least one R1 is methyl. In some embodiments, at least one R1 is -CF3. In some embodiments, at least one R1 is -CF2H. In some embodiments, at least one R1 is -CFH2. [00218] In some embodiments, R1 is halogen, -CN, -OR, -NR2, C1-6 alkyl, or C1-6 haloalkyl. In some embodiments, R1 is halogen. In some embodiments, R1 is fluoro, chloro, or bromo. In some embodiments, R1 is -CN. In some embodiments, R1 is -OR. In some embodiments, R1 is -NR2. In some embodiments, R1 is -NH2. In some embodiments, R1 is C1-6 alkyl or C1-6 haloalkyl. In some embodiments, R1 is C1-6 alkyl. In some such embodiments, R1 is methyl. In some embodiments, R1 is C1-6 haloalkyl. In some such embodiments, R1 is -CF3, -CF2H, or -CFH2. [00219] In some embodiments, R1 is as depicted in Table 1, below. [00220] In some embodiments, R1 is as described above and herein, wherein m is 0, 1, 2, 3, or 4. In some such embodiments, m is 0. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, m is 3. In some such embodiments, m is 4. [00221] As described above and herein, R2 represents independently for each occurrence halogen, oxo, C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L1-R4; wherein R2 is substituted with p occurrences of R6. [00222] In some embodiments, R2 represents independently for each occurrence halogen. In some embodiments, R2 represents independently for each occurrence chloro flouro, or bromo. In some embodiments, R2 represents independently for each occurrence chloro or flouro. [00223] In some embodiments, R2 represents independently for each occurrence C1-6 aliphatic. In some such embodiments, R2 represents independently for each occurrence C1-6 alkyl. In some such embodiments, R2 represents independently for each occurrence methyl, ethyl, or propyl. [00224] In some embodiments, R2 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 represents independently for each occurrence a 7-membered saturated monocyclic carbocyclic ring.
[00225] In some embodiments, R2 represents independently for each occurrence a 3-4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 3 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 3-4 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00226] In some embodiments, R2 represents independently for each occurrence a 5 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 5 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00227] In some embodiments, R2 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 3 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. In some embodiments, R2 represents independently for each occurrence a 5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00228] In some embodiments, R2 represents independently for each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of R6. In some embodiments, R2 represents independently for each occurrence a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00229] In some embodiments, R2 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00230] In some embodiments, R2 represents independently for each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence an 8- 10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence an 8 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 9 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00231] In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 represents independently for each occurrence a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00232] In some embodiments, R2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0 heteroatoms. In some embodiments, R2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00233] In some embodiments, R2 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00234] In some embodiments, R2 represents independently for each occurrence Lx-R4.
[00235] In some embodiments, R2 is Ci-6 aliphatic. In some such embodiments, R2 is Ci-6 alkyl. In some such embodiments, R2 is methyl, ethyl, or propyl. In some embodiments, R2 is - CH2CH(OH)CH3.
[00236] In some embodiments, R2 is halogen. In some embodiments, R2 is flouro or chloro. In some embodiments, R2 is flouro.
[00237] In some embodiments, R2 is oxo. In some embodiments, R2 is phenyl.
[00238] In some embodiments, R2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R2 is a 3-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 4-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 5-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 6-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 7-membered saturated monocyclic carbocyclic ring. In some embodiments, R2 is a 3-4 membered saturated monocyclic carbocyclic ring.
[00239] In some embodiments, R2 is a 3-4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 3 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 4 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 3-4 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00240] In some embodiments, R2 is a 5 membered saturated monocyclic carbocyclic ring substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 5 membered saturated monocyclic carbocyclic ring substituted with 1-2 occurrences of R6 In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00241] In some embodiments, R2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 3 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 4 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 4 membered saturated monocyclic heterocyclic ring having 1 heteroatom independently selected from nitrogen. In some embodiments, R2 is a 5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00242] In some embodiments, R2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of R6. In some embodiments, R2 is a 4-5 membered monocyclic heterocyclic ring having 1 nitrogen atom. In some embodiments, R2 is a 4-5 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 occurrences of R6. In some such embodiments, at least one R6 is fluoro. In some such embodiments, two R6 are fluoro. In some such embodiments, at least one R6 is methyl. In some such embodiments, at least one R6 is -CN.
[00243] In some embodiments, R2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00244] In some embodiments, R2 is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is an 8 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 9 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00245] In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0 heteroatoms. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00246] In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0 heteroatoms. In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated spirocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00247J In some embodiments, R2 is a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00248] In some embodiments, R2 is I?-R4.
[00249] As described above and herein, each L1 represents independently for each occurrence a Ci-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or - S(O)2-. In some embodiments, L1 is a C1-2 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)- , -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. As described above and defined herein, L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L is a bond. In some embodiments, L is -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.
[00250] In some embodiments, L1 is -O-, -C(O)-, -OC(O)-, or -C(O)O-.
[00251] As described above and defined herein, R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00252] In some embodiments, R4 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00253] As described above and herein, R6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl. [00254] In some embodiments, R6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, N(R)NR2, -N(R)S(O)2NR2, N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, or -N(R)CN.
[00255] In some embodiments, R6 represents independently for each occurrence halogen, -CN, -OR, or -S(O)2R. In some embodiments, R6 represents independently for each occurrence fluoro, -CN, or -OH.
[00256] In some embodiments, at least one R6 is halogen. In some embodiments, at least one R6 is fluoro. In some embodiments, at least two R6 are fluoro. In some embodiments, at least one R6 is methyl. In some embodiments, at least one R6 is cyano.
[00257] In some embodiments, R2 is selected from:
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
[00259] In some embodiments, R2 is selected from:
Figure imgf000092_0002
[00260] In some embodiments, R2 is selected from:
Figure imgf000093_0001
[00261] In some embodiments, R2 is as described above and herein, wherein R2 is substituted with p occurrences of R6. In some such embodiments, p is 0. In some such embodiments, p is 1. In some such embodiments, p is 2. In some such embodiments, p is 3. In some such embodiments, p is 4. In some such embodiments, p is 5.
[00262] In some embodiments, R2 is as depicted in Table 1, below.
[00263] As described above and herein, RA is of either of the following structures:
Figure imgf000093_0002
each of which is substituted by n occurrences of R3.
[00264] In some embodiments, RA is
Figure imgf000093_0003
In some embodiments, RA is
Figure imgf000093_0004
[00265] In some embodiments, RA is any of those depicted in Table 1 below.
[00266] As described above and herein, each RA is substituted by n occurrences of R3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.
[00267] As descibed above and herein RB is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RB is substituted with q occurrences of R2.
[00268] In some embodiments, RB is phenyl. In some embodiments, RB is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with q occurrences of R2. In some embodiments, RB is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q occurrences of R2. In some embodiments, RB is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q occurrences of R2.
[00269] In some embodiments, RB is selected from:
Figure imgf000094_0001
[00270] As described above and herein, R3 represents independently for each occurrence oxo, halogen, CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L2-R5, or an optionally substituted group selected from C1-6 aliphatic, C1-6 haloaliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-1 1 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R; or: two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is substituted with r instance of R.
[00271] In some embodiments, R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, - C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or -L2-R5.
[00272] In some embodiments, R3 represents independently for each occurrence halogen. In some embodiments, R3 is halogen. In some embodiments, R3 is -CN. In some embodiments, at least one R3 is fluoro. In some embodiments, at least one R3 is chloro. In some embodiments, at least one R3 is bromo. In some embodiments, at least one R3 is -CN. In some embodiments, at least one R3 is -OR. In some embodiments, wherein at least one R3 is -OR, wherein R is Ci-6 alkyl. In some embodiments, at least one R3 is -OR, wherein R is methyl, ethyl, or propyl. In some embodiments, at least one R3 is -OR, wherein R is methyl. In some embodiments, at least one R3 is -OR, wherein R is ethyl. In some embodiments, at least one R3 is -OR, wherein R is propyl. In some embodiments, at least one R3 is -OCRs, wherein at least one R is fluoro. In some embodiments, at least one R3 is -NR2. In some embodiments, wherein at least one R3 is -NR2, at least one R is hydrogen. In some embodiments, wherein at least one R3 is -NR2, at least one R is methyl or ethyl. In some embodiments, wherein at least one R3 is -NR2, at least one R is optionally substituted phenyl. In some embodiments, wherein at least one R3 is -NR2,the two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R3 is - N(R)S(O)2R. In some such embodiments, each R is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, naphthalenyl, or a 5-membered heteroaryl ring having one, two, or three heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00273] In some embodiments, at least one R3 is -L2-R5 In some such embodiments, one, two, or three methylene units of L2 are independently replaced by -O- or -Cy-. In some such embodiments, one, two, or three methylene units of L2 are independently replaced by -N(R)- or - Cy-.
[00274] In some embodiments, at least one R3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, at least one R3 is oxetane.
[00275] In some embodiments, at least one R3 is -CF3, -CF2H, or -CFH2.
[00276] In some embodiments, R3 represents independently for each occurrence C1-6 aliphatic or C1-6 haloaliphatic.
[00277] In some embodiments, R3 represents independently for each occurrence phenyl or naphthal enyl.
[00278] In some embodiments, R3 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
[00279] In some embodiments, R3 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00280] In some embodiments, R3 represents independently for each occurrence a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00281] In some embodiments, R3 represents independently for each occurrence an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00282] In some embodiments, R3 represents independently for each occurrence a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00283] In some embodiments, R3 represents independently for each occurrence a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00284] In some embodiments, R3 represents independently for each occurrence or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00285] In some embodiments, two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 5 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having one heteroatom independently selected from oxygen.
[00286] In some embodiments, R3 represents independently for each occurrence -L2-R5.
[00287] As described above and herein, each L2 represents independently for each occurrence a Ci-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)- , -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- , -S(O)2- or -Cy-. In some embodiments, each L2 represents independently for each occurrence a Ci-6 bivalent saturated straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2- or -Cy-.
[00288] As described above and herein, -Cy- represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00289] In some embodiments, -Cy- represents independently for each occurrence phenyl. [00290] In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated monocyclic carbocyclic ring. In some embodiments, -Cy- represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00291] As described above and herein, R5 represents independently for each occurrence hydrogen, OR, C1-6 aliphatic, C1-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5 represents independently for each occurrence hydrogen. In some embodiments, R5 represents independently for each occurrence OR. In some such embodiments, R5 represents independently for each occurrence OH or OMe. In some embodiments, R5 represents independently for each occurrence C1-6 aliphatic or C1-6 haloaliphatic. In some embodiments, R5 represents independently for each occurrence phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00292] In some embodiments, each R3 group is independently substituted with r instances of R. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. [00293] In some embodiments, R3 is independently for each occurrence selected from:
Figure imgf000099_0001
O H S N HO O ,
Figure imgf000100_0001
[00294] In some embodiments, R is -OMe or -OiPr. [00295] In some embodiments, R3 is as depicted in Table 1 below. [00296] In some embodiments X is O. In some embodiments, X is S. [00297] As defined above and herein, R is independently for each occurrence, hydrogen, -CN, halogen, or an optionally substituted group selected from C1-6 aliphatic; phenyl; naphthalenyl; a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00298] In some embodiments, R is independently for each occurrence hydrogen, -CN, halogen, or an optionally substituted Ci-6 aliphatic. In some embodiments, R is independently for each occurrence hydrogen. In some embodiments, R is fluoro. In some embodiments, R is independently for each occurrence an optionally substituted Ci-6 alkyl. In some such embodiments, R is methyl.
[00299] In some embodiments, R is independently for each occurrence an optionally substituted group selected from phenyl or naphthal enyl.
[00300] In some embodiments, R is independently for each occurrence an optionally substituted group selected from a a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00301] In some embodiments, two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00302] In some embodiments, a compound of the present disclosure is represented by any of the following or a pharmaceutically acceptable salt thereof:
Figure imgf000102_0001
I-c-1 I-d-1 wherein RA, R1, X, L, and RB are as defined above and described herein.
[00303] In some embodiments, a compound of the present disclosure is represented by the following or a pharmaceutically acceptable salt thereof
Figure imgf000103_0001
I-e-1 wherein RA, R1, X, L, and RB are as defined above and described herein.
[00304] In some embodiments, a compound of the present disclosure is represented by either of the following or a pharmaceutically acceptable salt thereof
Figure imgf000103_0002
I-f-1 I-g-1 wherein RA, R1, L, and RB are as defined above and described herein.
[00305] In some embodiments, a compound of the present disclosure is represented by any of the following or a pharmaceutically acceptable salt thereof
Figure imgf000104_0001
I-k-1 1-1-1 wherein R1, R3, L, and RB are as defined above and described herein. In some such embodiments,
A'"/ selected from F
Figure imgf000104_0002
[00306] In some embodiments, a compound of the present disclosure is represented by the following, or a pharmaceutically acceptable salt thereof:
Figure imgf000104_0003
I-m-1 wherein R1, R2, and RA are as defined above and described herein. In some embodiments, a compound is of any of formulae I-a-1 - I-m-1 above, wherein n is 0. In some embodiments, a compound is of any of formulae I-a-1 - I-m-1 above, wherein n is 1.
[00307] In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from Compound II- 1 to II- 70 of Table 1, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound selected from Compound II- 1 to 11-70 of Table 1.
TABLE 1.
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
ʼnll
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
II. Therapeutic Applications
C-Kit Kinase Mediated Diseases and Disorders
[00308] It is contemplated that compounds described herein, such those of Formula I, provide therapeutic benefits to subjects suffering from a c-kit kinase-mediated disease, disorder or condition. Accordingly, one aspect of the invention provides a method of treating a disorder associated with c-kit kinase in a subject. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to a subject in need thereof to treat the disorder. In certain embodiments, the compound is a compound of any of Formulae I, II, I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-i, I-j, I-k, 1-1, or I-m defined by one of the embodiments described above.
[00309] It is contemplated that compounds described herein, such those of Formula 1-1, provide therapeutic benefits to subjects suffering from a c-kit kinase-mediated disease, disorder or condition. Accordingly, one aspect of the invention provides a method of treating a disorder associated with c-kit kinase in a subject. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula 1-1, to a subject in need thereof to treat the disorder. In certain embodiments, the compound is a compound of any of Formulae 1-1, 11-1, I-a-1, I-b- 1, 1-c-1, 1-d-1, 1-e-1, 1-f-1, 1-g-1, 1-h-1, 1-i-1, 1- j-1, I-k- 1 , 1-1-1, or I-m-1 defined by one of the embodiments described above.
[00310] In some embodiments, the c-kit kinase-mediated disease, disorder or condition is associated with wild-type c-kit kinase. In some embodiments, the c-kit kinase-mediated disease, disorder or condition is associated with mutant c-kit kinase.
[00311] In some embodiments, the kit mutation is selected from D419, D816Y, D816F, N822, V559, K558Q, I517P, Duplication 572-573, V559A, V559D, W557R, V560G, L576P, K642E, D820V, V560G, D52N, D816V, D816, V825A, E490K, W557R, V559A, V560Del, V560G, K642E, V654A, D816H, D820E, A829P, T417, Y418, D419, A502, K5091, V530I, F552C, A533D, V560, ITD, V559D, K704, N705, S715, 1748T, L773S, V8251, and D816N.
[00312] Non-limiting examples of the c-kit kinase-mediated disease include Acute Myeloid Leukemia, Mastocytosis, AMI-HMCI-cell line, GIST, Melanoma, Myeloproliferative Disease, Renal Cell Carcinoma, Papillary renal carcinoma, Sinonasal NK/Tcell Lymphoma, Thymic Carcinoma, Acute Lymphoblastic leukemia, Germ cell tumor, Acute Myelogenous Leukemia, and Extranodal NK/T cell lymphoma.
[00313] The method may be further characterized according to the c-kit kinase mediated disease or disorder that is to be treated in the patient. In some embodiments, the c-kit kinase mediated disease or disorder is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a dermatological disease, an allergic disease, a cardiovascular disease, or a neurological disorder. In some embodiments, the c-kit kinase mediated disease or disorder is a mast-cell associated disease. In some embodiments, the c-kit kinase mediated disease or disorder is an inflammatory disorder. In some embodiments, the c-kit kinase mediated disease or disorder is an autoimmune disorder. In some embodiments, the c-kit kinase mediated disease or disorder is a metabolic disease. In some embodiments, the c-kit kinase mediated disease or disorder is a fibrotic disease. In some embodiments, the c-kit kinase mediated disease or disorder is a dermatological disease. In some embodiments, the c-kit kinase mediated disease or disorder is an allergic disease. In some embodiments, the c-kit kinase mediated disease or disorder is a cardiovascular disease. In some embodiments, the c-kit kinase mediated disease or disorder is a neurological disorder.
[00314] In some embodiments, the disease or disorder is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn’s disease, or systemic and cutaneous lupus erythematosus and dermatomyositis. In some embodiments, the disease or disorder is asthma. In some embodiments, the disease or disorder is allergic rhinitis. In some embodiments, the disease or disorder is pulmonary arterial hypertension (PAH). In some embodiments, the disease or disorder is primary pulmonary hypertension (PPH). In some embodiments, the disease or disorder is pulmonary fibrosis. In some embodiments, the disease or disorder is hepatic fibrosis. In some embodiments, the disease or disorder is cardiac fibrosis. In some embodiments, the disease or disorder is scleroderma. In some embodiments, the disease or disorder is irritable bowel syndrome (IBS). In some embodiments, the disease or disorder is inflammatory bowel disease (IBD). In some embodiments, the disease or disorder is urticaria. In some embodiments, the disease or disorder is dermatosis. In some embodiments, the disease or disorder is atopic dermatitis. In some embodiments, the disease or disorder is allergic contact dermatitis. In some embodiments, the disease or disorder is rheumatoid arthritis. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is melanoma. In some embodiments, the disease or disorder is a gastrointestinal stromal tumor. In some embodiments, the disease or disorder is a mast cell tumor. In some embodiments, the disease or disorder is mastocytosis. In some embodiments, the disease or disorder is anaphylactic syndrome. In some embodiments, the disease or disorder is food allergy. In some embodiments, the disease or disorder is chronic rhinosinusitis. In some embodiments, the disease or disorder is type I diabetes. In some embodiments, the disease or disorder is type II diabetes. In some embodiments, the disease or disorder is systemic sclerosis. In some embodiments, the disease or disorder is allergic keratoconjunctivitis. In some embodiments, the disease or disorder is vernal keratoconjunctivitis. In some embodiments, the disease or disorder is Crohn’s disease. In some embodiments, the disease or disorder is systemic and cutaneous lupus erythematosus and dermatomyositis.
[00315] In some embodiments, the c-kit mediated disease or disorder is urticaria.
[00316] In some embodiments, the disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD), ulcerative colitis, eosinophilic gastritis (EG), or eosinophilic colitis (EC). In some embodiments, the disease or disorder is mast cell gastrointestinal disease. In some embodiments, the disease or disorder is prurigo nodularis. In some embodiments, the disease or disorder is allergic conjunctivitis. In some such embodiments, the allergic conjunctivitis is seasonal conjunctivitis. In some such embodiments, the allergic conjunctivitis is perennial conjunctivitis. In some embodiments, the disease or disorder is eosinophilic esophagitis. In some embodiments, the disease or disorder is mast cell activation syndrome. In some embodiments, the disease or disorder is eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD). In some embodiments, the disease or disorder is ulcerative colitis. [00317] In some embodiments, the present invention provides a method for treating a c-kit kinase mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
[00318] In some aspects and embodiments, 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 c- kit kinase, 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. In some aspects and embodiments, 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 of c-kit kinase 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.
[00319] As used herein, the terms "increased," "elevated," or "enhanced," are used interchangeably and encompass any measurable increase in a biological function and/or biological activity and/or a concentration. For example, 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.
[00320] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a companion animal. In certain embodiments, the subject is a canine, feline, or equine.
[00321] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as a c-kit kinase mediated disorder.
[00322] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein (for example, a c-kit kinase mediated disorder).
[00323] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula 1-1, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as a c-kit kinase mediated disorder.
[00324] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula 1-1, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein (for example, a c-kit kinase mediated disorder).
II. Pharmaceutical Compositions and Dosing Considerations
[00325] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a described compound may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a described compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered “in combination” when a patient or individual is simultaneously exposed to both agents. In many embodiments, two or more agents are considered to be administered “in combination” when a patient or individual simultaneously shows therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in brain, in serum, etc.).
[00326] When the compounds of this disclosure are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this disclosure may comprise a combination of a compound of Formula I and another therapeutic or prophylactic agent. Alternatively, pharmaceutical or prophylactic compositions according to this disclosure may comprise a combination of a compound of Formula 1-1 and another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as “agents appropriate for the disease, or condition, being treated.”
[00327] In some embodiments, the subject method includes administering a therapeutically effective amount of one or more additional active agents. By combination therapy is meant that a c-kit inhibiting compound can be used in a combination with another therapeutic agent to treat a single disease or condition. In particular embodiments, a compound of the present disclosure is administered concurrently with the administration of another therapeutic agent, which can be administered as a component of a composition including the compound of the present disclosure or as a component of a different composition.
[00328] The subject compounds can be administered in combination with other therapeutic agents in a variety of therapeutic applications. Therapeutic applications of interest for combination therapy include those applications in which activity of a target c-kit kinase is the cause or a compounding factor in disease progression. As such, the subject compounds find use in combination therapies in which the inhibition of a target c-kit kinase in the subject is desired. The compounds utilized in the compositions and methods of this disclosure may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those, which increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and/or alter rate of excretion.
[00329] The term “treatment” is used interchangeably herein with the term “therapeutic method” and refers to both 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions, disease or disorder, and 2) and prophylactic/preventative measures. Those in need of treatment may include individuals already having a particular medical disease or disorder as well as those who may ultimately acquire the disorder (i.e., those at risk or needing preventive measures). [00330] The term “subject” as used herein refers to any individual or patient to which the subject methods are performed. Generally, the subject is human, although as will be appreciated by those in the art, the subject may be an animal. [00331] The terms “therapeutically effective amount”, “effective dose”, “therapeutically effective dose”, “effective amount,” or the like refer to the amount of a subject compound that will elicit the biological or medical response in a tissue, system, animal or human that is being sought by administering said compound. Generally, the response is either amelioration of symptoms in a patient or a desired biological outcome. In some embodiments, such amount should be sufficient to inhibit a c-kit kinase. [00332] Unless specified otherwise, the term “about” refers to within ±10% of the stated value. The invention encompasses embodiments where the value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value. [00333] In some embodiments, an effective amount of a c-kit inhibiting compound is an amount that ranges from about 50 ng/ml to 50 pg/ml (e.g., from about 50 ng/ml to 40 pg/ml, from about 30 ng/ml to 20 pg/ml, from about 50 ng/ml to 10 μg/ml, from about 50 ng/ml to 1 μg/ml, from about 50 ng/ml to 800 ng/ml, from about 50 ng/ml to 700 ng/ml, from about 50 ng/ml to 600 ng/ml, from about 50 ng/ml to 500 ng/ml, from about 50 ng/ml to 400 ng/ml, from about 60 ng/ml to 400 ng/ml, from about 70 ng/ml to 300 ng/ml, from about 60 ng/ml to 100 ng/ml, from about 65 ng/ml to 85 ng/ml, from about 70 ng/ml to 90 ng/ml, from about 200 ng/ml to 900 ng/ml, from about 200 ng/ml to 800 ng/ml, from about 200 ng/ml to 700 ng/ml, from about 200 ng/ml to 600 ng/ml, from about 200 ng/ml to 500 ng/ml, from about 200 ng/ml to 400 ng/ml, or from about 200 ng/ml to about ng/ml). [00334] In some embodiments, an effective amount of a c-kit inhibiting compound is an amount that ranges from about 10 pg to 100 mg, e.g., from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1 ng, from about 1 ng to 10 ng, from about 10 ng to 50 ng, from about 50 ng to 150 ng, from about 150 ng to 250 ng, from about 250 ng to 500 ng, from about 500 ng to 750 ng, from about 750 ng to 1 mg, from about 1 pg to 10 pg, from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1 mg, from about 1 mg to 50 mg, from about 1 mg to 100 mg, or from about 50 mg to 100 mg. The amount can be a single dose amount or can be a total daily amount. The total daily amount can range from about 10 pg to 100 mg, or can range from about 100 mg to 500 mg, or can range from about 500 mg to 1000 mg.
[00335] Also disclosed herein are pharmaceutical compositions including compounds as disclosed herein e.g., compounds of Formula I and pharmaceutically acceptable salts thereof. Also disclosed herein are pharmaceutical compositions including compounds as disclosed herein e.g., compounds of Formula 1-1 and pharmaceutically acceptable salts thereof.
[00336] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier that may be administered to a patient, together with a compound of this disclosure, and which does not destroy the pharmacological activity thereof. Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00337] In pharmaceutical compositions comprising only the compounds described herein as the active component, methods for administering these compositions may additionally comprise the step of administering to the subject an additional agent or therapy. Such therapies include, but are not limited to, an anemia therapy, a diabetes therapy, a hypertension therapy, a cholesterol therapy, neuropharmacologic drugs, drugs modulating cardiovascular function, drugs modulating inflammation, immune function, production of blood cells, hormones and antagonists, drugs affecting gastrointestinal function, chemotherapeutics of microbial diseases, and/or chemotherapeutics of neoplastic disease. Other pharmacological therapies can include any other drug or biologic found in any drug class. For example, other drug classes can comprise allergy/cold/ENT therapies, analgesics, anesthetics, anti-inflammatories, antimicrobials, antivirals, asthma/pulmonary therapies, cardiovascular therapies, dermatology therapies, endocrine/metabolic therapies, gastrointestinal therapies, cancer therapies, immunology therapies, neurologic therapies, ophthalmic therapies, psychiatric therapies or rheumatologic therapies. Other examples of agents or therapies that can be administered with the compounds described herein include a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.
[00338] The term “therapeutically effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) Preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
Pharmaceutically Acceptable Compositions
[00339] The compounds and compositions, according to the method of the present disclosure, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided above. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure 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.
[00340] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the disclosure are 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.
[00341] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00342] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00343] 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.
[00344] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. 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.
[00345] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure 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.
[00346] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, 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 and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[00347] 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 pol ethylene glycols and the like.
[00348] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00349] Dosage forms for topical or transdermal administration of a compound of this disclosure 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 disclosure. Additionally, the present disclosure 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.
[00350] All features of each of the aspects of the disclosure apply to all other aspects mutatis mutandis. Each of the references referred to herein, including but not limited to patents, patent applications and journal articles, is incorporated by reference herein as though fully set forth in its entirety.
[00351] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.
ENUMERATED EMBODIMENTS
[00352] Embodiment 1. A compound represented by Formula 1-1 :
Figure imgf000165_0001
(1-1) or a pharmaceutically acceptable salt thereof; wherein:
RA is of either of the following structures:
Figure imgf000166_0001
each of which is substituted by n occurrences of R3;
R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, - N(R)S(O)R, -N(R)CN, -L2-R5, or an optionally substituted group selected from C1-6 aliphatic, C1-6 haloaliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1- 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R; or: two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with r instances of R;
L2 represents independently for each occurrence a C1-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2- or - Cy-; Cy represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R5 represents independently for each occurrence hydrogen, OR, Ci-6 aliphatic, Ci-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
X is O or S;
R1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, -C(O)OR, - C(0)NR2, C1-6 alkyl, or C 1-6 haloalky 1;
L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or-S(O)2-;
RB is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RB is substituted with q occurrences of R2;
R2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or I.'-R4; wherein R2 is substituted with p occurrences of R6;
L1 represents independently for each occurrence a Ci-2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -S-, -S(O)-, or-S(O)2-;
R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCRs, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, - N(R)S(O)R, -N(R)CN, or optionally substituted phenyl; each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthalenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, or 5.
[00353] Embodiment 2. The compound of embodiment 1, wherein the compound is a compound of Formula 1-1.
[00354] Embodiment 3. The compound of either of embodiments 1-2 wherein when L is a bond
Figure imgf000169_0001
[00355] Embodiment 4. The compound of either of embodiment 1 or 2, wherein X is O.
[00356] Embodiment 5. The compound of either of embodiment 1 or 2, wherein X is S.
[00357] Embodiment 6. The compound of any one of embodiments 1-5, wherein R1 is halogen.
[00358] Embodiment 7. The compound of any one of embodiments 1-5, wherein R1 is Ci-6 alkyl.
[00359] Embodiment 8. The compound of any one of embodiments 1-5, wherein R1 is methyl.
[00360] Embodiment 9. The compound of any one of embodiments 1-5, wherein R1 is Ci-6 haloalkyl.
[00361] Embodiment 10. The compound of any one of embodiments 1-5, wherein R1 is -OR, - NR2, -C(O)R, -C(O)OR, -or C(O)NR2. [00362] Embodiment 11 . The compound of embodiment 10, wherein R1 is -OH, -OCH3, -NH2, -N(CH3)2, -C(O)CH3, -C(O)OCH3, -C(O)NH2, -C(O)NHCH3, or -C(O)N(CH3)2.
[00363] Embodiment 12. The compound of any one of embodiments 1-5, wherein m is 0.
[00364] Embodiment 13. The compound of any one of embodiments 1-11, wherein m is 1.
[00365] Embodiment 14. The compound of any one of embodiments 1-11, wherein the compound is represented by the following or a pharmaceutically acceptable salt thereof:
Figure imgf000170_0001
[00366] Embodiment 15. The compound of any one of embodiments 1-11, wherein the compound is represented by the following or a pharmaceutically acceptable salt thereof:
Figure imgf000170_0002
[00367] Embodiment 16. The compound of embodiment 1, wherein the compound is represented by either of the following or a pharmaceutically acceptable salt thereof:
Figure imgf000171_0001
I-f-1 I-g-1.
[00368] Embodiment 17. The compound of embodiment 1, wherein the compound is represented by one of the following or a pharmaceutically acceptable salt thereof:
Figure imgf000171_0002
[00369] Embodiment 18. The compound of any one of embodiments 1-14, wherein n is 0.
[00370] Embodiment 19. The compound of any one of embodiments 1-14, wherein n is 1.
[00371] Embodiment 20. The compound of any one of embodiments 1-14, wherein n is 2. [00372] Embodiment 21 . The compound of any one of embodiments 1-14, wherein n is 3.
[00373] Embodiment 22. The compound of any one of embodiments 1-14, wherein n is 4.
[00374] Embodiment 23. The compound of any one of embodiments 1-14, wherein n is 5.
[00375] Embodiment 24. The compound of any one of embodiments 1-2 or 4-23, wherein RB is selected from:
Figure imgf000172_0001
[00376] Embodiment 25. The compound of any one of embodiments 1-20 or 19-24, wherein at least one R3 is halogen.
[00377] Embodiment 26. The compound of any one of embodiments 1-20 or 19-24, wherein at least one R3 is bromo.
[00378] Embodiment 27. The compound of any one of embodiments 1-20 or 19-24, wherein at least one R3 is -CN.
[00379] Embodiment 28. The compound of any one of embodiments 1-27, wherein at least one R2 is Ci-6 alkyl.
[00380] Embodiment 29. The compound of any one of embodiments 1-27, wherein at least one R2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. [00381] Embodiment 30. The compound of embodiment 29, wherein at least one R2 is a 3-4 membered saturated monocyclic carbocyclic ring.
[00382] Embodiment 31. The compound of any one of embodiments 1-27, wherein at least one R2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00383] Embodiment 32. The compound of embodiment 31, wherein at least one R2 is a 4-5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 nitrogen atom.
[00384] Embodiment 33. The compound of any one of embodiments 1-27, wherein at least one R2 is L’-R4
[00385] Embodiment 34. The compound of embodiment 33, wherein L1 is a C1-2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, - S(O)-, or -S(O)2-.
[00386] Embodiment 35. The compound of embodiment 33, wherein R4 is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
[00387] Embodiment 36. The compound of embodiment 33, wherein R4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
[00388] Embodiment 37. The compound of any one of embodiments 1-36, wherein R6 represents independently for each occurrence oxo, halogen, -CN, -OR, -OCR3, -SR, -NR2, or -S(O)2R.
[00389] Embodiment 38. The compound of any one of embodiments 1-37, wherein R6 represents independently for each occurrence halogen, -CN, -OR, or -S(O)2R.
[00390] Embodiment 39. The compound of any one of embodiments 1-437, wherein R6 represents independently for each occurrence fluoro, -CN, or -OH.
[00391] Embodiment 40. The compound of any one of embodiments 1-27, wherein each R2 is independently selected from:
Figure imgf000174_0001
[00392] Embodiment 41. The compound embodiment 40, wherein each R2 is independently selected from
Figure imgf000174_0002
wherein each of RA, X, R1, and m are as defined above in embodiment 1.
[00394] Embodiment 43. The compound of any one of those depicted in Table 1 herein, or a pharmaceutically acceptable salt thereof.
[00395] Embodiment 44. A pharmaceutical composition comprising a compound of any one of embodiments 1-43 and a pharmaceutically acceptable carrier. [00396] Embodiment 45. A method of inhibiting the activity of a c-kit kinase in a patient, comprising administering to said patient a compound of any one of embodiments 1-43.
[00397] Embodiment 46. A method of treating a c-kit kinase mediated disease or disorder in a patient, comprising administering to said patient a compound of any one of embodiments 1-43.
[00398] Embodiment 47. The method according to embodiment 46, wherein the c-kit kinase mediated disease or disorder is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a dermatological disease, an allergic disease, a cardiovascular disease, or a neurological disorder.
[00399] Embodiment 48. The method according to embodiment 46, wherein the c-kit kinase mediated disease or disorder is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn’s disease, or systemic and cutaneous lupus erythematosus and dermatomyositis.
[00400] Embodiment 49. The method according to embodiment 46, wherein the c-kit kinase mediated disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD), ulcerative colitis, eosinophilic gastritis (EG), or eosinophilic colitis (EC).
[00401] Embodiment 50. The method of embodiment 46, wherein the c-kit kinase mediated disease or disorder is urticaria.
[00402] Embodiment 51. The method of any one of embodiments 46-50, wherein the patient is a human. EXAMPLES
[00403] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Starting materials described herein can be obtained from commercial sources or may be readily prepared from commercially available materials using transformations known to those of skill in the art.
[00404] Abbreviations used in the Examples are described below. Any abbreviations not described are intended to convey their generally accepted meaning.
Abbreviations
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
[00405] Compounds containing one or more stereocenters are a mixture of stereoisomers, unless otherwise stated or described (for example, with use of dashed or wedged bonds denoting stereochemistry). Generally, enhanced stereochemical representation introduces three types of identifiers that can be attached to a stereogenic center. A stereochemical group label is composed from an identifier and a group number. Each stereogenic center marked with wedge bonds belongs to one (and only one) stereochemical group. Grouping allows to specify relative relationships among stereogenic centers.
[00406] ABS denotes a stereogenic center where the absolute configuration is known. As used herein, “or” denotes a stereogenic center where the relative configuration is known, but the absolute configuration is not known. The structure represents one stereoisomer that is either the structure as drawn (R,S) or the epimer in which the stereogenic centers have the opposite configuration (S,R). One of skill in the art would understand that if a single stereogenic center is present, the designation “or” represents a single isomer for which the absolute configuration is not known. In some such instances, two compounds may be depicted identically with “or” at the single stereogenic center, one of which has a single stereogenic center which is in the R configuration, the other of which is in the S configuration. The designations “and”
Figure imgf000181_0001
are used interchangeably and denote a mixture of stereoisomers. It can be a pair of enantiomers or all the diastereomers.
[00407] All starting materials and solvents were obtained either from commercial sources or prepared according to the literature. Unless otherwise stated all reactions were stirred. Organic solutions were routinely dried over anhydrous magnesium sulfate or other drying agent.
EXAMPLE 1 - Synthesis of Compounds
[00408] The compounds of Table 1 were synthesized by one of the Schemes below.
Figure imgf000181_0002
Synthesis of compound 3:
[00409] To a stirred solution of acid 1 (1.0 eq) in dry DCM (0.1 M) was cooled to 0°C and oxalyl chloride (2 eq) was added drop wise and followed by dry DMF and stirred at RT for 1.5 h and reaction mixture was concentrated under vacuum to obtain crude material. The obtained crude material was added to a stirred solution of aniline 2 (1.1 eq) in pyridine (20 mL) at 0°C. The resulting reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic layer dried over Na2SO4, concentrated to obtain crude material. The obtained crude material was purified by column chromatography (SiOs, hexane: EtOAc, 2:3) to afford intermediate compound 3 in a 43-65% yield as an off-white solid.
Synthesis of final compound 4:
[00410] To a stirred solution of compound 3 (1 eq) in toluene (0.1 M mL) was added Lawessons reagent (1.2 eq) at RT, in a microwave compatible vial. The resulting reaction mixture was irradiated in microwave reactor at 150°C for 1 h. Progress of the reaction was monitored by TLC analysis. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layer dried over Na2SO4, concentrated to obtain crude material. The obtained crude material was first purified by column chromatography (SiCL, hexane:EtOAc, 2:3) The impure material further re-purified by prep-HPLC purification. Prep fractions were lyophilized to afford the desired thioamide in a 5- 39% yield as off-white solid.
2. Synthetic scheme B:
Figure imgf000182_0001
Synthesis of intermediate 3:
[00411] To a stirred solution of 3-amino-4-methylbenzonitrile 1 (1 eq), imidazo[l,2- a]pyridine-3 -carboxylic acid 2 (1 .05 eq), DMAP (1 .3 eq) in DMF (0.1 M) was added pyridine (3 eq) into the reaction mixture at RT. After 10 min EDC.HC1 (3 eq) was added (reaction mixture does not turn to a clear solution, looks like thick precipitate). The reaction mixture was heated to 60°C for 16 h. Upon heating, it slowly turned to clear brown solution. The reaction was monitored by TLC and LCMS. If SM was still observed an additional equivalent of EDC.HC1 was added to the reaction mixture and allowed to stir for an additional 8 h at 60°C. After completion of the reaction, the reaction mixture was poured drop-wise to ice-cold water (1.5 L) and stirred for 30 min. The resulting solid was fdtered, washed with water (200 mb) and hexane (500 mL) and dried under reduced pressure to afford intermediate 3 as off-white solid in a greater than 90% yield.
Synthesis of intermediate 4:
[00412] To a stirred solution of compound 3 (1 eq) in toluene (0.1 M) was added Lawessons reagent (1.2 eq) at RT, in a microwave compatible vial. The resulting reaction mixture was irradiated in microwave reactor at 150°C for 1 h. Progress of the reaction was monitored by TLC analysis. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layer dried over Na2SC>4, concentrated to obtain crude material. The obtained crude material was first purified by column chromatography (SiC>2, hexane:EtOAc, 2:3) The impure material further re-purified by prep-HPLC Purification. Prep fractions were lyophilized to afford thioamide 4 in a 5-39% yield as off-white solid.
Synthesis of intermediate 5:
[00413] To a stirred solution of intermediate 3 (1 eq) in IPA (0.35 M) was added DIPEA (2 eq) and hydroxylamine hydrochloride (2 eq) sequentially at RT. The reaction mixture was then heated to 60°C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to RT. The resulting solid were collected by vacuum filtration, washed with 50% IPA & Water, dried and triturated in EtOAc at 60°C for 4 h. The obtained solid was filtered and dried under vacuum to afford carboxamide 5 in a 30-43% yield as an off-white solid.
Synthesis of compound 7:
[00414] To stirred solution of carboxylic acid 6 (1 eq) in NMP (0.03 M) was added 1'- Carbonyldiimidazole (1 eq) at RT and allowed to stirred for 20 min. After 20 min, intermediate 5 (0.5 eq) was added and the reaction mixture was stirred for 30 min at RT. The reaction mixture was subjected to microwave irradiation at 125°C in a microwave reactor for 15-20 min. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice water. The precipitate obtained was filtered and dried under reduced pressure to get crude. The obtained crude material was purified by prep-HPLC Purification. Prep fractions were lyophilized to afford desired final compound 7 in a 20-80% yield.
3. Synthetic scheme C:
Figure imgf000184_0001
Synthesis of intermediate 2:
[00415] To a solution of Ri-substituted nitrile 1 (1 eq) in EtOH (0.2 M) was added hydroxylamine (4 eq) and stirred at 60°C for 3 h. The reaction mixture was concentrated in vacuo to give carboxamidine 2 (18.0% yield) as crude yellow oil. The crude was carried forward without purification.
Synthesis of common intermediate 4:
[00416] To a solution of benzoic acid 3 (1 eq) in NMP (0.03 M) was added CDI (1.2 eq) and stirred at 25°C for 0.5 h. Carboxamidine 2 (1 eq) was added and stirred at 25°C for an additional 0.5 h. The reaction mixture was subjected to microwave irradiation at 125°C for 15-20 min.
Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice water. The precipitate obtained was filtered and dried under reduced pressure to obtain crude solid. The reaction mixture was diluted with water (10 ml), extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EtOAc, 3 : 1) to give aniline 4 in a 40-95% yield as yellow solid.
Synthesis of compound 6:
[00417] To a stirred solution of aniline 4 (1 eq), carboxylic acid 2 (1.05 eq), DMAP (1.3 eq) in DMF (0.1 M) was added pyridine (3 eq) into the reaction mixture at RT. After 10 min EDC.HC1 (3 eq) was added. The reaction mixture was heated to 60°C for 16 h. Upon heating, it slowly turned to clear brown solution. The reaction was monitored by TLC and LCMS. If SM was still observed an additional equivalent of EDC.HC1 was added to the reaction mixture and allowed to stir for an additional 8 h at 60°C. After completion of the reaction, the reaction mixture was poured drop-wise to ice-cold water (1.5 L) and stirred for 30 min. The resulting solid was filtered, washed with water (200 mL) and hexane (500 mL) and dried under reduced pressure to afford intermediate as off-white solid in a greater than 35-60% yield.
4. Synthetic scheme D:
Figure imgf000185_0001
[00418] To a stirred solution 3 -bromo- 1 -methyl- IH-pyrazole 2 or related aryl bromide (1 eq) in 1,4 dioxane:water (4: 1; 8.0 mL) were added K2CO3 (2 eq) (3-amino-4-methylphenyl) boronic acid 1 (1 eq) and degassed with argon for 10 min then Pd(dppf)Ch (0.1 eq) was added and reaction mixture was stirred at 90°C for 16 h. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was quenched with ice-water and extracted with EtOAc. Organic layer was separated and washed with brine (10 mL), filtered, dried over Na2SO4 and concentrated under reduced pressure to afford 2-methyl-5-(l-methyl-lH-pyrazol-3- yl)aniline 3 in a 25-60% yield as brown solid. Synthesis of final compound 5.
[00419] To a stirred solution of carboxylic acid, 4 (1 eq) in DMF (5 mL) was added DIPEA (2 eq) at 0°C followed by HATU (2 eq) at same temperature and stirred for 10 min. Then added aniline 3 (1.1 eq) to the reaction mixture and left to stir at ambient temperature for 16 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-water and a solid was precipitated. The solid was filtered and washed with water and dried under vacuum to get crude. The crude was purified by prep-HPLC purification. Prep fractions were lyophilized to afford the desired final compound in a 25-60% yield as off-white solid.
5. Synthetic scheme E:
Figure imgf000186_0001
Synthesis of final compound 3.
[00420] In a microwave vial was added intermediate 1 (1 eq), 4-methyl-lH-pyrazole 2 or related heterocycle (5 eq), CS2CO3 (2 eq) and Cui (0.01 eq) in NMP (5 mL) at RT and reaction mixture was stirred at 180°C for 2 h in microwave reactor. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture diluted with EtOAc and extracted with water, organic layer dried over Na?SO4 and concentrated under vacuum to get crude. The obtained crude material was purified by column chromatography (DCM:MeOH, 99: 1) to afford final compound 3 in a 30-70% yield as off-white solid.
6. General synthetic scheme F:
Figure imgf000187_0001
Synthesis of intermediate 3.
[00421] To a stirred solution of 2-methyl-5-nitroaniline 2 (1 eq) and carboxylic acid 1 (1.0 eq) in DMF (10 mL) was added pyridine (2.5 eq) dropwise, followed by DMAP (1.1 eq) and stirred for 10 min. Then EDC1 (2 eq) was added to the reaction mixture and gradually warmed at 70°C for 16 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-water and the solid precipitated out. Precipitated solid was filtered through Buchner funnel, dried under reduced pressure to afford carboxamide 3 in a 30- 55% yield as an off-brown solid.
Synthesis of intermediate 4.
[00422] To a stirred solution of intermediate 3 (1 eq) in EtOH:water (2:1, 0.2 M), was added Fe (5 eq), NH4CI (5 eq) slowly added at RT solution was stirred for 2 h at 100°C stirring.
Progress of the reaction was monitored by TLC analysis. After completion of the reaction, the reaction mixture diluted with DCM extracted with saturated NaHCO?, organic layer dried over Na2SO4 and concentrated under vacuum to get crude. The obtained crude material was purified by purified by column chromatography (DCM:MeOH, 85: 15) to afford intermediate aniline 4 in a 60-90% yield as off-white solid.
Synthesis of final compounds 6.
To a stirred solution of carboxamide 4 (1 eq), cyclobutanamine or desired amine (2 eq) in THF (5 mL) was added TEA (4 eq), and Triphosgene (1 eq) at 0°C, catalytic DMF sequentially added and reaction mixture was stirred for 2 days. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture diluted with DCM extracted with saturated NaHCOs, organic layer dried over Na2SC>4 and concentrated under vacuum to get crude. The crude was purified by prep-HPLC purification. Prep fractions were lyophilized under lyopholizer to afford the final urea as off-white solid in a 45-60% yield.
7. General synthetic scheme G: Synthesis of final compound 3.
Figure imgf000188_0001
[00423] To a stirred solution of acid 1 (1.0 eq) in dry DCM (0.1 M) was cooled to 0°C and oxalyl chloride (2 eq) was added drop wise and followed by dry DMF and stirred at RT for 1.5 h and reaction mixture was concentrated under vacuum to obtain crude material. The obtained crude material was added to a stirred solution of aniline 2 (1.1 eq) in pyridine (20 mL) at 0°C. The resulting reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic layer dried over Na2SC>4, concentrated to obtain crude material. The obtained crude material was purified by column chromatography (SiCL, hexane: EtOAc, 2:3) to afford intermediate compound 3 in a 60-68% yield as an off-white solid.
EXAMPLE 2 - Preparation of N-(2-chloro-5-(3-((lR,2S)-2-fluorocyclopropyl)-l,2,4- oxadiazol-5-yl)phenyl)-7-((2-hydroxy-2-methylpropoxy)methyl)imidazo[l,2-a]pyridine-3- carboxamide (11-71)
Figure imgf000188_0002
[00424] To a stirred solution of ethyl 7-[(2-hydroxy-2-methyl-propoxy)methyl]imidazo[l,2- a]pyridine-3 -carboxylate (346 mg, 1.0 eq) and 2-chloro-5-[3-[(lR,2S)-2-fluorocyclopropyl]- l,2,4-oxadiazol-5-yl]aniline (300 mg, 1 .0 eq) in toluene (5 mL) was added trimethylaluminium in toluene (2 M, 2.5 eq) at 0°C. The reaction mixture was warmed to 80 °C. After 12 h, the reaction mixture was quenched with saturated aqueous NH4CI (5 mL), extracted with di chloromethane (200 mL), and fdtered. The fdtrate was washed with brine (100 mL x 3), then the organic phase was dried over ISfeSCL, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenom enex Luna Cl 8 150*25mm* lOum; mobile phase: [water(formic acid)-acetonitrile]; gradients 5%-65% B over 10 min) to give N-[2-chloro-5-[3- [(lR,2S)-2-fluorocyclopropyl]-l,2,4-oxadiazol-5-yl]phenyl]-7-[(2-hydroxy-2-methyl- propoxy)methyl]imidazo[l,2-a]pyridine-3-carboxamide (11-71, 325 mg, 98.9% purity) as a white solid. ' H NMR (400 MHz, DMSO4) 8 10.25 (s, 1H), 9.39 (d, J= 7.2 Hz, 1H), 8.61 (s, 1H), 8.36 (d, J= 2.0 Hz, 1H), 7.95 (dd, J = 2.0, 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.15 (dd, J = 1.6, 7.2 Hz, 1H), 5.28 - 4.98 (m, 1H), 4.66 (s, 2H), 4.45 (s, 1H), 3.28 (s, 2H), 2.80 (m, 1H), 1.79 (m, 1H), 1.45 - 1.35 (m, 1H), 1.14 (s, 6H); MS (ESI): m/z for C25H25N5O6CIF [M+H] 1 500.2.
EXAMPLE 3 - Preparation of N-(2-chloro-5-(3-((lR,2S)-2-fluorocyclopropyI)-l,2,4- oxadiazol-5-yl)phenyl)-7-((2-hydroxyethoxy)methyl)imidazo[l,2-a]pyridine-3-carboxamide (11-72)
Figure imgf000189_0001
Figure imgf000190_0001
[00425] Step 1: To a stirred solution of (1R,2S)-2-fluorocyclopropanecarboxamide (5 g, 1.0 eq) in dichloromethane (80 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (13.87 g, 1.2 eq), at 25°C. After 16 hours, the reaction mixture was concentrated in vacuum, diluted with ethyl acetate (100 mL), washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated in vacuo below 30 °C to give (1R,2S)-2-fluorocyclopropanecarbonitrile (3.5 g, crude) as brown oil.1H NMR (400 MHz, DMSO-d6) δ 5.42 - 5.16 (m, 1H), 2.41 (m, 1H), 1.72 - 1.58 (m, 1H), 1.50 - 1.37 (m, 1H). [00426] Step 2: To a stirred solution of (1R,2S)-2-fluorocyclopropanecarbonitrile (3.5 g, 1.0 eq) in ethanol (30 mL) was added hydroxylamine (10.87 g, 50% purity, 4.0 eq), and the reaction mixture warmed to 80°C. After 3 hours, the reaction mixture was concentrated in vacuum below 35°C to give a residue. The residue was further lyophilized to give (1R,2S)-2-fluoro-N'-hydroxy- cyclopropanecarboxamidine (3 g, crude) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 9.16 - 8.94 (m, 1H), 5.74 (s, 2H), 4.88 - 4.63 (m, 1H), 1.87 (m, 1H), 1.32 - 1.13 (m, 1H), 1.12 - 0.97 (m, 1H). [00427] Step 3: To a solution of 3-amino-4-chloro-benzoic acid (4.07 g, 1.0 eq) in NMP (50 mL) was added CDI (4.61 g, 1.2 eq), the mixture was stirred at 25°C for 0.5 hours, then (1R,2S)- 2-fluoro-N'-hydroxy-cyclopropanecarboxamidine (2.8 g, 1.0 eq) was added, the reaction mixture was heated to 120°C. After 3 h, the reaction mixture was cooled, diluted with ethyl acetate (300 mL), washed with brine (100 mL x 4), and the organic layer dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 20:1 to 3:1) to give 2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]- 1,2,4-oxadiazol-5-yl]aniline (3 g, 97% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 2.0, 8.4 Hz, 1H), 5.82 (s, 2H), 5.20 - 4.98 (m, 1H), 2.74 (m, 1H), 1.85 - 1.69 (m, 1H), 1.42 - 1.29 (m, 1H). [00428] Step 4: To a stirred solution of 2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4- oxadiazol-5-yl]aniline (500 mg, 1.0 eq) and ethyl 7-(2-tetrahydropyran-2- yloxyethoxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (686 mg, 1.0 eq) in toluene (10 mL) was added trimethylaluminium in toluene (2 M, 2.5 eq) at 0°C, then the reaction mixture was warmed at 80°C for 12 hours under N2. The reaction mixture was cooled, quenched with saturated aqueous ammonium chloride (5 mL), extracted with dichloromethane (200 mL), and the organic phase filtered. The filtrate was washed with brine (100 mL x 3), then the organic layer was dried (Na2SO4), filtered and concentrated in vacuum to give N-[2-chloro-5-[3- [(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]phenyl]-7-(2-tetrahydropyran-2- yloxyethoxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (1 g, 74% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.39 (d, J = 7.2 Hz, 1H), 8.61 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 2.0, 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.15 (dd, J = 1.6, 7.2 Hz, 1H), 5.22 - 5.02 (m, 1H), 4.68 - 4.64 (m, 2H), 4.63 - 4.60 (m, 1H), 3.83 - 3.72 (m, 2H), 3.70 - 3.64 (m, 2H), 3.61 - 3.55 (m, 1H), 3.46 - 3.39 (m, 1H), 2.80 (m, 1H), 1.85 - 1.70 (m, 2H), 1.68 - 1.59 (m, 1H), 1.52 - 1.36 (m, 5H); MS (ESI): m/z for C27H27ClFN5O5 [M+H]+ calcd.: 555.2 [M+H]+ found: 556.2. [00429] Step 5: To a solution of N-[2-chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4- oxadiazol-5-yl]phenyl]-7-(2-tetrahydropyran-2-yloxyethoxymethyl)imidazo[1,2-a]pyridine-3- carboxamide (900 mg, 1.0 eq) in methanol (10 mL) was added 4-methylbenzenesulfonic acid, pyridine (81 mg, 0.2 eq), and the reaction mixture was stirred at 25°C for 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL), extracted with dichloromethane (200 mL), then the mixture was filtered and the filtrate washed with brine (100 mL x 3). The organic phase was dried (Na2SO4) filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)-acetonitrile];gradient:30%-60% B over min) to give N-[2- chloro-5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]phenyl]-7-(2- hydroxyethoxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (II-72, 465.84 mg, 96.8% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.39 (d, J = 7.2 Hz, 1H), 8.61 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 2.0, 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (s,
Figure imgf000192_0001
1H), 7.16 (dd, J = 1.6, 7.2 Hz, 1H), 5.24 - 5.03 (m, 1H), 4.74 (t, J = 5.6 Hz, 1H), 4.64 (s, 2H), 3.63 - 3.50 (m, 4H), 2.80 (m, 1H), 1.79 (m, 1H), 1.39 (dd, J = 6.4, 12.4 Hz, 1H); MS (ESI): m/z for C22H19N5O4ClF [M+H]+ calcd.: 472.2, [M+H]+ found: 472.2. EXAMPLE 4 - N-(5-(3-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-5-yl)-2- methylphenyl)-7-(isopropoxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (II-73)
Figure imgf000192_0002
, -carboxylate (1.00 g, 4.54 mmol, 1.00 eq) in N,N-dimethylformamide (10 mL) was added sodium hydride (272 mg, 6.81 mmol, 60% purity, 1.50 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then 2-iodopropane (1.54 g, 9.08 mmol, 907 μL, 2.00 eq) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of water (40 mL) then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether : ethyl acetate = 5:1 to 3:1) to give ethyl 7-(isopropoxymethyl)imidazo[1,2-a]pyridine-3- carboxylate (70 mg, 0.267 mmol, 6%) as a yellow oil.1H NMR (400 MHz, CDCl3-d) δ 9.23 (d, J = 7.2 Hz, 1H), 8.33 - 8.20 (m, 1H), 8.01 (s, 8H), 7.68 (s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 4.60 (s, 2H), 4.50 - 4.33 (m, 2H), 3.80 - 3.64 (m, 1H), 1.42 (t, J = 6.8 Hz, 3H), 1.25 (d, J = 6.0 Hz, 6H); MS (ESI): m/z for C14H18N2O3 [M+H]+ calcd: 263.1, [M+H]+ found: 263. [00431] Step 2: To a solution of ethyl 7-(isopropoxymethyl)imidazo[1,2-a]pyridine-3- carboxylate (70.0 mg, 0.267 mmol, 1.00 eq) and 5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4- oxadiazol-5-yl]-2-methyl-aniline (62 mg, 0.267 μmol, 1.00 eq) in toluene (2 mL) was added a 2M solution of trimethylaluminum in toluene (333.58 μL, 2.50 eq) under an N2 atmosphere. The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL x 3), dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150×25mm×10um; mobile phase:[water(formic acid)-acetonitrile]; gradient:35%-65% B over 10 min) to give N-[5-[3-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-5-yl]-2-methyl- phenyl]-7-(isopropoxymethyl)imidazo [1,2-a]pyridine-3-carboxamide (II-73, 12 mg, 0.027 mmol, 10%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.38 (d, J = 7.2 Hz, 1H), 8.56 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.92 - 7.80 (m, 1H), 7.67 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.17 - 7.06 (m, 1H), 5.25 - 4.99 (m, 1H), 4.59 (s, 2H), 3.75 - 3.64 (m, 1H), 2.86 - 2.71 (m, 1H), 2.39 (s, 3H), 1.84 - 1.69 (m, 1H), 1.44 - 1.32 (m, 1H), 1.18 (d, J = 6.0 Hz, 6H); MS (ESI): m/z for C24H24FN5O3 [M+H]+ calcd: 450.2, [M+H]+ found: 450.2. EXAMPLE 5 - Preparation of N-(5-{3-[3,3-difluoro-2-hydroxypropyl]-1,2,4-oxadiazol-5- yl}-2-tolyl)-6-methoxy-1,3a-diaza-3-indenecarboxamide (II-74)
Figure imgf000193_0001
Figure imgf000194_0001
[00432] Step 1: To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutanoic acid (5 g, 1.0 eq) in DMF (50 mL) was added saturated aqueous ammonium chloride (1.06 g, 1.5 eq), HATU (7.53 g, 1.5 eq), and DIPEA (5.12 g, 3 eq). The mixture was stirred at 25 °C for 6 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL x 4), dried over Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate=1:1) to give 3-((tert-butyldiphenylsilyl)oxy)- 4,4-difluorobutanamide (2.4 g) as a white solid. MS (ESI): m/z for C20H25F2NO2Si [M+Na]+ calcd.: 400.1 [M+Na]+ found: 400.1. [00433] Step 2: To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutanamide (2.40 g, 1.0 eq) in dichloromethane (25 mL) was added Burgess reagent (1.82 g, 1.2 eq). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, filtered and concentrated in vacuum to give 3-((tert- butyldiphenylsilyl)oxy)-4,4-difluorobutanenitrile (2.3 g, crude) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 7.68 - 7.58 (m, 4H), 7.55 - 7.42 (m, 6H), 6.15-5.80 (m, 1H), 4.17 - 3.96 (m, 1H), 2.87 - 2.71 (m, 2H), 1.04 (s, 9H). [00434] Step 3: To a solution of 3-((tert-butyldiphenylsilyl)oxy)-4,4-difluorobutanenitrile (2.3 g, 1.0 eq) in ethanol (30 mL) was added hydroxylamine (845 mg, 50% purity, 2.0 eq).The mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to give (Z)-3-((tert-butyldiphenylsilyl)oxy)-4,4-difluoro-N'-hydroxybutanimidamide (2.3 g, crude) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 8.96 (s, 1H), 7.67-7.59 (m, 4H), 7.51 - 7.36 (m, 6H), 6.04 - 5.63 (m, 1H), 5.39 (s, 2H), 4.30-4.14 (m, 1H), 2.40 - 2.22 (m, 2H), 0.99 (s, 8H). [00435] Step 4: To a solution of 3-amino-4-methylbenzoic acid (0.85 g, 1.0 eq) in NMP (8 mL) was added di(imidazol-1-yl)methanone (1.00 g, 1.1 eq). The mixture was stirred at 25 °C for 0.5 hour. Then (Z)-3-((tert-butyldiphenylsilyl)oxy)-4,4-difluoro-N'-hydroxybutanimidamide (1.8 g, 1.0 eq) was added. The mixture was stirred at 120 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 1/1) to give 5-(3-(2-((tert- butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (2 g) as a yellow solid.1H NMR (400 MHz, methanol-d4) δ = 7.69 - 7.64 (m, 2H), 7.47 - 7.42 (m, 3H), 7.42 - 7.37 (m, 2H), 7.33 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.27 - 7.21 (m, 3H), 7.19 - 7.14 (m, 1H), 6.00 - 5.65 (m, 1H), 4.44 - 4.29 (m, 1H), 3.15 - 3.05 (m, 1H), 2.99 - 2.91 (m, 1H), 2.24 (s, 3H), 0.93 (s, 9H). [00436] Step 5: To a solution of 7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (160 mg, 1.6 eq), then reaction mixture was stirred at 25 °C for 0.5 hours. Then 5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4- oxadiazol-5-yl)-2-methylaniline (291 mg, 1.1 eq) was added and the reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 0/1) to give N-(5-(3-(2-((tert-butyldimethylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)- 2-methylphenyl)-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide (90 mg) as a white solid. MS (ESI): m/z for C37H37F2N5O4Si [M+H]+ calcd.: 682.2 [M+H]+ found: 682.2. [00437] Step 6: To a solution of N-(5-(3-(2-((tert-butyldimethylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide (85 mg, 1.0 eq) in THF (2 mL) was added TBAF (1 M, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (15 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 0/1) to give N-(5-(3- (3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-methoxyimidazo[1,2- a]pyridine-3-carboxamide (II-74, 38 mg) as a white solid.1H NMR (400 MHz, methanol-d4) δ = 9.32 (d, J = 7.6 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 1.6, 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 2.4, 7.6 Hz, 1H), 6.07-5.71 (m, 1H), 4.36 - 4.20 (m, 1H), 3.95 (s, 3H), 3.12 - 2.96 (m, 2H), 2.44 (s, 3H); MS (ESI): m/z for C21H19F2N5O4 [M+H]+ calcd.: 444.2 [M+H]+ found: 444.2. EXAMPLE 6 - Preparation of N-[2-methyl-5-(1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,2- a]pyridine-3-carboxamide (II-75)
Figure imgf000196_0001
, e (20 mL) was added (COCl)2 (2.80 g, 1.93 mL, 2.0 eq) and DMF (81 mg, 84.95 μL, 0.1 eq), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to give 4-methyl-3-nitro-benzoyl chloride (2.2 g, crude) in dichloromethane (20 mL) as a yellow liquid. MS (ESI): m/z for C8H6O3ClN [methyl ester+H]+ calcd.: 196.1 [methyl ester+H]+ found: 196.1 [00439] Step 2: To a solution of NH3•water (9.1 g, 10 mL, 28% purity, 6.6 eq) was added the mixture of 4-methyl-3-nitro-benzoyl chloride (2.2 g, 1.0 eq) in dichloromethane (20 mL) and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and the filter cake was washed with water (100 mL), and dried under vacuum to give 4-methyl-3- nitrobenzamide (1.9 g, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 8.10 (dd, J = 2.0, 8.0 Hz, 1H), 7.66 - 7.57 (m, 2H), 2.56 (s, 3H). [00440] Step 3: A mixture of 4-methyl-3-nitrobenzamide (0.7 g, 1.0 eq) in DMF-DMA (1:1, 10 mL) was stirred at 110 °C for 1 hour. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1) to give N-(dimethylaminomethylene)-4-methyl-3-nitro-benzamide (910 mg, 99.56%) as red solid. 1H NMR (400 MHz, CDCl3-d) δ 8.86 (d, J = 1.2 Hz, 1H), 8.67 (s, 1H), 8.36 (dd, J = 1.6, 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.24 (d, J = 9.2 Hz, 6H), 2.65 (s, 3H). [00441] Step 4: To a solution of hydroxylamine hydrochloride (222 mg, 1.5 eq) and NaOH (5 M, 2.50 mL, 5.88 eq) in dioxane (20 mL) and acetic acid (25 mL) was added N- (dimethylaminomethylene)-4-methyl-3-nitro-benzamide (500 mg, 1.0 eq), and the reaction mixture was stirred at 25°C for 0.5 hour. The mixture was warmed at 80 °C for 2 hours, then the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2), the organic layer was washed with saturated aqueous sodium bicarbonate (70 mL x 3) and brine (100 mL x 1), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 3:1) to give 5-(4- methyl-3-nitro-phenyl)-1,2,4-oxadiazole (300 mg, 69 %) as a yellow solid.1H NMR (400 MHz, CDCl3-d) δ 8.76 (d, J = 1.6 Hz, 1H), 8.54 (s, 1H), 8.27 (dd, J = 2.0, 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 2.72 (s, 3H). [00442] Step 5: To a solution of 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (100 mg, 1.0 eq) and 4-(4-pyridyl)pyridine (2.00 mg, 0.03 eq) in DMF (2 mL) was added hypoboric acid (131 mg, 3.0 eq), and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL x 3), the organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give 2-methyl-5-(1,2,4-oxadiazol-5-yl)aniline (85 mg, quantitative yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.24 - 7.11 (m, 2H), 2.13 (s, 3H). [00443] Step 6: To a solution of imidazo[1,2-a]pyridine-3-carboxylic acid (79 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (149 mg, 1.6 eq), the mixture was stirred at 25 °C for 0.5 hour, then 2-methyl-5-(1,2,4-oxadiazol-5-yl)aniline (85 mg, 1.0 eq) was added, and the reaction mixture stirred at 60°C for 2 hours. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL), the organic layer was washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(formic acid)- acetonitrile];gradient:12%-42% B over 10 min) to give N-[2-methyl-5-(1,2,4-oxadiazol-5- yl)phenyl]imidazo[1,2-a]pyridine-3-carboxamide (II-75, 52 mg, 30 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.46 (d, J = 7.2 Hz, 1H), 9.11 (s, 1H), 8.60 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 2.0, 8.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.62 - 7.47 (m, 2H), 7.18 (m, 1H), 2.40 (s, 3H); MS (ESI): m/z for C18H15N5O4 [M+H]+calcd.:320.1, [M+H]+ found: 320.1. EXAMPLE 7 - Preparation of 7-methyl-N-(2-methyl-5-(1H-1,2,4-triazol-3- yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (II-76)
Figure imgf000198_0001
[00444] Step 1: To a solution of 3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (340 mg, 1.0 eq) in DMF (6 mL) was added 4-(4-pyridyl)pyridine (3 mg) slowly. To the mixture was added hypoboric acid (448 mg, 3.0 eq) slowly. The mixture was stirred at 25°C for 0.5 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-methyl-5-(1H-1,2,4-triazol-3-yl)aniline (300 mg, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 14.41 - 13.67 (m, 1H), 7.30 (s, 1H), 7.12 (s, 1H), 7.01 (s, 1H), 5.16 - 4.85 (m, 2H), 2.09 (s, 3H); MS (ESI): m/z for : C9H10N4 [M+H]+ calcd.: 175.09 [M+H]+ found:175.3. [00445] Step 2: To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) and 2-methyl-5-(1H-1,2,4-triazol-3-yl)aniline (110 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (130 mg, 1.2 eq). The mixture was stirred at 60°C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18 150×30mm; mobile phase: [water(formic acid)-acetonitrile]; gradient:10%-40% B over 7 min) to give 7-methyl-N-(2-methyl-5-(1H-1,2,4-triazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3- carboxamide (II-76, 25.44 mg, 12%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 14.00 (s, 1H), 9.95 (s, 1H), 9.34 (d, J = 7.2 Hz, 1H), 8.52 (s, 1H), 8.05 (s, 1H), 7.90 - 7.81 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.41 ( d, J = 8.0 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 2.43 (s, 3H), 2.32 (s, 3H); MS (ESI): m/z for : C18H16N6O [M+H]+ calcd.: 333.14 [M+H]+ found:333.1. EXAMPLE 8 - Preparation of 6-(difluoromethyl)-N-(2-methyl-5-(3-methyl-1,2,4-oxadiazol- 5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-77)
Figure imgf000199_0001
, mg, 1.0 eq) in DMSO (5 mL) was added Pd(OAc)2 (33 mg, 0.2 eq) and DPPP (31 mg, 0.1 eq), Et3SiH (173 mg, 2.0 eq), and triethylamine (226 mg, 3.0 eq). The mixture was stirred at 80 °C for 12 hours under CO at 45 psi. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 5), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:1) to give ethyl 6-formylpyrazolo[1,5-a]pyridine-3-carboxylate (50 mg) as a white solid.1H NMR (400 MHz, methanol-d4) δ = 9.99 (d, J = 0.8 Hz, 1H), 9.37 - 9.32 (m, 1H), 8.71 - 8.69 (m, 1H), 8.68-8.64 (m, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.23 - 8.18 (m, 1H), 8.13 (s, 1H), 8.11 (dd, J = 0.8, 9.2 Hz, 1H), 7.91 (dd, J = 1.2, 9.2 Hz, 1H), 7.63 (dd, J = 1.2, 9.2 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.14 - 7.07 (m, 1H), 4.48 - 4.30 (m, 2H), 1.47 - 1.36 (m, 3H). [00447] Step 2: To a solution of ethyl 6-formylpyrazolo[1,5-a]pyridine-3-carboxylate (50 mg, 1.0 eq) in dichloromethane (1 mL) was added DAST (37 mg, 1.0 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (20 mL) and then extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica gel, petroleum ether:ethyl acetate= 3:1) to give ethyl 6-(difluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (30 mg) as a white solid.1H NMR (400 MHz, methanol-d4) δ = 8.95 (s, 1H), 8.47 (s, 1H), 8.25 (d, J = 9.2 Hz, 1H), 7.68 (dd, J = 1.2, 9.2 Hz, 1H), 7.13 - 6.74 (m, 1H), 4.44 - 4.34 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H). [00448] Step 3: To a solution of 2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)aniline (26 mg, 1.1 eq) in toluene (1 mL) was added trimethylaluminium in toluene (2 M, 2.5 eq) at 25 °C, then the reaction mixture was stirred at 25 °C for 0.5 hour. Ethyl 6-(difluoromethyl)pyrazolo[1,5- a]pyridine-3-carboxylate (30 mg, 1.0 eq) was added, then the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) then was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid condition; column: C18150×30mm; mobile phase: [water(formic acid)- acetonitrile]; gradient:42%-72% B over 7 min) to give 6-(difluoromethyl)-N-(2-methyl-5-(3-methyl-1,2,4-oxadiazol-5- yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-77, 11.81 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.87 (s, 1H), 9.22 (s, 1H), 8.89 (s, 1H), 8.36 (d, J = 9.2 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.87 (dd, J = 1.6, 8.0 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 55.2 Hz, 1H), 2.42 (s, 3H), 2.40 (s, 3H); MS (ESI): m/z for C19H15F2N5O2 [M+H]+ calcd.: 383.12; [M+H]+ found: 384.3.
EXAMPLE 9 - Preparation of N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5- yl)-2-methylphenyl)-6-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (II-78)
Figure imgf000201_0001
1,2,4-oxadiazol-5-yl)-2-methylaniline (194 mg, 1.05 eq) in toluene (3 mL) was added trimethylaluminium in toluene (2 M, 2.5 eq). The reaction mixture was stirred at 25 °C for 0.5 hours, then ethyl 6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 1 eq) was added. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (20 mL) then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 0:1) to give N-(5-(3-(2- ((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6- methoxypyrazolo[1,5-a]pyridine-3-carboxamide (100 mg) as a white solid. MS (ESI): m/z for C37H37F2N5O4Si [M+H]+ calcd.: 604.2 [M+H]+ found: 604.2. [00450] Step 2: To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-methoxypyrazolo[1,5-a]pyridine-3-carboxamide (100 mg, 1.0 eq) in THF (2 mL) was added TBAF (1 M, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 0/1) to give N-(5-(3- (3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-methoxypyrazolo[1,5- a]pyridine-3-carboxamide (II-78, 36 mg) as a white solid.1H NMR (400 MHz, methanol-d4) δ = 8.54 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 9.6 Hz, 1H), 7.95 (dd, J = 1.6, 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 2.0, 9.8 Hz, 1H), 5.90 (d, J = 3.6 Hz, 1H), 4.39 - 4.21 (m, 1H), 3.91 (s, 3H), 3.10 - 2.97 (m, 2H), 2.44 (s, 3H); MS (ESI): m/z for C21H19F2N5O4 [M+H]+ calcd.: 444.3 [M+H]+ found: 444.3. EXAMPLE 10 - Preparation of N-(5-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methylphenyl)- 7-methylimidazo[1,2-a]pyridine-3-carboxamide (II-79)
Figure imgf000202_0001
Figure imgf000202_0002
Figure imgf000202_0004
[00451] Step 1: To a solution of 4-methyl-3-nitro-benzoic acid (7.4 g, 1.0
Figure imgf000202_0003
mL) was added CDI (7.99 g, 1.2 eq) and DMF (35 mg, 0.01 eq). The mixture was stirred at 25 °C for 1 hour to give (1H-imidazol-1-yl)(4-methyl-3-nitrophenyl)methanone (9.45 g, crude) in THF as a clear solution which was used directly in the next step without further work-up. [00452] Step 2: To a solution of (1H-imidazol-1-yl)(4-methyl-3-nitrophenyl)methanone (9.45 g, 1.0 eq) in THF (100 mL) was added NH3•water (11.24 mL, 28% purity, 2.0 eq). The mixture was stirred at 25°C for 12 hours. The mixture was diluted with NaOH (1N, 100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-methyl- 3-nitrobenzamide (6.4 g, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 1.6 Hz, 1H), 8.22 (s, 1H), 8.12 - 8.07 (m, 1H), 7.66 - 7.53 (m, 2H), 2.56 (s, 3H); MS (ESI): m/z for : C8H8N2O3 [M+H]+ calcd.181.05 [M+H]+ found:181.3. [00453] Step 3: A mixture of 4-methyl-3-nitro-benzamide (3.2 g, 1.0 eq) and DMF-DMA (32 mL, 13.56 eq) was heated to 110°C for 1 hour. The mixture was cooled then concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1) to give N-((dimethylamino)methylene)-4-methyl-3-nitrobenzamide (3.5 g, 80%) as a yellow solid. MS (ESI): m/z for: C11H13N3O3 [M+H]+ calcd.:236.1 [M+H]+ found: 236.0. [00454] Step 4: To a solution of N-((dimethylamino)methylene)-4-methyl-3-nitrobenzamide (3.0 g, 1.0 eq) in acetic acid (30 mL) was added hydrazine hydrate (977 mg,, 98% purity, 1.5 eq). The mixture was stirred at 95 °C for 2 hours, then cooled to room temperature, and diluted with water (60 mL). The mixture was filtered and the solid precipitate was washed with water (10 mL) then dried under high vacuum to give 3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (2.3 g, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 14.36 (s, 1H), 8.68 - 8.50 (m, 2H), 8.32 - 8.17 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 2.56 (s, 3H); MS (ESI): m/z for: C9H8N4O2 [M+H]+ calcd.: 205.06 [M+H]+ found: 205.0. [00455] Step 5: To a mixture of 3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (500 mg, 1.0 eq) and cyclopropylboronic acid (2.10 g, 10.0 eq) in dichloroethane (10 mL) was added Cu(OAc)2 (667 mg, 1.5 eq), 2-(2- pyridyl)pyridine (573 mg, 1.5 eq) and Na2CO3 (1.3 g, 5.0 eq) under O2 (15 psi). The mixture was stirred at 80 °C for 12 hours under O2, then cooled to room temperature and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1) to give 1-cyclopropyl- 3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (500 mg, 76 %) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.69 (d, J = 1.6 Hz, 1H), 8.23 - 8.18 (m, 1H), 8.16 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 3.72 - 3.63 (m, 1H), 2.63 (s, 3H), 1.28 - 1.21 (m, 2H), 1.20 - 1.11 (m, 2H); MS (ESI): m/z for: C12H12N4O2 [M+H]+ calcd.: 245.10 [M+H]+ found: 245.2. [00456] Step 6: To a solution of 1-cyclopropyl-3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazole (200 mg, 1.0 eq) in DMF (6 mL) was added 4-(4-pyridyl)pyridine (1.48 mg, 0.01 eq) slowly. To the mixture was added hypoboric acid (220 mg, 3.0 eq) slowly. The mixture was stirred at 25 °C for 0.5 hours. The mixture was diluted with water (10 mL) then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-(1-cyclopropyl-1H-1,2,4-triazol-3- yl)-2-methylaniline (190 mg, crude) as a yellow oil. MS (ESI): m/z for: C12H14N4 [M+H]+ calcd.:215.12 [M+H]+ found: 215.3. [00457] Step 7: To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (100 mg, 1.0 eq) and 5-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methylaniline (190 mg, 1.0 eq) in pyridine (2 mL) was added EDCI (163 mg, 1.5 eq). The mixture was stirred at 60 °C for 2 hours. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: C18150×30mm; mobile phase: [water(formic acid)-acetonitrile]; gradient:15%- 45% B over 7 min) to give N-(5-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methylphenyl)-7-methylimidazo[1,2- a]pyridine-3-carboxamide (II-79, 102.8 mg, 42 %) as a white solid.1H NMR (400 MHz, DMSO- d6) δ = 9.90 (s, 1H), 9.33 (d, J = 7.2 Hz, 1H), 8.63 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.82 - 7.72
Figure imgf000204_0001
(m, 1H), 7.55 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.04 - 6.98 (m, 1H), 3.87 - 3.78 (m, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 1.19 - 1.10 (m, 2H), 1.10 - 1.04 (m, 2H); MS (ESI): m/z for: C21H20N6O [M+H]+ calcd.: 373.17 [M+H]+ found: 373.2. EXAMPLE 11 - Preparation of N-(5-(1-(2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-2- methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-carboxamide (II-80)
Figure imgf000204_0002
y y , , g, . eq) in DMF (5 mL) was added Cs2CO3 (1.20 g, 1.5 eq) and 2-methyloxirane (569 mg, 4.0 eq). The mixture was stirred at 40 °C for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, ethyl acetate/methanol=1/0 to 10/1) to give 1-(3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazol-1- yl)propan-2-ol (400 mg, 55 %) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.53 (s, 1H), 8.11 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.35 - 4.21 (m, 2H), 4.12 - 4.01 (m, 1H), 3.67 - 3.53 (m, 1H), 2.62 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H); MS (ESI): m/z for: C12H14N4O3 [M+H]+ calcd.: 263.11 [M+H]+ found: 263.1. [00459] Step 2: To a solution of 1-(3-(4-methyl-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)propan-2- ol (200 mg, 1.0 eq) in THF (5 mL) and ethanol (5 mL) was added Pd/C (100 mg, 10% purity, 0.1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15psi) at 25°C for 12 hours. The mixture was filtered and concentrated to give 1-(3-(3-amino-4-methylphenyl)-1H-1,2,4-triazol-1-yl)propan-2-ol (180 mg, crude) as a white solid. MS (ESI): m/z for: C12H16N4O [M+H]+ calcd.: 233.13 [M+H]+ found: 233.1. [00460] Step 3: To a solution of 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (120 mg, 1.0 eq) and 1-(3-(3-amino-4-methylphenyl)-1H-1,2,4-triazol-1-yl)propan-2-ol (180 mg, 1.02 eq) in pyridine (2 mL) was added EDCI (157 mg, 1.2 eq). The mixture was stirred at 60 °C for 2 hours. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: C18150×30mm; mobile phase: [water(formic acid)-acetonitrile]; gradient:15%-45% B over 7 min) to give N-(5-(1-(2-hydroxypropyl)-1H-1,2,4-triazol-3-yl)-2-methylphenyl)-7- methylimidazo[1,2-a]pyridine-3-carboxamide (II-80, 40.72 mg, 13%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.89 (s, 1H), 9.33 (d, J = 7.2 Hz, 1H), 8.48 (d, J = 15.2 Hz, 2H), 8.03 (s, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.55 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 5.11 - 4.96 (m, 1H), 4.19 - 3.95 (m, 3H), 2.42 (s, 3H), 2.31 (s, 3H), 1.11 (d, J = 6.0 Hz, 3H); MS (ESI): m/z for: C21H22N6O2 [M+H]+ calcd.: 391.18 [M+H]+ found: 391.2.
EXAMPLE 12 – Preparation of N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5- yl)-2-methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3- carboxamide (II-81)
Figure imgf000206_0001
ate (1 g, 1.0 eq) in DMF (10mL) was added t-BuONa (655 mg, 1.5 eq) and 4-bromo-2-methylbutan- 2-ol (1.14 g, 1.5 eq). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, ethyl acetate:methanol=100/1 to 20/1) to give ethyl 7-((3-hydroxy-3- methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (190 mg) as a white solid.1H NMR (400 MHz, methanol-d4) δ = 9.26 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.67 (s, 1H), 7.17 (dd, J = 1.2, 6.8 Hz, 1H), 4.64 (s, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.73 (t, J = 6.8 Hz, 2H), 1.86 (t, J = 6.8 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.24 (s, 6H). [00462] Step 2: To a solution of 5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylaniline (183 mg, 1.1 eq) in toluene (2 mL) was added trimethylaluminium in toluene (2 M, 2.5 eq), the reaction mixture was stirred at 25 °C for 0.5 hour, then ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 1 eq) was added, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) then was extracted with dichloromethane (25 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1 to 0 /1) to give N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4- oxadiazol-5-yl)-2-methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine- 3-carboxamide (85 mg) as a white solid. MS (ESI): m/z for C42H47F2N5O5Si [M+H]+ calcd.: 768.4 [M+H]+ found: 768.4 [00463] Step 3: To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2- a]pyridine-3-carboxamide (83 mg, 1.0 eq) in THF (1 mL) was added TBAF (1 M, 1.1 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 0/1) to give N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5-yl)-2- methylphenyl)-7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-81, 42.18 mg) as an off -white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.03 (s, 1H), 9.40 (d, J = 7.2 Hz, 1H), 8.57 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 1.6, 8.0 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 1.2, 7.2 Hz, 1H), 6.23 - 5.84 (m, 2H), 4.58 (s, 2H), 4.25 (s, 1H), 4.23 - 4.12 (m, 1H), 3.61 (t, J = 7.2 Hz, 2H), 3.05 - 2.89 (m, 2H), 2.40 (s, 3H), 1.73 (t, J = 7.2 Hz, 2H), 1.12 (s, 6H); MS (ESI): m/z for C26H29F2N5O5 [M+H]+ calcd.: 530.2 [M+H]+ found: 530.2.
EXAMPLE 13 - Preparation of N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-5- yl)-2-methylphenyl)-6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide (II-82) NH2 O HO HO NH2
Figure imgf000208_0001
[00464] Step 1: To a solution of 3-methylbutane-1,3-diol (7.21 g, 2.5 eq) in DMF (100 mL) was added NaH (3.32 g, 60% purity, 3.0 eq) slowly at 0°C. The mixture was stirred at 25°C for 0.5 h. To the mixture was added 3-(bromomethyl)pyridine (7.0 g, 1.0 eq, HBr) and TBAI (511 mg, 0.05 eq). The mixture was stirred at 25°C for 12 hours. The mixture was diluted with saturated aqueous NH4Cl (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/1) to give 2-methyl-4-(pyridin-3-ylmethoxy)butan-2- ol (1.8 g, 30 %) as colorless oil.1H NMR (400 MHz, chloroform-d) δ = 8.67 - 8.55 (m, 2 H), 7.77 - 7.65 (m, 1H), 7.34 - 7.29 (m, 1 H), 4.56 (s, 2 H), 3.75 (t, J = 6.0 Hz, 2 H), 1.84 (t, J = 6.0 Hz, 2 H), 1.26 (s, 6 H); MS (ESI): m/z for C11H17NO2 [M+H]+ calcd.: 196.3 [M+H]+ found:196.3. [00465] Step 2: To a solution of 2-methyl-4-(pyridin-3-ylmethoxy)butan-2-ol (1.8 g, 1.0 eq) in acetonitrile (20 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (1.84 g, 1.0 eq). The mixture was stirred at 40°C for 16 hours. The mixture was concentrated to give 1-amino-3-((3- hydroxy-3-methylbutoxy)methyl)pyridin-1-ium (1.95 g, crude) as a yellow oil. MS (ESI): m/z for C18H16N6O [M+H]+ calcd.: 211.14 [M+H]+ found: 211.3. [00466] Step 3: To a solution of 1-amino-3-((3-hydroxy-3-methylbutoxy)methyl)pyridin-1-ium (1.95 g, 1.0 eq) and ethyl prop-2-ynoate (905 mg, 1.0 eq) in DMF (20 mL) was added K2CO3 (3.19 g, 2.5 eq). The mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1 to 15/1) to give ethyl 6-((3-hydroxy-3- methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (300 mg, 10 %) as a yellow solid.1H NMR (400 MHz, chloroform-d) δ = 8.51 (s, 1 H), 8.41 (s, 1 H), 8.16 (d, J = 8.8 Hz, 1 H), 7.44 - 7.37 (m, 1 H), 4.59 (s, 2H), 4.45 - 4.37 (m, 2 H), 3.77 (t, J = 6.0 Hz, 2 H), 2.71 - 2.59 (m, 1 H), 1.85 (t, J = 6.0 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.28 (s, 6 H); MS (ESI): m/z for: C16H22N2O4 [M+H]+ calcd.: 307.16 [M+H]+ found: 307.3. [00467] Step 4: To a solution of ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2- a]pyridine-3-carboxylate (200 mg, 1 eq) in toluene (2 mL) was added Al(CH3)3 (2 M, 492 μL, 2.5 eq) under N2. The mixture was stirred at 25°C for 0.5 hour. To the mixture was added ethyl 6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (121 mg, 1.0 eq) and the mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature. The mixture was poured into 20 mL of ice/water, then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1 to 1/3) to give N-(5-(3-(2-((tert- butyldiphenylsilyl)oxy)-3,3-difluoropropyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-((3- hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (170 mg, 48%) as a yellow oil. MS (ESI): m/z for : C42H47F2N5O5Si [M+H]+ calcd.768.33 [M+H]+ found: 768.4. [00468] Step 5: To a solution of N-(5-(3-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide (170 mg, 1 eq) in THF (3 mL) was added TBAF (1 M, 265 μL, 1.2 eq). The mixture was stirred at 25°C for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=0/1 ) to give a white solid which was further purified by prep-HPLC (column: waters Xbridge 150*25mm* 5um; mobile phase: [water (ammonia hydroxide v/v)-acetonitrile]; gradient:18%-48% B over 10 min) to give N-(5-(3-(3,3-difluoro-2-hydroxypropyl)-1,2,4- oxadiazol-5-yl)-2-methylphenyl)-6-((3-hydroxy-3-methylbutoxy)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide (II-82, 49.52 mg, 93.52 μmol, 42 % yield, 100% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.76 (s, 1H), 8.81 (s, 1H), 8.78 (s, 1H), 8.26 - 8.20 (m, 2H), 7.90 - 7.85 (m, 1H), 7.56 - 7.53 (m, 1H), 7.52 - 7.48 (m, 1H), 6.22 - 5.85 (m, 2H), 4.54 (s, 2H), 4.22 (s, 1H), 4.21 - 4.11 (m, 1H), 3.58 (t, J = 7.2 Hz, 2H), 3.06 - 2.98 (m, 1H), 2.96 - 2.87 (m, 1H), 2.40 (s, 3H), 1.69 (t, J = 7.2 Hz, 2H), 1.10 (s, 6H); MS (ESI): m/z for: C26H29F2N5O5 [M+H]+ calcd.: 530.21 [M+H]+ found: 530.3. EXAMPLE 14 - Preparation of N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2- methylphenyl)-7-((2-hydroxy-2-methylpropoxy)methyl)imidazo[1,2-a]pyridine-3- carboxamide (II-83)
Figure imgf000210_0001
[00469] Step 1: To a solution of 3,3-difluorocyclobutane-1-carbonitrile (2 g, 1.0 eq) in ethanol (20 mL) was added hydroxylamine (2.26 g, 50% purity, 2.0 eq). The mixture was stirred at 70 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to title give (Z)-3,3-difluoro-N'-hydroxycyclobutane-1-carboximidamide (2.56 g, crude) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 9.07 (s, 1H), 5.44 (s, 2H), 2.85 - 2.60 (m, 5H). [00470] Step 2: To a solution of (Z)-3,3-difluoro-N'-hydroxycyclobutane-1-carboximidamide (2.56 g, 1.0 eq) in NMP (30 mL) was added CDI (3.30 g, 1.2 eq). The mixture was stirred at 25 °C for 0.5 hour. The mixture was used directly without work up. To the solution was added 3- hydroxy-4-methylbenzoic acid (2.54 g, 1.0 eq). The mixture was stirred at 120 °C for 1.5 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (70 mL x 3). The organic phase was separated, washed with brine (60 mL x 5), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)- 2-methylaniline (1.8 g) as a green solid.1H NMR (400 MHz, DMSO-d6) δ = 7.39 (d, J = 1.6 Hz, 1H), 7.23 - 7.11 (m, 2H), 5.33 (s, 2H), 3.72 - 3.54 (m, 1H), 3.19 - 2.84 (m, 4H), 2.14 (s, 3H). [00471] Step 3: To a solution of ethyl 7-((3-hydroxy-3-methylbutoxy)methyl)imidazo[1,2- a]pyridine-3-carboxylate (110 mg, 1.0 eq) in toluene (2 mL) was added Al(CH3)3 (3 M, 314 μL, 2.5 eq). The mixture was stirred at 25 °C for 0.5 hour, then 5-(3-(3,3-difluorocyclobutyl)-1,2,4- oxadiazol-5-yl)-2-methylaniline (100 mg, 1 eq) was added. The mixture was stirred at 80 °C for 1.5 hours. The reaction mixture was quenched by addition saturated ammonium chloride in water (20 mL) at 0 °C, and then diluted with water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18150×30mm; mobile phase: [water(formic acid)-acetonitrile]; gradient:35%-65% B over 7 min) to give N-(5-(3-(3,3-difluorocyclobutyl)- 1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2-hydroxy-2-methylpropoxy)methyl)imidazo[1,2- a]pyridine-3-carboxamide (II-83, 22 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.04 (s, 1H), 9.41 (d, J = 7.2 Hz, 1H), 8.57 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 1.6, 8.0 Hz, 1H), 7.73 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.14 (dd, J = 1.2, 7.2 Hz, 1H), 4.65 (s, 2H), 4.45 (s, 1H), 3.67 (dd, J = 6.4, 9.2 Hz, 1H), 3.27 (s, 2H), 3.16 - 3.07 (m, 2H), 3.03 - 2.90 (m, 2H), 2.40 (s, 3H), 1.14 (s, 6H); MS (ESI): m/z for C26H27F2N5O4 [M+H]+ calcd.512.2 [MH]+ found: 512.2. EXAMPLE 15 – Preparation of N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2- methylphenyl)-7-((2-hydroxyethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-84)
Figure imgf000212_0001
ate (1 g, 1.0 eq) in DMF (10 mL) was added t-BuONa (655 mg, 1.5 eq) at 25°C and stirred 0.5 h at 25°C, then was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.42 g, 1.5 eq). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure and was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water( NH4HCO3)-acetonitrile]; gradient:28%-58% B over 20 min) to give ethyl 7-((2-((tetrahydro-2H- pyran-2-yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (220 mg) as a yellow oil. MS (ESI): m/z for C18H24N2O5 [M+H]+ calcd.: 349.2 [M+H]+ found: 349.2. [00473] Step 2: To a solution of 5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2- methylaniline (76 mg, 1.0 eq) in toluene (2 mL) was added trimethylaluminium in toluene (2 M, 359 μL, 2.5 eq) and stirred at 25°C for 0.5h. Then ethyl 7-((2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (100 mg, 1.0 eq) was added. The mixture was stirred at 80°C for 3 hours. The reaction mixture was diluted with water (3 mL), concentrated under reduced pressure and then purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1/1 to 0/1) to give N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4- oxadiazol-5-yl)-2-methylphenyl)-7-((2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (80 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.05 (s, 1H), 9.40 (d, J = 7.2 Hz, 1H), 8.57 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 1.6, 8.0 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.13 (dd, J = 1.6, 7.2 Hz, 1H), 4.65 (s, 2H), 4.62 (t, J = 3.6 Hz, 1H), 3.84 - 3.73 (m, 2H), 3.69 - 3.56 (m, 4H), 3.32 - 3.23 (m, 1H), 3.18 - 3.06 (m, 2H), 3.03 - 2.89 (m, 2H), 2.40 (s, 3H), 1.79 - 1.59 (m, 2H), 1.53 - 1.39 (m, 4H); MS (ESI): m/z for C29H31F2N5O5 [M+H]+ calcd.: 568.3 [M+H]+ found: 568.3. [00474] Step 3: To a solution N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2- methylphenyl)-7-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)imidazo[1,2-a]pyridine-3- carboxamide (40 mg, 1.0 eq) in dichloromethane (2 mL) was added TFA (614 mg, 0.4 mL, 76 eq) and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and was purified by prep-HPLC (column: C18150×30mm;mobile phase: [water(formic acid)- acetonitrile];gradient: 28%-58% B over 7 min) to give N-(5-(3-(3,3- difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7-((2- hydroxyethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (II-84, 19 mg) as a yellow gum. 1H NMR (400 MHz, DMSO-d6) δ = 10.16 (s, 1H), 9.45 (d, J = 7.2 Hz, 1H), 8.67 (s, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.92 (dd, J = 1.6, 8.0 Hz, 1H), 7.79 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 4.67 (s, 2H), 3.67 (d, J = 2.0 Hz, 1H), 3.59 (d, J = 4.4 Hz, 2H), 3.57 (s, 2H), 3.16 - 3.07 (m, 2H), 3.01 - 2.88 (m, 2H), 2.40 (s, 3H); MS (ESI): m/z for C24H23F2N5O4 [M+H]+ calcd.: 484.1 [M+H]+ found: 484.1 EXAMPLE 16 - Preparation of N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2- methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-carboxamide (II-85) N N [
Figure imgf000213_0001
00475] To a solution of ethyl 7-methylimidazo[1,2-a]pyridine-3-carboxylate (100 mg, 1 eq) in toluene (2 mL) was added Al(CH3)3 (2 M, 314 μL, 2.5 eq). The mixture was stirred at 25 °C for 0.5 hour, then 5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylaniline (77 mg, 1 eq) was added. The mixture was stirred at 80 °C for 1.5 hours. The reaction mixture was quenched by addition of saturated ammonium chloride in water (5 mL) at 0 °C, and then diluted with water (5 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18 150×30mm; mobile phase: [water(formic acid)-acetonitrile]; gradient:30%-60% B over 7 min) to give N-(5-(3-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-5-yl)-2-methylphenyl)-7- methylimidazo[1,2-a]pyridine-3-carboxamide (II-85, 86 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.99 (s, 1H), 9.37 (d, J = 7.2 Hz, 1H), 8.56 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.24 – 5.86 (m, 2H), 4.83 – 4.68 (m, 1H), 4.59 (s, 2H), 4.37 (d, J = 2.0 Hz, 3H), 3.19 – 3.09 (m, 2H), 2.36 (s, 3H), 1.19 (s, 6H); MS (ESI): m/z for C22H19F2N5O2 [M+H]+ calcd.424.4 [MH]+ found: 424.2. EXAMPLE 17 - Preparation of N-[5-(3-bromo-1,2,4-oxadiazol-5-yl)-2-methyl-phenyl]-7- methyl-imidazo[1,2-a]pyridine-3- carboxamide (II-86)
Figure imgf000214_0001
p y g, . q was added diisopropylethylamine (1.43 g, 1.92 mL, 2 eq) and HATU (2.52 g, 1.2 eq). The mixture was stirred at 25 °C for 0.3 hour, then NH2CN (302 mg, 1.3 eq) was added and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and purified by reverse phase HPLC (0.1% formic acid condition) to give N-cyano-4-methyl-3-nitro- benzamide (1.02 g, 90 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 1.6 Hz, 1H), 8.10 (dd, J = 1.6, 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 2.59 (s, 3H). [00477] Step 2: To a solution of N-cyano-4-methyl-3-nitro-benzamide (800 mg, 1 eq) in pyridine (8 mL) was added NH2OH.HCl (271 mg, 1 eq), then the reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (80 mL x 3), then the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=0/1 to 1/1) to give 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazol-3-amine (180 mg, 21%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 1.6 Hz, 1H), 8.19 (dd, J = 1.6, 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 6.51 (s, 2H), 2.61 (s, 3H). [00478] Step 3: To a solution of 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazol-3-amine (110 mg, 1.0 eq) in water (0.4 mL) was added the solution of NaNO2 (62.05 mg, 1.8 eq) in HBr (1 mL) at 0 °C, the mixture was stirred at 0.1 hour, then CuBr (72 mg, 1 eq) was added, and then the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (30 mL), and the organic layer was concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=1:0 to10:1) to give 3-bromo-5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (100 mg, 70 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 1.6 Hz, 1H), 8.31 (dd, J = 1.6, 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 2.63 (s, 3H). [00479] Step 4: To a solution of 3-bromo-5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (100 mg, 1.0 eq) and 4-(4-pyridyl)pyridine (1.4 mg) in DMF (1 mL) was added hypoboric acid (95 mg, 3.0 eq), then the reaction mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (20 mL x 3), then the organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give 5-(3-bromo-1,2,4-oxadiazol-5- yl)-2-methyl-aniline (80 mg, 89%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 1.6 Hz, 1H), 7.23 - 7.14 (m, 2H), 5.37 (s, 2H), 2.14 (s, 3H). [00480] Step 5: To a solution of 5-(3-bromo-1,2,4-oxadiazol-5-yl)-2-methyl-aniline (60 mg, 1.0 eq) in toluene (1 mL) was added trimethylaluminium in toluene (2 M, 295 μL, 2.5 eq) at 0 °C and the mixture was stirred at 25 °C for 0.5 hour under N2. Then ethyl 7-methylimidazo[1,2- a]pyridine-3-carboxylate (48 mg, 1.0 eq) was added and the reaction mixture was stirred at 80 °C for 2 hours under N2. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (1 mL), extracted with dichloromethane (50 mL), washed with brine (10 mL x 2), and then the organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(formic acid)-acetonitrile]; gradient:22%-52% B over 8 min) to give N-[5-(3-bromo-1,2,4- oxadiazol-5-yl)-2-methyl-phenyl]-7-methyl-imidazo[1,2-a]pyridine-3- carboxamide (II-86, 3.71 mg, 3 % yield, 97% purity, formic acid salt) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.32 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 1.6, 8.0 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.04 (dd, J = 1.6, 7.2 Hz, 1H), 2.42 (d, J = 6.8 Hz, 6H); MS (ESI): m/z for C19H16N5O4Br [M+H]+ calcd.: 413.9 [M+H]+ found: 413.9. EXAMPLE 18 - Preparation of N-[5-(3-chloro-1,2,4-oxadiazol-5-yl)-2-methyl-phenyl]-7- methyl-imidazo[1,2-a]pyridine-3- carboxamide (II-87)
Figure imgf000216_0001
as added diisopropylethylamine (1.43 g, 1.92 mL, 2 eq) and HATU (2.52 g, 1.2 eq), the mixture was stirred at 25 °C for 0.3 hour, then NH2CN (301.70 mg, 1.3 eq) was added and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered. The residue was purified by reverse phase HPLC (0.1% formic acid condition) to give N-cyano-4-methyl-3-nitro- benzamide (800 mg, 71%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.43 (m, 1H), 8.10 (dd, J = 1.6, 8.0 Hz, 1H), 7.68 - 7.62 (m, 1H), 2.58 (s, 3H). [00482] Step 2: To a solution of N-cyano-4-methyl-3-nitro-benzamide (800 mg, 1.0 eq) in pyridine (8 mL) was added NH2OH.HCl (271 mg, 1 eq), the reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (80 mL x 3), and the organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=0/1 to 1/1) to give 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazol-3-amine (220 mg, 26 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 1.6 Hz, 1H), 8.18 (dd, J = 1.6, 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 6.51 (s, 2H), 2.61 (s, 3H). [00483] Step 3: To a solution of 5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazol-3-amine (220 mg, 1.0 eq) in water (0.8 mL) was added a solution of NaNO2 (124 mg, 1.8 eq) in HCl (2 mL) at 0 °C. The mixture was stirred for 0.1 hour, then CuCl (297 mg, 1.0 eq) was added, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (40 mL), and the organic layer was concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether : ethyl acetate=1:0 to 10:1) to give 3-chloro-5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (130 mg, 54%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 2.0, 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 2.63 (s, 3H). [00484] Step 4: To a solution of 3-chloro-5-(4-methyl-3-nitro-phenyl)-1,2,4-oxadiazole (130 mg, 1.0 eq) and 4-(4-pyridyl)pyridine (2.2 mg, 2.63e-2 eq) in DMF (2 mL) was added hypoboric acid (146 mg, 3.0 eq), the reaction mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (20 mL x 3), the organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give 5-(3-chloro-1,2,4-oxadiazol- 5-yl)-2-methyl-aniline (110 mg, 97%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 1.2 Hz, 1H), 7.22 - 7.14 (m, 2H), 5.37 (s, 2H), 2.14 (s, 3H). [00485] Step 5: To a solution of 5-(3-chloro-1,2,4-oxadiazol-5-yl)-2-methyl-aniline (83 mg, 1.1 eq) in pyridine (2 mL) was added EDCI (132 mg, 1.6 eq). The mixture was stirred at 25 °C for 0.5 hours, then 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid (90 mg, 1.0 eq) was added. The reaction mixture was stirred at 60 °C for 3.5 hours, then cooled and concentrated in vacuum. The residue was purified by prep-HPLC (column: C18150×30mm; mobile phase: [water(formic acid)-acetonitrile]; gradient:25%-55% B over 7 min) to give N-[5-(3-chloro-1,2,4-oxadiazol-5- yl)-2-methyl-phenyl]-7-methyl-imidazo[1,2-a]pyridine-3- carboxamide (II-87, 13.6 mg, 7% yield, formic acid salt) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.32 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 1.6, 8.0 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.04 (dd, J = 1.2, 7.2 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H); MS (ESI): m/z for C19H16N5O4Cl [M+H]+ calcd.: 368.1 [M+H]+ found: 368.1. EXAMPLE 19 - Preparation of 6-Fluoro-N-(2-methyl-5-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (II-88) (60 mg, 0.319 mmol,
Figure imgf000218_0001
1.0 eq) in toluene (1 mL) was added a solution of 2 M trimethylaluminum in toluene (2 M, 319 μL, 2.0 eq) under nitrogen. The mixture was stirred at 25 °C for 0.5 h. Ethyl 6- fluoropyrazolo[1,5-a]pyridine-3-carboxylate (66 mg, 0.319 mmol, 1.0 eq) was added into the mixture and stirred at 80 °C for 2 h. The mixture was cooled to room temperature and quenched with ice water (10 mL). The solution was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150×25mm×5um; mobile phase: [water (formic acid)- acetonitrile ]; gradient:25%-45% B over 15 min) to give 6-fluoro-N-[2-methyl-5-(1-methyl- 1,2,4-triazol-3-yl)phenyl]pyrazolo[1,5-a]pyridine-3-carboxamide (II-88, 21 mg, 0.054 mmol, 17 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.75 (s, 1H), 9.22 - 9.17 (m, 1H), 8.79 (s, 1H), 8.50 (s, 1H)
Figure imgf000218_0002
8.31 - 8.21 (m, 1H), 8.04 (s, 1H), 7.80 - 7.74 (m, 1H), 7.69 - 7.59 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 2.30 (s, 3H); MS (ESI): m/z for: C18H15FN6O [M+H]+ calcd: 351.1, [M+H]+ found: 351.1.
EXAMPLE 20 - Preparation of N-(2-Methyl-5-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-7- (thiazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (II-89) O2N O2N H2N K2CO3 MeI B2(OH)4 44'-bipyridine
Figure imgf000219_0001
mmol, 1.0 eq) in acetonitrile (10 mL) was added potassium carbonate (1.62 g, 11.75 mmol, 2.0 eq) and iodomethane (1.0 g, 7.05 mmol, 439 μL, 1.2 eq). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated and diluted with water (20 mL). The yellow suspension was filtered, dissolved in ethyl acetate (20 mL), dried over anhydrous sodium sulfate, and concentrated to give 1-methyl-3-(4-methyl-3-nitro-phenyl)-1,2,4-triazole (0.78 g, crude) as a white solid.1H NMR (400 MHz, chloroform-d) δ = 8.69 (d, J = 1.6 Hz, 1H), 8.24 - 8.17 (m, 1H), 8.09 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H), 2.64 (s, 3H); MS (ESI): m/z for: C10H10N4O2 [M+H]+calcd: 219.1, [M+H]+ found: 219.0. [00488] Step 2: To a solution of 1-methyl-3-(4-methyl-3-nitro-phenyl)-1,2,4-triazole (280 mg, 1.28 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL) was added 4-(4-pyridyl)pyridine (10 mg, 0.64 mmol, 0.05 eq) and hypoboric acid (345 mg, 3.85 mmol, 3.0 eq). The mixture was stirred at 25 °C for 10 minutes. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- methyl-5-(1-methyl-1,2,4-triazol-3-yl)aniline (220 mg, crude) as a white solid. MS (ESI): m/z for: C10H12N4 [M+H]+calcd: 189.1, [M+H]+found: 189.0. [00489] Step 3: To a solution of 2-methyl-5-(1-methyl-1,2,4-triazol-3-yl)aniline (60 mg, 3.19 mmol, 1.0 eq) in toluene (1 mL) was added a solution of 2M trimethylaluminum in toluene (2 M, 319 μL, 2.0 eq) under nitrogen. The mixture was stirred at 25 °C for 0.5 h. Ethyl 7-thiazol-4- ylimidazo[1,2-a]pyridine-3-carboxylate (87 mg, 3.19 mmol, 1.0 eq) was added into the mixture and stirred at 80 °C for 2 h. The mixture was cooled to room temperature and quenched with ice water (10 mL). The solution was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Welch Xtimate C18150×25mm×5um; mobile phase: [water (formic acid)- acetonitrile]; gradient:15%-35% B over 15 min) to give N-[2-Methyl-5-(1-methyl-1,2,4-triazol- 3-yl)phenyl]-7-thiazol-4-yl-imidazo[1,2-a]pyridine-3-carboxamide (II-89, 18 mg, 0.038 mmol, 12 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.00 (s, 1H), 9.49 (d, J = 7.2 Hz, 1H), 9.29 (d, J = 1.6 Hz, 1H), 8.62 (s, 1H), 8.57 - 8.48 (m, 2H), 8.35 (s, 1H), 8.06 (s, 1H), 7.86 - 7.77 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 2.33 (s, 3H); MS (ESI): m/z for: C21H17N7OS [M+H]+calcd: 416.1, [M+H]+ found: 416.1 EXAMPLE 21 – Preparation of 7-(1-Methyl-1H-pyrazol-3-yl)-N-(2-methyl-5-(1-methyl-1H- 1,2,4-triazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (II-90) NH2 N N N H N N
Figure imgf000220_0001
, , , 0.019 mmol, 1.0 eq) in toluene (2 mL) was added a solution of 2M trimethylaluminum in toluene (2 M, 231μL, 2.5 eq) under nitrogen. The mixture was stirred at 25 °C for 0.5 h. Ethyl 7-(1- methylpyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxylate (50 mg, 0.185 mmol, 1.0 eq) was added into the mixture and it was stirred at 80 °C for 3 h. The mixture was cooled to room temperature and quenched with ice water (10 mL). The solution was extracted with dichloromethane (25 mL×2). The combined organic layers were washed with brine (10 mL×2), dried over with anhydrous sodium sulfate, filtered and concentrated reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (formic acid) – acetonitrile]; gradient:12%-42% B over 9 min) to give 7-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-5-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (II-90, 28 mg, 0.066 mmol, 36 %) as an off- white solid.1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.45 (d, J = 7.2 Hz, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 8.11 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 1.6, 8.0 Hz, 1H), 7.66 (dd, J = 1.6, 7.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 3.93 (d, J = 5.6 Hz, 6H), 2.32 (s, 3H); MS (ESI): m/z for C22H20ON8 [M+H]+ calcd: 413.2 [M+H]+ found: 413.2. EXAMPLE 22 - Preparation of 7-(1,1-Difluoroethyl)-N-(2-methyl-5-(1-methyl-1H-1,2,4- triazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (II-91)
Figure imgf000221_0001
mg, 3.19 mmol, 1.0 eq) in toluene (2 mL) was added a solution of 2M trimethylaluminum in toluene (2 M, 319 μL, 2.0 eq) under nitrogen. The mixture was stirred at 25°C for 0.5 h. Ethyl 7-(1,1- difluoroethyl)imidazo[1,2-a]pyridine-3-carboxylate (65 mg, 2.55 mmol, 0.8 eq) was added into the mixture and stirred at 80 °C for 2 h. The mixture was cooled to room temperature and quenched with ice water (10 mL). The solution was extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150×25mm×10um; mobile phase: [water(formic acid)-acetonitrile]; gradient:25%-55% B over 9 min) to give 7-(1,1-difluoroethyl)- N-[2-methyl-5-(1-methyl-1,2,4-triazol-3-yl)phenyl]imidazo[1,2-a]pyridine-3-carboxamide (II- 91, 31 mg, 0.79 mmol, 25 %) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.09 (s, 1H), 9.54 (d, J = 7.2 Hz, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.08 - 8.04 (m, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.99 (s, 1H), 7.89 - 7.70 (m, 1H), 7.47 - 7.30 (m, 2H), 3.93 (s, 3H), 2.33 (s, 3H), 2.08 (t, J = 19.2 Hz, 3H); MS (ESI): m/z for : C20H18F2N6O [M+H]+ calcd: 397.2, [M+H]+ found: 397.1. EXAMPLE 23 - Preparation of N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)- 2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (II-92) [00492]
Figure imgf000222_0001
yl)-2- methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (180 mg, 0.477 mmol, 1.0 eq) in N,N- dimethylformamide (4 mL) was added sodium hydride (29 mg, 0.715 mmol, 60% purity, 1.5 eq) at 0 °C and the reaction mixture was stirred at 25 °C for 0.5 h. Iodomethane (81 mg, 0.572 mmol, 1.2 eq) was added, and then the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched by the addition of water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x.5), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150×25mm×10um; mobile phase: [water(formic acid)-acetonitrile]; gradient:20%-50% B over 10 min) to give N-(5-(5-((1R,2S)-2- fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (II-92, 91 mg, 0.233 mmol, 49%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.68 - 9.33 (m, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.70 - 7.56 (m, 2H), 7.54 - 7.40 (m, 1H), 7.20 -7.10 (m, 1H), 6.51 - 6.25 (m, 1H), 5.39 - 5.06 (m, 1H), 3.37 (s, 3H), 2.70 - 2.65 (m, 1H), 2.22 (s, 3H), 1.95 - 1.79 (m, 1H), 1.68 - 1.53 (m, 1H); MS (ESI): m/z for C21H18FN5O2 [M+H]+ calcd: 392.1 [M+H]+ found: 392.2.
EXAMPLE 24 - Preparation of N-(5-(5-(3,3-difluoro-2-hydroxypropyl)-1,2,4-oxadiazol-3- yl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (II-93)
Figure imgf000223_0001
[00493] Step 1: To a solution of 5-(5-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-3-yl)-2-methylaniline (300 mg, 0.591 mmol, 1.0 eq) in hexafluoroisopropanol (3 mL) was added methyl trifluoromethanesulfonate (126 mg, 0.768 mmol,1.3 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether : ethyl acetate = 8 : 1) to give 5-(5-(2-((tert-butyldiphenylsilyl)oxy)-3,3- difluoropropyl)-1,2,4-oxadiazol-3-yl)-N,2-dimethylaniline (100 mg, 0.185 mmol, 96%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 7.64 - 7.59 (m, 2H), 7.51 - 7.38 (m, 6H), 7.37 - 7.31 (m, 2H), 7.15 - 7.07 (m, 2H), 6.95 (d, J = 1.2 Hz, 1H), 6.24 - 5.92 (m, 1H), 5.33 (s, 1H), 4.44 - 4.32 (m, 1H), 3.31 - 3.29 (m, 2H), 2.78 (s, 3H), 2.14 (s, 3H), 0.87 (s, 9H); MS (ESI): m/z for C29H33F2N3O2Si [M+H]+ calcd: 522.2, [MH]+ found: 522.3. [00494] Step 2: To a solution of 5-(5-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-3-yl)-N,2-dimethylaniline (80 mg, 0.153 mmol, 1.0 eq) in dichloromethane (2 mL) was added diisopropylethylamine (50 mg, 0.383 mmol, 2.5 eq) and imidazo[1,2-a]pyridine- 3-carbonyl chloride (33 mg, 0.153 mmol, 1.0 eq, HCl) at 0 °C. The mixture was stirred at 25 °C for 12 h under an N2 atmosphere. The reaction was purified directly by prep-TLC (silica gel, petroleum ether : ethyl acetate = 1:1) to give N-(5-(5-(2-((tert-butyldiphenylsilyl)oxy)-3,3- difluoropropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3- carboxamide (85 mg, 0.121 mmol, 79%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 9.52 (d, J = 3.6 Hz, 1H), 7.91 - 7.11 (m, 16H), 6.48 - 6.30 (m, 1H), 6.26 - 5.94 (m, 1H), 4.44 - 4.31 (m, 1H), 3.39 (s, 3H), 2.24 (s, 3H), 1.23 (s, 1H), 0.90 - 0.66 (m, 9H); MS (ESI): m/z for C37H37F2N5O3Si [M+H]+ calcd: 666.3, [M+H]+ found: 666.3. [00495] Step 3: To a solution of N-(5-(5-(2-((tert-butyldiphenylsilyl)oxy)-3,3-difluoropropyl)- 1,2,4-oxadiazol-3-yl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (75 mg, 0.113 mmol, 1.0 eq) in tetrahydrofuran (1 mL) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 0.135 mmol, 1.2 eq). The mixture was stirred at 25 °C for 1 h. The reaction was purified directly by prep-TLC (silica gel, petroleum ether : ethyl acetate = 1:1) to give the crude product. The crude product was purified by prep-HPLC (formic acid condition; column: YMC-Actus Triart C18150×30mm×7um; mobile phase: [water(formic acid)- acetonitrile]; gradient:20%-50% B over 10 min) to give N-(5-(5-(3,3-difluoro-2-hydroxypropyl)- 1,2,4-oxadiazol-3-yl)-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (II-93, 17 mg, 0.035 mmol, 31%) as a white solid and as a formic acid salt.1H NMR (400 MHz, DMSO-d6) δ = 9.49 (s, 1H), 8.04 - 7.94 (m, 2H), 7.69 - 7.55 (m, 2H
Figure imgf000224_0001
), 7.47 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 6.8 Hz, 1H), 6.49 - 6.24 (m, 1H), 6.20 - 5.84 (m, 2H), 4.22 (d, J = 4.4 Hz, 1H), 3.38 (s, 3H), 3.29 - 3.23 (m, 1H), 3.18 - 3.06 (m, 1H), 2.23 (s, 3H); MS (ESI): m/z for C21H19F2N5O3 [M+H]+ calcd: 428.15, [M+H]+ found: 428.2. EXAMPLE 25. Analytical Data for Compounds of the Present Invention [00496] The compounds listed in Table 2 below were prepared using experimental procedures analogous to those described in the Examples and Detailed Description. Table 2 also list each compound’s 1H NMR characterization data and mass-to-charge ratio observed by high-resolution MS or LC/MS. Chemical structures are presented in Table 1 above. TABLE 2. Compound Mass Spec. Chemical Shift Data
Figure imgf000224_0002
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Compound Mass Spec. Chemical Shift Data No. m/z (ppm, DMSO-d6, RT, unless stated otherwise) , z, 6
Figure imgf000236_0001
Exemplary compounds were tested for ability to inhibit the phosphorylation of a peptide substrate by the tyrosine kinase wt KIT, PDGFR ^, or CSF-1R. Assay procedures and results are described below. Part I – Procedures for HTRF Assay [00497] Enzyme, substrate, and cofactors (ATP and Mn2+) are combined in a well of a microtiter plate and incubated for 3 hours at 25oC. At the end of the incubation, the reaction is quenched by the addition of an EDTA-containing buffer. Assay Parameters: Peptide Substrate [00498] The substrate used in the CSF-1R and PDGFR ^ assay is FAM- KKKKEEIYFFF- CONH2 (FAM is carboxyfluorescein). Peptide should be >95% purity. The substrate for the KIT assay is FAM-GEEPLYWSFPAKKK-NH2. [00499] Assay Setup & Conditions 1. To a well of a 384-wellplate add 5μL of 2X enzyme buffer (or control). 2. Add 100 nL of 100X compound. Enzyme and compound may be pre-incubated at this time if desired. 3. Add 5 μL of 2X substrate buffer. 4. Incubate plate at 25°C for 3 hours. 5. Add 10uL of anti-phosphotyrosine antibody buffer. 6. Read plate in BioTek Synergy Reader. Reaction Conditions for wtKIT assay Final Assay Reaction Mixture 100 mM HEPES, pH 7.50.1% BSA 0.01% Triton x-100 1 mM DTT 10 mM MnCl2 10 μM Sodium Orthovanadate 10 μM Beta-Glycerophosphate 400 μM ATP 1% DMSO (from compound) 1 μM FAM-KKKKEEIYFFF-CONH2, 5.0 nM wtKIT Enzyme (1888289AM)* *Specific activity may vary from lot to lot. Enzyme concentration may need to be adjusted to yield 10-20% conversion of substrate to product. TABLE 3: Protein Lots and assay conditions Protein Assay Assay Vendor and [Enzyme], ATP Substr Incubat l Pl f l M i
Figure imgf000237_0001
Part II – Results [00500] Experimental results are provided in Table 4, below. The symbol “****” indicates an IC50 less than or equal to 0.05 ^M. The symbol “***” indicates an IC50 in the range of greater than 0.05 ^M and less than or equal to 0.5 ^M. The symbol “**” indicates an IC50 in the range of greater than 0.5 ^M and less than or equal to 5 ^M. The symbol “*” indicates an IC50 in the range of greater than 5 ^M to 30 ^M. Table 4. Compound KIT Biochemical CSF-1R Biochemical PDFGRα Biochemical No. IC50 avg (µM) IC50 avg (µM) IC50 avg (µM)
Figure imgf000238_0001
Figure imgf000239_0001
Compound KIT Biochemical CSF-1R Biochemical PDFGRα Biochemical No. IC50 avg (µM) IC50 avg (µM) IC50 avg (µM)
Figure imgf000240_0001
EXAMPLE 27 – Caliper Biochemical Assay for wtKIT, PDGFR ^ and CSF-1R Part I – Procedures for Biochemical caliper wtKIT Assay [00501] Enzyme, substrate, and cofactors (ATP and Mn2+) are combined in a well of a microtiter plate and incubated for 3 hours at 25oC. At the end of the incubation, the reaction is quenched by the addition of an EDTA-containing buffer. Substrate and product are separated electrophoretically using the microfluidic-based LabChip 3000 Drug Discovery System from Caliper Life Sciences* and quantitated by fluorescence intensity. Assay Parameters: Peptide Substrate [00502] The substrate used in the CSF-1R and PDGFR ^ assay is FAM- KKKKEEIYFFF- CONH2 (FAM is carboxyfluorescein). Peptide should be >95% purity. The substrate for the KIT assay is FAM-GEEPLYWSFPAKKK-NH2. Assay Setup & Conditions 1. To a well of a 384-well plate add 5 μL of2 X enzyme buffer(or control) 2. Add 100 nL of 100X compound. 3. Add 5 μL of 2X substrate buffer. 4. Incubate plate at 25°C for 3 hours. 5. Add 10uL of anti-phosphotyrosine antibody buffer. 6. Read plate LabChip 3000 Drug Discovery System Reaction Conditions 3 hours at 25°C where 100% Inhibitor: No enzyme. Final Assay Reaction Mixture 100 mM HEPES, pH 7.50.1% BSA 0.01% Triton X-100 1 mM DTT 10 mM MnCl2 10 μM Sodium Orthovanadate 10 μM Beta-Glycerophosphate 400 μM ATP 1% DMSO (from compound) 1 μM FAM-KKKKEEIYFFF-CONH25.0 nM wtKIT Enzyme (1888289AM)* *Specific activity may vary from lot to lot. Enzyme concentration may need to be adjusted to yield 10-20% conversion of substrate to product. TABLE 5: Materials & Buffers ITEM VENDOR PART NUMBER sis
Figure imgf000241_0001
Figure imgf000242_0003
Materials:
IX Core Buffer
100 mM HEPES, pH 7.5 0.1% BSA
0.01% Triton X-100
10 mM MnC12
1 mM DTT
10 μM. Sodium Orthovanadate 10 μM. Beta-Glycerophosphate
2X Enzyme Buffer
IX Core Buffer
10 nM c-KIT Enzyme (lot 1888289AM)
2X Substrate Buffer
IX Core Buffer
800 μM. ATP
2 μM. FAM-KKKKEEIYFFF-CONH2
2X Anti-phosphotyrosine antibody Buffer
50mM HEPES
0.05% Brij-35
145ng/mL Anti-Phosphotyrosine-Biotin antibody 20ng/ML Streptavidin
Part II - Results
[00503] Experimental results are provided in Table 6, below. The symbol “tTTt” indicates an
IC50 less than or equal to 0.05 μM. The symbol
Figure imgf000242_0001
indicates an IC50 in the range of greater than 0.05 μM. and less than or equal to 0.5 μM.. The symbol
Figure imgf000242_0002
indicates an IC50 in the range of greater than 0.5 μM. and less than or equal to 5 μM. The symbol “t” indicates an IC50 in the range of greater than 5 μM. to 30 μM..
TABLE 6.
Figure imgf000243_0001
Figure imgf000244_0001
EXAMPLE 28 - Cell-Based Assay for Inhibiting wtKIT
[00504] Exemplary compounds were tested for ability to inhibit KIT phosphorylation using M- 07e cells as monitored by pKIT ELISA. M-07e cells are also represented as M-07E, M-07e, M07-e, M07e, Mo7e, M07e, M07E and M07E. Assay procedures and results are described below.
Part I - Procedures for determining KIT inhibition inM-07e cells using pKIT ELISA
[00505] Reagents and consumables:
• M-07e cells: Initially obtained from Accegen, cat# ABC-TC1313
• p-cKIT Capture ELISA antibody: anti- Human Phospho-CDl 17/c-kit, R&D cat# DYC3527-5
• Anti-pY-HRP antibody: R&D cat# DYC3527-5
• 25x wash buffer: Quantikine ELISA Wash Buffer 1, R&D cat# WA126
• PBS: R&D cat# DY006
• 96well ELISA plates: Clear Polystyrene Microplates, R&D Cat# DY990
• 96well Tissue culture plates: Corning® 96 Well TC-Treated Microplates, cat# CLS3894
• RPMI medium : ATCC® RPMI- 1640 Medium, Cat# 30-2001 FBS: Fetal Bovine Serum, certified, United States Gibco, Thermo-Fisher 16000044 GM-CSF: Recombinant Human GM-CSF Protein, R&D cat# 215-GM SCF: Recombinant Human SCF Protein, R&D cat# 255-SC
[00506] Protocol:
1. Prepare cells: a. Culture M-07e cells in RPMI medium +20% serum +GM-CSF+penstrep To make 50mL of growth medium i. 40 mL RPMI media ii. lO mL FBS iii. 10 uL of GM-CSF (lOOug/mL stock) iv. 0.5 mL pen strep (lOOx) b. Harvest cells c. Re-suspend cells in 100% RPMI media (without serum) to final concentration of 1 million cells/ mL d. Transfer 100 uL of cell solution to 11 columns of a 96 well flat bottom cell culture plate e. Incubate cells over night at 37C
2. Prepare ELISA Plates: a. Dilute capture antibody to concentration 4 ug/mL in PBS b. Coat 96 well microplates with 100 uL of capture antibody c. Seal plates and incubate at RT overnight d. Wash plates with 300 uL of wash buffer e. Repeat wash f. Treat plates with 300 uL of blocking buffer at RT for 1 hour
3. Addition of compounds: a. Prepare compound dilutions in RPMI media i. Top test concentration is 1 uM ii. Serially dilute compounds 3x for a total of 8 concentrations b. Add 10 uL of lOx compound dilutions to cells i. No compounds added in column 11 (for controls) c. Incubate cells with compounds for 2 hours at 37C d. Stimulate cells with SCF for 5 min at concentration of lOOng/mL (final) i. In column 11 stimulate top 4 wells. Leave bottom 4 wells unstimulated e. Remove cell culture media with multichannel pipet f. Add 110 uL of Lysis buffer to all wells g. Incubate plates at RT for 30 min while shaking
4. Transfer lOOuL of cell lysis to each prepared Elisa plate
5. Add 100 uL of the standard pc-KIT dilutions to the standard wells in column 12 a. Top concentration = 2000 pg/mL b. 2x dilutions
6. Incubate ELISA plate with cell lysate for 2 hours at RT
7. Wash Plate with wash buffer (wash 1)
8. Repeat wash (wash 2)
9. Repeat wash (wash 3) (do not allow plate to dry)
10. Add 100 uL of diluted anti-pY-HRP (1/1000 dilution in detection antibody dilution buffer) and incubate 2 hours at RT
11. Wash plate with wash buffer (wash 1)
12. Repeat wash (wash 2)
13. Repeat wash (wash 3)
14. Add 100 uL of substrate solution to each well
15. Incubate plates 20 min
Note: Plate development is indicated by aqua color
16. Add 50 uL of stop solution to each well
17. Determine optical density on Bitek Synergy Neo2: a. Make new experiment
Select absorbance 1 set to 450 nm
Figure imgf000246_0001
Part II - Results
[00507] Experimental results are provided in Table 7, below. The symbol “++++” indicates an
IC50 less than or equal to 0.05 μM.. The symbol “+++” indicates an IC50 in the range of greater than 0.05 qM and less than or equal to 0.5 qM. The symbol “++” indicates an IC50 in the range of greater than 0.5 qM and less than or equal to 5 qM. The symbol “+” indicates an IC50 in the range of greater than 5 qM to 30 qM.
TABLE 7.
Figure imgf000247_0001
EXAMPLE 29 - Permeability Assays and/or inhibition Assays and/or efflux assays in Caco-2, MDCKII-MDR1, and MDCKII-BCRP Cell Lines
[00508] Exemplary compounds were tested for cell permeability in Caco-2, MDCKII-MDR1 and MDCKII-BCRP cell lines with efflux transporter engagement inferred from the efflux ratios determined. Procedures and results are described below. As described above and herein, it has been surprisingly found that certain compounds of the present invention have reduced brain penetration. This feature of certain compounds is in part due to efflux transporter engagement. See, for instance, exemplary such compounds included in data tables below.
Part I - Procedures for Assays
5. Caco-2 Permeability Assay
Methodology
Materials coming 96-well insert plate Cat:351131 coming 96-well acceptor plate Cat: 353925
Caco-2 Culture
[00509] Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96-well Coming Insert plates at 1 x 105 cells/ cm2, and refreshed medium every 4~5 days until to the 21st to 28th day for confluent cell monolayer formation.
Experimental Procedures
[00510] The transport buffer in the study was HBSS with 10.0 mM HEPES at pH 7.40±0.05. Test compound was tested at 2.00 μM. bi-directionally in duplicate. Digoxin was tested at 10.0 μM. bi-directionally in duplicate, while nadolol and metoprolol were tested at 2.00 μM. in A to B direction in duplicate. Final DMSO concentration was adjusted to less than 1%. The plate was incubated for 2 hours in CO2 incubator at 37±1°C, with 5% CO2 at saturated humidity without shaking. And all samples after mixed with acetonitrile containing internal standard were centrifuged at 3200 xg for 10 min. For nadolol and metoprolol, 200 pL supernatant solution was diluted with 600 pL ultra-pure water for LC-MS/MS analysis. For digoxin and test compounds, 200 pL supernatant solution was diluted with 200 pL ultra-pure water for LC-MS/MS analysis. Concentrations of test and control compounds in starting solution, donor solution, and receiver solution were quantified by LC-MS/MS methodologies, using peak area ratio of analyte/internal standard.
[00511] After transport assay, lucifer yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity.
[00512] After transport assay, Lucifer yellow rejection assay was applied to determine the Caco-2 cell monolayer integrity. And permeation of lucifer yellow through the monolayer was measured to evaluate the cellular integrity.
Data Analysis
[00513] The apparent permeability coefficient Papp (cm/s) was calculated using the equation:
Papp = (dCr/dt) x Vr / (A x Co), where dCr/dt is the cumulative concentration of compound in the receiver chamber as a function of time (μM/.s); Vr is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, i.e. 0.0804 cm2 for the area of the monolayer; Co is the initial concentration in the donor chamber (μM)..
[00514] The efflux ratio was calculated using the equation: Efflux Ratio = Papp (BA) / Papp (AB).
[00515] Percent recovery was calculated using the equation: % Solution Recovery = 100 x [(Vr x Cr) + (Va x Cd)] / (Vd x Co), where Vd is the volume in the donor chambers (0.075 mL on the apical side, 0.25 mL on the basolateral side); Cd and Cr are the final concentrations of transport compound in donor and receiver chambers, respectively.
B. MDCKII-BCRP Assay
[00516] The reference compound Teriflunomide and test compounds are tested in the bidirectional assay. Test compound and reference compounds incubations were tested in duplicates.
[00517] The transport assay can be performed between days 12 to day 15 using ready to use PreadyPort™ BCRP-MDCKII monolayer in 96 well plate.
[00518] PreadyPart™ plate was removed from the incubator and placed in the laminar flow hood. [00519] The medium was aspirated from the apical and basal compartments and 75 and 235 pL assay buffer was added to each of the 96 wells of apical and basal compartments of the PreadyPoRT™ plate.
[00520] The plates were pre-incubated for 15 min at 37°C with 5% CO2 in humidified atmosphere. After preincubation the assay buffer was removed from the apical and basal inserts of the plate.
[00521] In apical to basolateral (A— >B) transport, 75 pL of test or reference compound working solution to apical inserts and 235 pL of blank assay buffer were added to the corresponding basal compartments.
[00522] In basolateral to apical transpo, 235 pL of test or reference compound working solution to the basal compartments and 75 pL of blank assay buffer solution were added to corresponding apical inserts.
[00523] The sandwich plate was incubated for 120 min in incubator at 5 % CO2 and 37°C.
SAMPLE PROCESSING
[00524] After incubation, 60 pL was transferred from receiver and donor compartments to collection plate.
[00525] For donor and Co samples 20-fold dilution was accomplished by mixing 60 pL of collected sample with 1140 pL of transport buffer and from that solution aliquot 60pLtransfer Both receiver and donor samples were processed by adding 5 volumes of acetonitrile containing internal standard (60 pL of sample + 240 pL of acetonitrile containing glyburide as internal standard, 125 ng/mL) and vortexing the samples. The compound concentration was measured in all samples using respective calibration standards by LC-MS/MS.
Note:
• Any changes in the procedure should be captured in LNB.
• Replicates and test concentration can be only modified with due approval of the group leader.
• Choice of buffers, pH, and temperature can be modified as requested by the end user.
DATA ANALYSIS
Calculate the Papp and recovery using the given formula:
Figure imgf000251_0001
(donor volume x Cend,d) + (acceptorvolume x Cend, a)
Recovery% = 100 x donar volume x C HBSS
Where: dQ/dt = Permeability rate in μM/.sec
Co = Initial concentration in μM.
A = Membrane surface area (0.33 cm2)
V = Volume of receiver chamber
Cend, a = concentration in acceptor well at end of incubation Cend, d = concentration in donor well at end of incubation CHBSS = loading concentration measured in HBSS
Classification of transport is as follows:
Figure imgf000251_0004
Calculation for efflux ratio:
Figure imgf000251_0003
Criteria for efflux ratio:
Figure imgf000251_0005
LYR:
Figure imgf000251_0002
C. Permeability in MDR1-MDCKII cell protocol
[00526] MDR1-MDCKII cells (obtained from Piet Borst at the Netherlands Cancer Institute) were seeded onto polyethylene membranes (PET) in 96-well insert systems at 2.5 x 105 cells/ mL until to 4-7 days for confluent cell monolayer formation. [00527] Test compounds were diluted with the transport buffer (HBSS with lOmM Hepes, pH7.4) from DMSO stock solution to a concentration of 2.00 μM. (DMSO <1%) and applied to the apical or basolateral side of the cell monolayer. Permeation of the test compounds from A to B direction or B to A direction was determined in duplicate. Digoxin was tested at 10.0 μM. from A to B direction or B to A direction as well, while nadolol and metoprolol were tested at 2.00 μM. in A to B direction in duplicate. The plate was incubated for 2.5 hours in CO2 incubator at 37±1°C, with 5% CO2 at saturated humidity without shaking. In addition, the efflux ratio of each compound was also determined. Test and reference compounds were quantified by LC-MS/MS analysis based on the peak area ratio of analyte/IS.
[00528] After transport assay, Lucifer yellow rejection assay are applied to determine the cell monolayer integrity. Buffers are removed from both apical and basolateral chambers, followed by the addition of 75 pL of 100 μM. lucifer yellow in transport buffer and 250 pL transport buffer in apical and basolateral chambers, respectively. The plate is incubated for 30 minutes at 37°C with 5% CO2 and saturated humidity without shaking. After 30 minutes incubation, 20 pL of lucifer yellow samples are taken from the apical sides, followed by the addition of 60 pL of Transport Buffer. And then 80 pL of lucifer yellow samples are taken from the basolateral sides. The relative fluorescence unit (RFU) of lucifer yellow is measured at 425/528 nm (excitation/emission) with an Envision plate reader.
DATA ANALYSIS
[00529] The apparent permeability coefficient Papp (cm/s) was calculated using the equation: Papp = (dCr/dt) X Vr/ (Ax Co)
Where dCr/dt is the cumulative concentration of compound in the receiver chamber as a function of time (μM/.s); Vr is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, i.e. 0.0804 cm2 for the area of the monolayer; Co is the initial concentration in the donor chamber (μM)..
The efflux ratio was calculated using the equation:
Efflux Ratio = Papp (BA) / Papp (AB)
Percent recovery was calculated using the equation:
% Recovery = 100 x [(Vr x Cr) + (Vd x Cd)] / (Vd x Co) Where Va is the volume in the donor chambers (0.075 mb on the apical side, 0.25 mL on the basolateral side); Cd and Cr are the final concentrations of transport compound in donor and receiver chambers, respectively.
Part II - Results
TABLE 8.
Figure imgf000253_0001
EXAMPLE 30 - Three Time Point Assay for Plasma, Brain and Testes Distribution [00530] Exemplary compounds were tested for distribution in plasma, brain and testes tissue following oral dosing of the compounds in rats. Procedures and results are described below.
Part I - Procedures for Three Time Point Assay for Plasma, Brain and Testes Distribution Animal Husbandry:
[00531] Male SD Rats were group-housed (up to four animal s/sex/cage) in polysulfone cages with certified aspen wood bedding during acclimation and study period.
[00532] Environment controls were set to maintain a temperature range of 20-26°C, a relative humidity range of 40 to 70%, and a 12-hour light/12-hour dark cycle. The light/dark cycle was interrupted as needed for study-related activities. The temperature and relative humidity were continuous monitored by Vaisala ViewLinc Monitoring system.
Animal Fasting Detail Information:
[00533] Certified rodent diet and water was provided to all animals ad libitum, unless fasting for study procedures.
[00534] Water was autoclaved before it was provided to the animals. Water samples were periodically analyzed by a certified laboratory for specified microorganisms and environment contaminants. The diet was routinely analyzed by the manufacturer for specified microorganisms, nutritional components and environmental contaminants. Results were reviewed and assessed by veterinary staff and archived.
Dose Formulation
Formulation for PO:
[00535] Appropriate amount of test article was accurately weighed and mixed with an appropriate volume of vehicle to get a clear solution or a uniform suspension; vortexing or sonication in water bath may also be need. Animals were dosed within four hours after the formulation is prepared.
[00536] Formulation samples were removed from each of the formulation solutions or suspensions, transferred into 1.5 mb of polypropylene microcentrifuge tubes and run dose validation by LC/UV or LC-MS/MS.
Dose Administration:
[00537] For PO dosing, the dose formulation was administered via oral gavage following facility SOPs. The dose volume was determined by the animals’ body weight collected on the morning of dosing day. The dose was 10 mg/kg. Sample Collection
Blood Collection:
[00538] Each blood collection (about 1 mb per time point at one or more of 0.5h, 2h, 3h, 5.3h, and 7h) was performed from jugular vein or other suitable site of each animal into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifugation.
Plasma Processing:
[00539] Blood samples were processed for plasma by centrifugation at approximately 4°C, 3,200 g for 10 min. Plasma was collected respectively and transferred into pre-labeled 96 well plate or polypropylene tubes, quick frozen over dry ice and kept at -60°C or lower until LC- MS/MS analysis.
Brain and testis tissue processing:
[00540] Rat brain was perfused with PBS to remove blood before harvest.
[00541] After perfusion, brain and testis were homogenized using homogenizing buffer (15 mM PBS (pH7.4):MeOH=2: 1) at the ratio of 1 :9 (1 g tissue with 9 mL buffer, the dilution ratio is 10). The brain homogenate was kept at -60°C or lower until LC-MS/MS analysis. General sample processing procedure (brain homogenate & testis homogenate) using 96-well plate:
1). An aliquot of 40 pL unknown sample, calibration standard, quality control and dilution quality control (if have), single blank, and double blank sample was added to the 96-well plate respectively;
2). Each sample (except the double blank) was quenched with 400 pL of IS1 respectively (double blank sample was quenched with 400 pL of f), and then the mixture was vortex -mixed for 10 min at 800 rpm and centrifuged for 15 min at 3220 x g, 4°C;
3). An aliquot of 50 pL supernatant was transferred to another clean 96-well plate and centrifuged for 5 min at 3220 x g; 4°C, then the supernatant was directly injected for LC-MS/MS analysis.
Clinical Observations
[00542] All animals were observed at dosing and each scheduled collection. All abnormalities were recorded. Dose formulation concentration verification
■ A LC-UV or LC-MS/MS method was developed with a calibration curve consisting of 6 calibration standards.
■ The concentrations of the test compound in dose formulation samples were determined by the LC-UV or LC-MS/MS method.
■ Acceptance criteria for an analytical run: at least of 5 of 6 calibration standards should be within ±20% of nominal values by using LC-UV method and ±30% of nominal values by using LC-MS/MS method.
Bioanalytical method development and sample analysis
LC-MS/MS method development:
1. A LC-MS/MS method for the quantitative determination of test compound in biological matrix was developed under Non-GLP compliance.
2. A calibration curve with at least 6 non-zero calibration standards was applied for the method including LLOQ.
3. A set of QCs consisting of low, middle, and high concentrations were applied for the method.
4. N in 1 cassette LC-MS/MS method was developed for samples coming from different studies and the interference among all cassette analytes was evaluated during the method development.
5. Cassette administration assay was performed if the mass difference (Amass) among different analytes was more than 4 Da. In this case, interference evaluation was not necessary.
If the Amass among different analytes was less than 4 Da, there was a potential risk that interference would occur during LC-MS/MS analysis. Interference among analytes was evaluated but the LC separation of those analytes by using a generic method was tried. If these analytes could not be separated, the experiment record was documented.
6. Biological sample in matrix other than plasma was diluted with plasma first and then quantified against plasma calibration curve. And the corresponding dilution QC to ensure the dilution accuracy and no significant matrix difference, was inserted into analytical run.
Sample analysis: 1 . If sample number within a batch was < 12, at least one set of standard curve separated with two parts through begin and end of the sequence, was included in the run, and QCs were not required. The recommended injection order was C8, C6, C4, C2, study samples, C7, C5, C3, Cl.
2. If sample number within a batch was > 12, one standard curve and two sets of QCs with low, middle and high concentrations were applied for bioanalysis. Meanwhile, QCs number should be more than 5% of study sample number.
3. Samples with the same types of matrix in different studies were quantified in one analysis run by using the developed N in 1 cassette LC-MS/MS method.
4. Biological samples in matrix other than plasma were diluted with plasma and then quantified against plasma calibration curve. The corresponding dilution QC to ensure the dilution accuracy and no significant matrix difference, will be inserted into analytical run. Optionally, biological samples were quantified against calibration curves in their own corresponding matrix.
Acceptance criteria:
1. Linearity: > 75% STDs is back calculated to within ±20% of their nominal values in biofluid and within ±25% of their nominal values in tissue and feces sample. If the endpoints, such as LLOQ and ULOQ, on the calibration curve are eliminated, the calibration curve will be truncated. The truncated calibration curve should consist of at least 75% of the initial STDs.
2. Accuracy: > 67% QCs is back calculated to within ±20% of their nominal values for biofluid and within ±25% of their nominal values for tissue and feces samples.
3. Specificity: The mean calculated concentration in the single blank matrix should be < 50% LLOQ.
4. Sensitivity:
4.1 If the biological samples in matrix other than plasma were diluted with plasma and quantified against plasma calibration curve, the LLOQ of plasma calibration curve were targeted to < 2 ng/mL, which LLOQ is equivalent to < 4 ng/mL in biological matrix other than plasma (if dilution 2 folds is applied).
4.2 If the biological samples were quantified against the calibration curves prepared by their corresponding matrix, the LLOQ was targeted to < 3 ng/mL. 5. Carryover: The mean calculated carry-over peak area in the blank matrix immediately after the highest standard injection should be less than that of LLOQ. If the carryover couldn’t meet the criteria, the impact of the carryover on unknown samples should be evaluated according to the below procedure:
[00543] Carryover evaluation should be estimated according to absolute carryover. Carryover contribution is calculated by the area ratio of the blank with the highest carryover (Area max of carryover blank) to the ULOQ with the minimum calculated value (Area min of ULOQ);
Carryover impact is calculated by the area ratio of one injection (Area of one injection) to the following injection (Area of the following injection); Absolute carryover is calculated by carryover contribution multiplies carryover impact, the value of absolute carryover should be below the acceptable accuracy of the studies (e.g., 20% or 25%).
Carryover contribution = Areamax of carryover blank / Areamin of ULOQ
Carryover impact = Area of one injection / Area of the following injection
Absolute carryover = Carryover contribution * Carryover impact
REQUIREMENTS
Part II - Results
TABLE 9.
Figure imgf000258_0001
Figure imgf000259_0001
EXAMPLE 31 - Hepatocyte CYP Induction Assay
[00544] Exemplary compounds were tested for ability to induce CYP3A4 and/or CYP1A2 in hepatocytes. Procedures and results are described below.
Part I - Procedures for CYP Induction Assay
Materials and METHODS
Hepatocytes
[00545] Cryopreserved human hepatocytes were purchased from BioIVT (Baltimore, MD, USA), and they were stored in liquid nitrogen before using. The detailed information of hepatocytes is as follows:
Control Compound
Positive control was purchased from commercial vender.
The detailed information is as follows:
Catalog
Reference Compound Application Source Numbe r
Rifampicin positive control Sigma- Aldrich R3501
Reagents and Consumables
_ Name _ Source Catalog Number
Acetonitrile Merck Chemical 1.00030.4008
Dexamethasone Sigma-Aldrich D1756
Dimethyl sulfoxide Sigma-Aldrich D2650
Fetal bovine serum AusgeneX FBS500-S
HEPES Buffer Solution (I M) Gibco 15630-080
Methanol Merck Chemical 1.06007.4008 Matrigel BD Biosciences 4E+05
HBSS Gib co 14025-076
Incubation Medium BioIVT Z99009
Plating Medium BioIVT S03316
Penicillin & Streptomycin HyClone SV30010 Opti THAW Hepatocyte media Xenotech K8000 TaqMan universal PCR
Applied Biosystems 4E+06 MasterMix
Eukaryotic 18S rRNA
Applied Biosystems 4319413E Endogenous Control
Human CYP3A4 20X Gene Expression Assay labeled with Applied Biosystems Hs00604506-ml FAM/MGB iScript cDNA Synthesis Kit Bio-Rad 2E+06
Rneasy 96 QIAcube HT Kit QIAGEN 74171 QIAcube HT Kit Plasticware QIAGEN 1E+06
Lactate dehydrogenase
Beyotime C0016 cytotoxicity assay kit Collagen-coated 96-well plates Corning 4E+05 PCR Microplate Axygen PCR-96-FLT-C
Optical 96-Well Reaction Plate Bio-Rad HSP-9601 Optical 384-Well Reaction Plate Bio-Rad HSP-3805
Apparatus
Water purification system (PURELAB Classic, ELGA, England)
Pipettors (Single/Multiple channels, Eppendorf, Germany)
CO2 Incubator (Thermo, HERA CELL 240i, Germany)
QIAcube HT System (Qiagen, QIAcube HT, USA)
Cl 000 Touch Thermal Cycler (BIO-RAD, Cl 000 Touch, USA)
BIO-RAD CFX 384 Touch Real Time PCR System (BIO-RAD, CFX 384 Touch, USA)
NanoDrop ND-2000 Spectrophotometer (Thermo, NanoDrop ND2000, USA)
Centrifuge (Eppendorf, 5810R, Germany)
Microplate spectrophotometer (Molecular Devices, Spectra Max M2e, USA)
Microplate Shaker (Thermo, 100-240V, 50-60Hz, China)
Shaker (IKA, MS3 digital,
Germany)
Preparation of Solution Preparation of Stock Solution:
Figure imgf000261_0001
Preparation of Dosing Solution
[00546] Fresh dosing solutions of test compounds, and Rifampicin were prepared in the incubation medium on the day of dosing. The detailed information of the dosing solution is listed in the following table.
„ . x T . Concentration of
Compound Name Final Concentration _ . „ ,
Organic Solvent
0.100, 1.00, 3.00, n i 0/ nilcn i 1n0.o0 and j a 3n0.n0 u AM/T 0..1.% . DMSO
_ _ _ (v/v)
Rifampicin 10.0 μM.
Hepatocyte Preparations
[00547] Cryopreserved hepatocytes were thawed and counted to determine yield, viability was measured. Hepatocytes at the concentrations of 0.7 million/mL were transferred to collagen-coated 96-well plates for attachment (0.1 mb viable cells/well). After allowing 4 to 5 hours for attachment of cells, the plating medium was replaced with Incubation Medium containing 2% (v/v) Matrigel™ (sandwich medium) and the hepatocytes were incubated until use.
Hepatocyte Incubations
[00548] All incubations were conducted at 37°C, 5% CO2, and saturated humidity.
[00549] The sandwich medium was removed and the hepatocytes were treated with incubation solutions containing test articles in vehicle (0.1% DMSO), or positive control for 24 hours after the cultures were established. The incubation solution was aspirated and replaced with incubation solution containing the same concentrations of test articles, vehicle, or positive controls for an additional 24 hours. The total treatment period was 48 hours. Triplicate were used for each concentration of test compound and positive control.
[00550] After treatment period of 48 hours, the incubation solution was aspirated. Hepatocytes were washed once with pre-warmed HBSS and incubated with 140 pL of RLT (lysis buffer from Rneasy 96 Kit) supplemented with 1% P-mercaptoethanol. Plates were then stored at <-60°C freezer until RNA analysis.
Cytotoxicity Assessment
[00551] Cytotoxic potential of test articles was evaluated by determining the activity of lactate dehydrogenase (LDH) in the incubation medium following incubations with test compounds and vehicle for 24 hours and 48 hours, respectively, using a commercially available LDH kit. Cell lysis solution was used as a positive control and incubation medium was used as a blank control in this assay.
RNA Analysis
[00552] Before RNA extraction, the frozen plate was thawed and cell lysates were transferred to 96-well plates. RNA isolation was performed using QIAcube HT System. RNA concentration was measured with NanoDrop ND-2000 spectrophotometer. The purity of RNA preparation was calculated by the ratio of the OD260 nm/OD280 nm and the acceptable range is between 1.8 and 2.2. Reverse transcription was performed to obtain cDNA. Quantification of the selective genes by real time quantitative Polymerase Chain Reaction (qPCR) was performed with TaqMan universal PCR Master Mix on the BIO-RAD CFX 384 Touch Real Time PCR System. The following setting were used: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles of 95°C for 15 seconds and 60°C for 1 minute. 18S rRNA was used as the internal standard.
Data Analysis
Gene Expression
[00553] To account for variation in RNA yields and reverse transcription polymerase chain reaction (RT-PCR), the gene of interest in all samples was normalized to an internal control gene (18S ribosomal RNA) (Cttarget gene - Ctiss= ACt).
[00554] The relative quantitation or change in mRNA level of selected genes induced by each test compound was expressed in relation to the vehicle control sample (Actcompound -ACtvehicie= AACt). Fold changes in gene expression were determined by taking 2 to the power of this value (2‘
AACt' The percent of positive control was calculated with the formula below and reported.
% of positive control = [(fold change in treated sample)-!] / [(fold change in positive control)-!] * 100
Classification and Criteria
Parameters Classification Criteria
,, i i >4 fold of
Gene expression for PC Acceptable . . . x . vehicle control
<2 fold of Non-inducer vehicle control and <20% of PC >2 fold of vehicle control Gene expression for test T . and increased in
. Inducer A . compound a concentrationdependent manner <2 fold of Possible vehicle control
Figure imgf000263_0001
Part II - Results
[00555] Experimental results are provided in Table 10, below. The symbol “+” indicates induction fold of less than or equal to 2-fold. The symbol “++” indicates induction fold of greater than 2-fold to less than or equal to 3-fold. The symbol “+++” indicates induction fold of greater than 3-fold to less than or equal to 10-fold. The symbol “++++” indicates induction fold of greater than 10-fold.
TABLE 10.
Figure imgf000263_0002
EXAMPLE 32- Kinetic solubility assay procedure [00556] 10 pl. of 10 mM in DMSO of test article and control compounds was added into lower chambers of whatman miniuniprep vials, respectively. 490 pL of 50 mM PB (pH 7.4) was then added into lower chambers of the whatman miniuniprep vials, respectively. The solubility samples were then vortexed for at least 2 minutes. Miniuniprep vials were shaken for 24 hours at RT at the speed of 800 rpm, centrifuged 20 minutes (eg. 4000 rpm) and the filtrates were analyzed by UPLC-UV/HPLC-UV system to calculate the concentration with standard curve.
[00557J Filter Membrane: Miniuniprep (PTFE Filter Media with Polypropylene Housing) Cat. No.UN203NPUORG, GE Halthcare Whatman.
[00558] Experimental results are provided in Table 11, below. The symbol “++++” indicates a solubility less than or equal to 2 μM.. The symbol “+++” indicates a solubility greater than 2 μM. and less than or equal to 10 μM.. The symbol “++” indicates a solubility greater than 10 μM. and less than or equal to 50 μM.. The symbol “+” indicates a solubility greater than 50 μM..
TABLE 11
Figure imgf000264_0001
Figure imgf000265_0001
EXAMPLE 33 - BCRP Inhibition: Vesicular Transport Assays [00559] Vesicular transport assays are performed with inside-out membrane vesicles prepared from cells overexpressing human ABC transporters. The transporters are expressed by SOLVO Biotechnology mammalian (HEK293) cells. The mammalian cells are stably transfected with the ABC transporter BCRP. Test articles are incubated with membrane vesicle preparations and the probe substrate (E3S, 1 μM).. Incubations are conducted in the presence of 4 mM ATP or AMP to distinguish between transporter-mediated uptake and passive diffusion into the vesicles. Test compounds are added to the reaction mixture in 0.75 pL of solvent (1% of the final incubation volume). Reaction mixtures are preincubated for 15 minutes at 32 ± 1°C. Reactions are initiated by the addition of 25 pL of pre-warmed 12 mM Mg ATP (or 12 mM AMP in assay buffer as a background control). Reactions are quenched by the addition of 200 pL of ice-cold washing buffer and immediate filtration via glass fiber filters mounted to a 96-well plate (filter plate). The filters are washed (5 x 200 pL of ice-cold washing buffer), dried and the amount of substrate inside the filtered vesicles is determined by liquid scintillation counting.
INCORPORATION BY REFERENCE
[00560] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.
EQUIVALENTS
[00561] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

We Claim:
1. A compound represented by Formula I:
Figure imgf000267_0001
or a pharmaceutically acceptable salt thereof; wherein:
RA is of either of the following structures:
Figure imgf000267_0002
each of which is substituted by n occurrences of R3;
R3 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCRs, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2,
N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, - N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -L2-R5, or an optionally substituted group selected from C1-6 aliphatic, C1-6 haloaliphatic, phenyl, naphthalenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted with r instances of R; or: two R3 groups on adjacent carbon atoms are taken together with the carbon atoms to which they attach to form an optionally substituted 4-7 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with r instances of R;
L2 represents independently for each occurrence a Ci-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, S(O)2- or -Cy-;
Cy represents independently for each occurrence phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R5 represents independently for each occurrence hydrogen, OR, Ci-6 aliphatic, Ci-6 haloaliphatic, or phenyl fused to a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
X is O or S;
R1 represents independently for each occurrence halogen, -CN, -OR, -NR2, -C(O)R, - C(O)OR, -C(O)NR2, CI-6 alkyl, or Ci-6haloalkyl;
L is a bond or -N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;
RB is phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein RB is substituted with q occurrences of R2;
R2 represents independently for each occurrence halogen, oxo, Ci-6 aliphatic, phenyl, a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-10 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L'-R4; wherein R2 is substituted with p occurrences of R6;
L1 represents independently for each occurrence a Ci-2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2- , -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;
R4 represents independently for each occurrence a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R6 represents independently for each occurrence oxo, halogen, -CN, -NO2, -OR, -OCR3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(R)2OR, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -
N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, or optionally substituted phenyl;
R7 is hydrogen or C1-3 alkyl; each R is independently hydrogen, -CN, halogen, or an optionally substituted group selected from Ci-6 aliphatic; C1-6 haloaliphatic; phenyl; naphthal enyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0 or 1; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1, 2, 3, 4, or 5. The compound of claim 1, wherein the compound is a compound of Formula I.
The compound of either of claims 1-2 wherein when L is a bond and RB is
Figure imgf000270_0001
, X is S. The compound of either of claim 1 or 2, wherein X is O. The compound of either of claim 1 or 2, wherein X is S. The compound of any one of claims 1-5, wherein R1 is halogen. The compound of any one of claims 1-5, wherein R1 is Ci-6 alkyl. The compound of any one of claims 1-5, wherein R1 is methyl. The compound of any one of claims 1-5, wherein R1 is Ci-6 haloalkyl. The compound of any one of claims 1-5, wherein R1 is -OR, -NR2, -C(O)R, -C(O)OR, -or
C(O)NR2. The compound of claim 10, wherein R1 is -OH, -OCH3, -NH2, -N(CH3)2, -C(O)CH3, - C(O)OCH3, -C(O)NH2, -C(O)NHCH3, or -C(O)N(CH3)2. The compound of any one of claims 1-5, wherein m is 0. The compound of any one of claims 1-11, wherein m is 1. The compound of any one of claims 1-11, wherein the compound is represented by the following or a pharmaceutically acceptable salt thereof:
Figure imgf000271_0001
I-c I-d. The compound of any one of claims 1-11, wherein the compound is represented by the following or a pharmaceutically acceptable salt thereof:
Figure imgf000271_0002
I-e. The compound of claim 1, wherein the compound is represented by either of the following or a pharmaceutically acceptable salt thereof:
Figure imgf000272_0001
I-f I g- The compound of claim 1, wherein the compound is represented by one of the following or a pharmaceutically acceptable salt thereof:
Figure imgf000272_0002
I-k 1-1. The compound of any one of claims 1-14, wherein n is 0. The compound of any one of claims 1-14, wherein n is 1. The compound of any one of claims 1-14, wherein n is 2. The compound of any one of claims 1-14, wherein n is 3. The compound of any one of claims 1-14, wherein n is 4. The compound of any one of claims 1-14, wherein n is 5. The compound of any one of claims 1-2 or 4-23, wherein RB is selected from:
Figure imgf000273_0001
The compound of any one of claims 1-17 or 19-24, wherein at least one R3 is halogen. The compound of any one of claims 1-17 or 19-24, wherein at least one R3 is bromo. The compound of any one of claims 1-17 or 19-24, wherein at least one R3 is -CN. The compound of any one of claims 1-27, wherein at least one R2 is Ci-6 alkyl. The compound of any one of claims 1-27, wherein at least one R2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. The compound of claim 29, wherein at least one R2 is a 3-4 membered saturated monocyclic carbocyclic ring. The compound of any one of claims 1-27, wherein at least one R2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound of claim 31, wherein at least one R2 is a 4-5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 nitrogen atom. The compound of any one of claims 1-27, wherein at least one R2 is iJ-R4. The compound of claim 33, wherein L1 is a C1-2 bivalent saturated straight or branched hydrocarbon chain wherein one methylene unit of the chain is optionally and independently replaced by -C(R)2-, -N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. The compound of claim 33, wherein R4 is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. The compound of claim 33, wherein R4 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The compound of any one of claims 1-36, wherein R6 represents independently for each occurrence oxo, halogen, -CN, -OR, -OCR3, -SR, -NR2, or -S(O)2R. The compound of any one of claims 1-37, wherein R6 represents independently for each occurrence halogen, -CN, -OR, or -S(O)2R. The compound of any one of claims 1-38, wherein R6 represents independently for each occurrence fluoro, -CN, or -OH. The compound of any one of claims 1-27, wherein each R2 is independently selected from:
Figure imgf000274_0001
The compound claim 40, wherein each R2 is independently selected from
Figure imgf000274_0002
A compound represented by Formula II:
Figure imgf000274_0003
(II) wherein each of RA, X, R1, and m are as defined above in claim 1. The compound of any one of those depicted in Table 1 herein, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound of any one of claims 1-43 and a pharmaceutically acceptable carrier. A method of inhibiting the activity of a c-kit kinase in a patient, comprising administering to said patient a compound of any one of claims 1-43. A method of treating a c-kit kinase mediated disease or disorder in a patient, comprising administering to said patient a compound of any one of claims 1-43. The method according to claim 46, wherein the c-kit kinase mediated disease or disorder is a mast-cell associated disease, a respiratory disease, an inflammatory disorder, an autoimmune disorder, a metabolic disease, a fibrotic disease, a dermatological disease, an allergic disease, a cardiovascular disease, or a neurological disorder. The method according to claim 46, wherein the c-kit kinase mediated disease or disorder is asthma, allergic rhinitis, pulmonary arterial hypertension (PAH), primary pulmonary hypertension (PPH), pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, scleroderma, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), urticaria, dermatosis, atopic dermatitis, allergic contact dermatitis, rheumatoid arthritis, multiple sclerosis, melanoma, a gastrointestinal stromal tumor, a mast cell tumor, mastocytosis, anaphylactic syndrome, food allergy, chronic rhinosinusitis, type I diabetes, type II diabetes, systemic sclerosis, allergic keratoconjunctivitis, vernal keratoconjunctivitis, Crohn’s disease, or systemic and cutaneous lupus erythematosus and dermatomyositis. The method according to claim 46, wherein the c-kit kinase mediated disease or disorder is mast cell gastrointestinal disease, prurigo nodularis, allergic conjunctivitis, eosinophilic esophagitis, mast cell activation syndrome, eosinophilic gastritis and/or eosinophilic duodenitis (EG/EoD), ulcerative colitis, eosinophilic gastritis (EG), or eosinophilic colitis (EC). The method of claim 46, wherein the c-kit kinase mediated disease or disorder is urticaria. The method of any one of claims 46-50, wherein the patient is a human.
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