WO2023155886A1 - Composés de pyrazolopyridine utiles en tant qu'inhibiteurs de tam - Google Patents

Composés de pyrazolopyridine utiles en tant qu'inhibiteurs de tam Download PDF

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WO2023155886A1
WO2023155886A1 PCT/CN2023/076794 CN2023076794W WO2023155886A1 WO 2023155886 A1 WO2023155886 A1 WO 2023155886A1 CN 2023076794 W CN2023076794 W CN 2023076794W WO 2023155886 A1 WO2023155886 A1 WO 2023155886A1
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compound
pharmaceutically acceptable
acceptable salt
μmol
mmol
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PCT/CN2023/076794
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English (en)
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Bin Jiang
Ming Zhang
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Shanghai Antengene Corporation Limited
Antengene Discovery Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure generally relates to pyrazolopyridine compounds useful as inhibitors of TAM kinases, in particular as intibitors of AXL and MER kinases, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.
  • Receptor tyrosine kinases are cell-surface transmembrane receptors that contain regulated kinase activity within their cytoplasmic domain and play an important role in signal transduction in both normal and malignant cells. Overexpression or ectopic expression of the TAM receptors has been detected in a wide array of human cancers.
  • AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions.
  • TAM TYRO3-AXL-MER
  • AXL and MER are critical regulators of innate immunity, phagocytosis, and immune-suppressive activity. Therefore, targeting both AXL and MER kinases may not only impact the growth, survival and malignant progression of neoplastic cells directly, but also has the potential to restore and enhance host immunity against cancers.
  • TAM kinases in particular AXL and MER kinases.
  • the present disclosure provides compounds or pharmaceutically acceptable salts thereof, which are capable of inhibiting TAM kinases, in particular AXL and MER kinases. Methods for use of such compounds for treatment of various diseases or conditions, such as cancer, are also provided.
  • the present disclosure provides a compound having Formula (II) :
  • Ring A is phenyl or 6-membered heteroaryl comprising 1 or 2 nitrogen atoms
  • Ring B is phenyl or 6-membered heteroaryl comprising 1 or 2 nitrogen atoms, each of which is optionally substituted with one or two R 2 ;
  • Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more R a ;
  • W is CH, N, O, or S
  • R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more R b ;
  • R 2 is halogen, hydroxyl, cyano, amino or alkyl
  • R 3 is null, hydrogen, oxo, alkyl or haloalkyl
  • R 4 is NH 2 or haloalkyl
  • each R b is independently selected from oxo, hydroxyl, alkyl, alkoxyl, haloalkyl, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or –C (O) NH-R c , wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; and
  • R c is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • the present disclosure provides a compound selected from the group consisting of:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for inhibiting a TAM kinase, comprising contacting the TAM kinase with the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for inhibiting AXL and MER kinases, comprising contacting the AXL and MER kinases with the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method for treating a disease or disorder mediated by TAM in a subject in need thereof, comprising administering an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure to the subject.
  • linking substituents are described. It is specifically intended that each linking substituent includes both the forward and backward forms of the linking substituent.
  • -NR (CR’R”) -includes both -NR (CR’R”) -and - (CR’R”) NR-.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • alkyl refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms.
  • alkyl groups contain 1 to 10 carbon atoms.
  • alkyl groups contain 1 to 9 carbon atoms.
  • alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-10 alkyl examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • C 1-6 alkyl are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.
  • alkoxyl refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom.
  • C i-j alkoxy means that the alkyl moiety of the alkoxy group has i to j carbon atoms.
  • alkoxy groups contain 1 to 10 carbon atoms.
  • alkoxy groups contain 1 to 9 carbon atoms.
  • alkoxy groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-6 alkoxyl examples include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy) , t-butoxy, neopentoxy, n-hexoxy, and the like.
  • amino refers to —NH 2 group. Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amino groups.
  • aryl refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 12 ring members.
  • aryl include, but are 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 additional rings.
  • polycyclic ring system In the case of polycyclic ring system, only one of the rings needs to be aromatic (e.g., 2, 3-dihydroindole) , although all of the rings may be aromatic (e.g., quinoline) .
  • the second ring can also be fused or bridged.
  • polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • Aryl groups can be substituted at one or more ring positions with substituents as described above.
  • cycloalkyl refers to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms.
  • the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms.
  • Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic.
  • Examples of monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • polycyclic cycloalkyl group examples include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decanyl, bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, and the like.
  • cyano refers to —CN.
  • halogen refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .
  • haloalkyl refers to alkyl as defined herein substituted with one or more halogen atoms.
  • haloalkoxyl refers to alkoxyl as defined herein substituted with one or more halogen atoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxides) .
  • heteroaryl refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms.
  • the heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl.
  • the heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • polycyclic heteroaryl include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo [1, 3] dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl
  • heterocyclyl refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heterocyclyl also includes radicals wherein the heterocyclyl radicals are fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring.
  • the heterocyclyl radical may be carbon linked or nitrogen linked where such is possible.
  • the heterocycle is carbon linked.
  • the heterocycle is nitrogen linked.
  • a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) .
  • a group derived from imidazole may be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked) .
  • 3-to 12-membered heterocyclyl refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the fused, spiro and bridged ring systems are also included within the scope of this definition.
  • monocyclic heterocyclyl examples include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.
  • fused heterocyclyl examples include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1, 2-a] pyridinyl, [1, 2, 4] triazolo [4, 3-a
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, diazaspiro [3.3] heptanyl and the like.
  • bridged heterocyclyl examples include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo [3.1.0] hexane, 8-aza-bicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane (DABCO) , and the like.
  • hydroxyl or “hydroxy” refers to —OH.
  • partially unsaturated refers to a radical that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted” , references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the present disclosure provides a novel compound of Formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for making the compound, pharmaceutical compositions and various uses of the disclosed compounds.
  • the present disclosure provides a compound having Formula (II) :
  • Ring A is phenyl or 6-membered heteroaryl comprising 1 or 2 nitrogen atoms
  • Ring B is phenyl or 6-membered heteroaryl comprising 1 or 2 nitrogen atoms, each of which is optionally substituted with one or two R 2 ;
  • Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more R a ;
  • W is CH, N, O, or S
  • R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or more R b ;
  • R 2 is halogen, hydroxyl, cyano, amino or alkyl
  • R 3 is null, hydrogen, oxo, alkyl or haloalkyl
  • R 4 is NH 2 or haloalkyl
  • each R b is independently selected from oxo, hydroxyl, alkyl, alkoxyl, haloalkyl, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or –C (O) NH-R c , wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; and
  • R c is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • Ring A is phenyl
  • Ring A is a 6-membered heteroaryl comprising 1 nitrogen atom.
  • W is N.
  • W is O or S.
  • W is CH.
  • Ring B is phenyl
  • Ring B is 6-membered heteroaryl comprising 1 or 2 nitrogen atoms. In certain embodiments, Ring B is pyridinyl.
  • R 1 is cycloalkyl optionally substituted with one or more R b .
  • R 1 is C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, or C 3-5 cycloalkyl, each optionally substituted with one or more R b .
  • R 1 is cyclopropyl optionally substituted with one or more R b .
  • R 1 is heterocyclyl optionally substituted with one or more R b .
  • R 1 is C 3-8 heterocyclyl, C 3-7 heterocyclyl, C 3-6 heterocyclyl, or C 3-5 heterocyclyl, each optionally substituted with one or more R b .
  • each R b is independently selected from oxo, hydroxyl, alkyl, alkoxyl, haloalkyl, haloalkoxyl, aryl, heteroaryl or –C (O) NH-R c , wherein the aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, or cyano.
  • R 1 is cycloalkyl optionally substituted with one or more R b
  • R b is –C (O) NH-R c
  • R c is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • R 1 is heterocyclyl optionally substituted with one or more R b , each R b is independently selected from oxo, alkyl, alkoxyl, aryl, or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl.
  • R 1 is selected from the group consisting of:
  • R 2 is halogen. In certain embodiments, R 2 is fluoro or chloro. In certain embodiments, R 2 is fluoro.
  • R 2 is alkyl. In certain embodiments, R 2 is methyl.
  • R 2 is haloalkyl. In certain embodiments, R 2 is trifluoromethyl.
  • Ring C is heterocyclyl or aryl, each of which is optionally substituted with one or more R a .
  • Ring C is 6-membered heterocyclyl optionally substituted with one or more R a .
  • Ring C is piperidinyl optionally substituted with one or more R a . In certain embodiments, Ring C is 4-piperidinyl optionally substituted with one or more R a .
  • Ring C is piperazinyl optionally substituted with one or more R a . In certain embodiments, Ring C is 4-piperazinyl optionally substituted with one or more R a .
  • Ring C is 7-to 9-membered heterocyclyl optionally substituted with one or more R a .
  • Ring C is octahydroindolizinyl, octahydropyrrolo [1, 2-a] pyrazinyl, or 2, 6-diazaspiro [3.3] heptanyl, each optionally substituted with one or more R a .
  • R c is alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 5-6 membered heteroaryl.
  • R c is alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or 5-6 membered heteroaryl.
  • Ring C is 5-6 membered aryl optionally substituted with one or more R a .
  • Ring C is phenyl optionally substituted with one or more R a .
  • each R a is independently selected from the group consisting of halogen, cyano, alkyl, C 3-8 cycloalkyl and 5-6 membered heteroaryl.
  • two adjacent R a together with the atom they attached form C 5-8 cycloalkyl or 5-8 membered heterocyclyl.
  • Ring C is selected from the group consisting of:
  • R 3 is null.
  • R 3 is hydrogen
  • R 3 is oxo
  • R 3 is alkyl. In certain embodiments, R 3 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl or C 1-3 alkyl. In certain embodiments, R 3 is methyl or ethyl.
  • R 3 is haloalkyl. In certain embodiments, R 3 is C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl or C 1-3 haloalkyl. In certain embodiments, R 3 is difluoromethyl, trifluoroethyl or difluoroethyl.
  • R 4 is NH 2 .
  • R 4 is haloalkyl. In certain embodiments, R 4 is difluoromethyl.
  • the present disclosure provides a compound selected from the group consisting of:
  • the compound of the present disclosure may exist in a number of different forms or derivatives, including but not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites) , and their pharmaceutically acceptable salts, all within the scope of the present disclosure.
  • prodrugs refers to compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
  • Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems” , Vol. 14 of the A.C.S. Symposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley,Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety.
  • soft drug refers to compounds that exert a pharmacological effect but break down to inactive metabolites degradants so that the activity is of limited time. See, for example, “Soft drugs: Principles and methods for the design of safe drugs” , Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449-469, 1984, which is hereby incorporated by reference in its entirety.
  • metabolite e.g., active metabolite overlaps with prodrug as described above.
  • metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject.
  • metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodrug.
  • active metabolites are such pharmacologically active derivative compounds.
  • the prodrug compound is generally inactive or of lower activity than the metabolic product.
  • the parent compound may be either an active compound or may be an inactive prodrug.
  • Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem 40: 2011-2016; Shan et al., J Pharm Sci 86: 756-757; Bagshawe, 1995, DrugDev Res 34: 220-230; Wermuth, supra.
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as L-glycine, L-lysine, and L-arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compound of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • crystal form As used herein, the terms “crystal form” , “crystalline form” , “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system (for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole) .
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • the present disclosure is also intended to include all isotopes of atoms in the compounds.
  • Isotopes of an atom include atoms having the same atomic number but different mass numbers.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 I.
  • hydrogen includes protium, deuterium and tritium.
  • carbon includes 12 C and 13 C.
  • Synthesis of the compound provided herein, including pharmaceutically acceptable salts thereof, is illustrated in the synthetic schemes in the example.
  • the compound provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the schemes are for better illustration and can be changed as appropriate.
  • the embodiments of the compound in examples were synthesized for the purposes of research and potentially submission to regulatory agencies.
  • the reactions for preparing the compound of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of the compound of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley &Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G. M. Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) .
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ( “Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) ,
  • the known starting materials of the present disclosure can be synthesized by using or according to the known methods in the art, or can be purchased from commercial suppliers. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification.
  • the reactions of the present disclosure were all done under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • the Examples section below shows synthetic route for preparing the compound of the present disclosure as well as key intermediates. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • compositions comprising the compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • composition comprising the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.
  • composition refers to a formulation containing the molecule or compound of the present disclosure in a form suitable for administration to a subject.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient.
  • pharmaceutically acceptable excipient also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.
  • suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, dis
  • suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans.
  • a drug such as the compounds disclosed herein and, optionally, a chemotherapeutic agent
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.
  • compositions provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms
  • emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms.
  • emulsions and suspensions may be acceptable as liquid dosage forms
  • solutions, sprays, dry powders, and aerosols may be acceptable dosage form.
  • powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form.
  • pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.
  • the quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved.
  • therapeutically effective amount refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • compositions of the present disclosure may be in a form of formulation for oral administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations.
  • suitable pharmaceutically- acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) .
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • compositions of the present disclosure may be in a form of formulation for injection administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • compositions of the present disclosure may be in a form of formulation for inhalation administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.
  • the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure.
  • excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005) , which are incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form.
  • the amount of the compounds provided herein in the single dosage form will vary depending on the subject treated and particular mode of administration.
  • the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.001-1000 mg/kg body weight/day, for example, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body weight/day, 1-50 mg/kg body weight/day, 1-45 mg/kg body weight/day, 1-40 mg/kg body weight/day, 1-35 mg/kg body weight/day, 1-30 mg/kg body weight/day, 1-25 mg/kg body weight/day of the
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Accordingly, the pharmaceutical formulations of the present disclosure may also be formulated for controlled release or for slow release.
  • compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • an article for distribution can include a container having deposited therein the compositions in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • the compound of Formula (I) or pharmaceutically acceptable salts thereof are capable of inhibiting the activity of a TAM kinase.
  • the compound of the disclosure can be used to inhibit activity of a TAM kinase in a cell or in a subject in need of inhibition of the kinases by administering an inhibiting amount of the compound of the disclosure to the cell or subject.
  • the inhibitory properties of the compound may be demonstrated using the test procedures set out herein.
  • an ex vivo cell refers to a cell that is in vitro, ex vivo or in vivo.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • a “subject” refers to a human and a non-human animal.
  • a non-human animal include all vertebrates, e.g., mammals, such as non-human primates (particularly higher primates) , dog, rodent (e.g., mouse or rat) , guinea pig, cat, and non-mammals, such as birds, amphibians, reptiles, etc.
  • the subject is a human.
  • the subject is an experimental animal or animal suitable as a disease model.
  • the compound of the disclosure or pharmaceutically acceptable salts thereof are selective for the TAM kinases over one or more of other kinases.
  • the selectivity is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 25-fold or more, 50-fold or more, or 100-fold or more.
  • the compound of the disclosure or pharmaceutically acceptable salts thereof can inhibit one or more of AXL, MER and TYRO3. In some embodiments, the compound of the disclosure or pharmaceutically acceptable salts thereof are selective for one TAM kinase over another.
  • the term “selective” means that the compound binds to or inhibits a TAM kinase with greater affinity or potency, compared to a reference enzyme, such as another TAM kinase or kinases other than TAM kinases.
  • the compound of the disclosure or pharmaceutically acceptable salts thereof can be selective for AXL over MER and TYRO3, selective for MER over AXL and TYRO3, or selective for AXL and MER over TYRO3.
  • the compound of the disclosure or pharmaceutically acceptable salts thereof inhibit all of the TAM family members (e.g., AXL, MER and TYRO3) .
  • the compound of the disclosure or pharmaceutically acceptable salts thereof can be selective for AXL and MER over TYRO3 and other kinases.
  • the present disclosure provides a method for inhibiting a TAM kinase, which comprises contacting the TAM kinase with the compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for inhibiting AXL and MER kinases, which comprises contacting the AXL and MER kinases with the compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” the TAM kinase with the compound provided herein or a pharmaceutically acceptable salt thereof includes the administration of the compound provided herein, or a pharmaceutically acceptable salt thereof to a subject having the TAM kinase, as well as, for example, introducing the compound provided herein or a pharmaceutically acceptable salt thereof into a sample containing a cellular or purified preparation containing the TAM kinase.
  • the compound of the present disclosure or pharmaceutically acceptable salts thereof has an inhibitory activity against TAM kinases, they are useful in the treatment (therapeutic or prophylactic) of conditions or diseases associated with TAM kinases.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it. Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • prophylaxis or “prophylactic” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • the conditions or diseases associated with TAM kinases include proliferative disorders such as cancers, kidney diseases, immune system diseases, circulatory system diseases and viral diseases.
  • the compound provided herein or pharmaceutically acceptable salts thereof are useful for the treatment of cancer, for example but not limited to leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphatic leukemia) , melanoma, glioma, lymphoma (e.g., chronic lymphocytic lymphoma, B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s or non-Hodgkin’s lymphoma, hairy cell lymphoma, chronic myelogenic lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt’s lymphoma) , bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, large intestine cancer, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancers of the larynx, hypo
  • exocrine pancreatic carcinoma stomach cancer, thyroid cancer, parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer) , and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuro-ectodermal tumors, pineal tumors) .
  • skin cancer e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer
  • brain cancer e.g., astrocytoma, medulloblastoma, ependymoma, neuro-ectodermal tumors, pineal tumors
  • the compound provided herein or pharmaceutically acceptable salts thereof are useful for the treatment of kidney diseases, for example but not limited to glomerular nephritis, chronic nephritis, IgA nephritis, sequential (secondary) nephritis, nephrosis nephritis, acute renal failure, chronic renal failure, diabetic nephropathy, gouty nephropathy, interstitial nephritis, and nephro-pyelitis.
  • kidney diseases for example but not limited to glomerular nephritis, chronic nephritis, IgA nephritis, sequential (secondary) nephritis, nephrosis nephritis, acute renal failure, chronic renal failure, diabetic nephropathy, gouty nephropathy, interstitial nephritis, and nephro-pyelitis.
  • the compound provided herein or pharmaceutically acceptable salts thereof are useful for the treatment of immune system disease, for example but not limited to psoriasis and rheumatoid arthritis.
  • the compound provided herein or pharmaceutically acceptable salts thereof are useful for the treatment of circulatory system diseases, for example but not limited to atherosclerosis and thrombosis.
  • the compound provided herein or pharmaceutically acceptable salts thereof are useful for the treatment of viral diseases such as viral infections.
  • viruses causing infections include but are not limited to human immunodeficiency virus, papillomavirus, influenza virus, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes viruses (e.g., N7N, HSV-1, HAV-6, HSVII, and CMV, Epstein Barr virus) , human cytomegalovirus, severe acute respiratory syndrome virus, respiratory syncytial virus, ebola virus, Marburg virus, measles virus, flaviviruses (e.g., West Nile, dengue, tick-home encephalitis, yellow fever, Zika) , echovirus, rhinovirus, coxsackie virus, comovirus, mumpsvirus, rotavirus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, molluscum virus, polio
  • the compound provided herein or pharmaceutically acceptable salts thereof can be used as a metastasis suppressing agent to cancer cell.
  • the compound provided herein or pharmaceutically acceptable salts thereof may be used in combination with one or more additional pharmaceutical agents or therapies in order to supplement and/or enhance the preventive and/or therapeutic effect of the compound, to improve the kinetics, improvement of absorption, and reduction of the dose of the compound; and/or to eliminate the side effects of the compound.
  • the compound provided herein or pharmaceutically acceptable salts thereof can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the additional pharmaceutical agents or therapies.
  • the compound provided herein or pharmaceutically acceptable salts thereof may be administered before the additional pharmaceutical agents or therapies.
  • the additional pharmaceutical agents or therapies may be administered before the compound provided herein or pharmaceutically acceptable salts.
  • the method for the administration of these pharmaceutical agents or therapies may be the same as each other or different from each other.
  • Examples of pharmaceutical agents or therapies that can be used in combination with the compound provided herein or pharmaceutically acceptable salts thereof for the treatment of cancer include, but are not limited to chemotherapeutic agents, targeted cancer therapies, immunotherapy or radiation therapy, for example, alkylating agents (e.g., nitrogen mustard N-oxide hydrochloride, cyclophosphamide, ifosfa-mide, melphalan, thiotepa, carboquone, busulfan, nimustine hydrochloride, dacarbazine, ranimustine, carmustine, chlorambucil, bendamustine, and mechlorethamine) , antimetabolites (e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) , anticancer antibiotics (e.g., actinomycin D, mitomycin C, daunorubicin hydrochloride, doxorubicin hydrochlor
  • anti-CD52 antibodies e.g., alemtuzumab
  • anti-PD-1 antibodies e.g., nivolumab, pembrolizumab
  • an adoptive cell transfer an angiogenesis inhibitor, Bacillus Calmette-Guerin therapy, biochemotherapy, a cancer vaccine, a chimeric antigen receptor (CAR) T-cell therapy, a cytokine therapy, gene therapy, an immune checkpoint modulator, an immunoconjugate, a radioconjugate, an oncolytic virus therapy, a targeted drug therapy, G-CSF formulations (e.g., pegfilgrastim, filgrastim, lenograstim, and nartograstim) , acute promyelocytic leukemia differentiation-inducing agents, topoisomerase inhibitors (e.g., topotecan, teniposide, irinotecan, and sobuzoxane) , aromatase inhibitors (
  • Examples of pharmaceutical agents or therapies that can be used in combination with the compound provided herein or pharmaceutically acceptable salts thereof for the treatment of kidney diseases include but are not limited to steroids, immunosuppressants (e.g., azathioprine, ascomycin, everolimus, salazosulfapyridine, cyclosporine, cyclophosphamide, sirolimus, tacrolimus, bucillamine, methotrexate, and leflunomide) , angiotensin II antagonistic drugs (e.g., losartan, candesartan, valsartan, irbesartan, olm-esartan, telmisartan) , angiotensin-converting enzyme inhibitors (e.g., alacepril, imidapril hydrochloride, quinapril hydrochloride, temocapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, captopril, tran
  • Examples of pharmaceutical agents or therapies that can be used in combination with the compound provided herein or pharmaceutically acceptable salts thereof for the treatment of immune system diseases include but are not limited to immunosuppressants, steroid, diseasemodifying anti-rheumatic drugs, prostaglandins, prostaglandin synthase inhibitors, phosphodiesterase inhibitors, metalloprotease inhibitors, anti-cytokine protein formulations such as anti-TNF- ⁇ formulations, anti-IL-1 formulations, and anti-IL-6 formulation, cytokine inhibitors, and nonsteroidal anti-inflammatory agents.
  • Examples of pharmaceutical agents or therapies that can be used in combination with the compound provided herein or pharmaceutically acceptable salts thereof for the treatment of circulatory system diseases include but are not limited to antiplatelet drugs, angiotensin II antagonistic drugs, angiotensin-converting enzyme inhibitors, HMG-CoA reductase inhibitors, and thiazolidine derivatives.
  • the compound provided herein or pharmaceutically acceptable salts thereof are used in combination with radiation therapy or surgeries.
  • Radiation is commonly delivered internally (implantation of radioactive material near cancer site) or externally from a machine that employs photon (x-ray or gamma-ray) or particle radiation.
  • the combination therapy further comprises radiation treatment
  • the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved.
  • the present disclosure relates to labeled compounds provided herein (radio-labeled, fluorescent-labeled, and the like. ) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating TAM kinases in tissue samples, including human, and for identifying TAM kinase ligands by inhibition binding of a labeled compound. Accordingly, the present disclosure includes TAM kinase assays that contain such labeled compounds.
  • the present disclosure further includes isotopically-labeled compounds provided herein.
  • An “isotopically” or “radio-labeled” compound is a compound provided herein where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring) .
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro TAM kinases labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 I, 131 I, or 35 S will generally be most useful.
  • radio-imaging applications 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful. Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to the compouns provided herein and are well known in the art.
  • a radio-labeled compound provided herein can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • Step 3 1- (4- (3-amino-5-chloro- [1, 2, 4] triazolo [4, 3-a] pyridin-7-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-1-one
  • Step 4 1- (4- (3-amino-5- (4-aminophenyl) - [1, 2, 4] triazolo [4, 3-a] pyridin-7-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-1-one
  • Step 5 1- (4- (3-amino-5- (4-aminophenyl) imidazo [1, 2-a] pyridin-7-yl) piperidin-1-yl) -2-methylpropan-1-one
  • Step 6 N- (4- (3-amino-7- (1-isobutyrylpiperidin-4-yl) - [1, 2, 4] triazolo [4, 3-a] pyridin-5-yl) phenyl) -1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
  • Step 7 4- (4-aminophenyl) -6-bromo-1-methyl-1H-indazol-3-amine
  • Step 8 1- (4- (3-amino-4- (4-aminophenyl) -1-methyl-1H-indazol-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-1-one
  • Step 9 1- (4- (3-amino-4- (4-aminophenyl) -1-methyl-1H-indazol-6-yl) piperidin-1-yl) -2-methylpropan-1-one
  • Step 10 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1-methyl-1H-indazol-4-yl) phenyl) -1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
  • reaction mixture was diluted with water (500 mL) , extracted with EtOAc (150 mL *3) , the combined organic layer was washed with brine (300 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to get the desired product ethyl compound 23-4 (6.00 g, 21.5 mmol, 94.4%yield) as yellow oil.
  • Step 4 ethyl 4-chloro-6- (1-isobutyryl-1, 2, 3, 6-tetrahydropyridin-4-yl) - [1, 2, 3] triazolo [1, 5-a] pyridine-3-carboxylate
  • Step 7 ethyl 6- (1-isobutyrylpiperidin-4-yl) -4- (4- (1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamido) phenyl) - [1, 2, 3] triazolo [1, 5-a] pyridine-3-carboxylate
  • Step 8 6- (1-isobutyrylpiperidin-4-yl) -4- (4- (1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamido) phenyl) - [1, 2, 3] triazolo [1, 5-a] pyridine-3-carboxylic acid
  • Step 9 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) - [1, 2, 3] triazolo [1, 5-a] pyridin-4-yl) phenyl) -1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
  • Step 8 1- (4- (3-amino-4- (4-nitrophenyl) -1H-pyrazolo [3, 4-b] pyridin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-1-one
  • Step 10 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1H-pyrazolo [3, 4-b] pyridin-4-yl) phenyl) -1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
  • Step 3 4- (methylthio) -2-oxo-6- (piperidin-4-yl) -1, 2-dihydropyridine-3-carbonitrile
  • Step 4 (1-isobutyrylpiperidin-4-yl) -4- (methylthio) -2-oxo-1, 2-dihydropyridine-3-carbonitrile
  • Step 6 1- (4- (3-amino-4-bromo-1H-pyrazolo [4, 3-c] pyridin-6-yl) piperidin-1-yl) -2-methylpropan-1-one
  • Step 7 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1H-pyrazolo [4, 3-c] pyridin-4-yl) phenyl) -1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
  • Step 4 1- (4- (3-amino-4- (4-aminophenyl) -1-ethyl-1H-indazol-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-1-one
  • Step 5 1- (4- (3-amino-4- (4-aminophenyl) -1-ethyl-1H-indazol-6-yl) piperidin-1-yl) -2-methylpropan-1-one
  • Step 7 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1H-indazol-4-yl) phenyl) -1- (4-fluorophenyl) -4, 5-dimethyl-2-oxo-1, 2-dihydropyridine-3-carboxamide
  • Step 7 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1H-indazol-4-yl) phenyl) -1-ethyl-4- (2, 2, 2-trifluoroethoxy) -1H-pyrazole-3-carboxamide
  • Step 7 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1H-indazol-4-yl) phenyl) -5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridazine-3-carboxamide
  • Step 1 1- (4- (3-amino-4-bromo-1-methyl-1H-pyrazolo [4, 3-c] pyridin-6-yl) piperidin-1-yl) -2-methylpropan-1-one
  • Step 2 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1-methyl-1H-pyrazolo [4, 3-c] pyridin-4-yl) phenyl) -1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
  • Step 7 1- (4- (3-amino-1-methyl-4- (4-nitrophenyl) -1H-pyrazolo [3, 4-b] pyridin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-1-one
  • Step 8 1- (4- (3-amino-4- (4-aminophenyl) -1-methyl-1H-pyrazolo [3, 4-b] pyridin-6-yl) piperidin-1-yl) -2-methylpropan-1-one
  • Step 9 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1-methyl-1H-pyrazolo [3, 4-b] pyridin-4-yl) phenyl) -1-isopropyl-2, 4-dioxo-3- (pyridin-2-yl) -1, 2, 3, 4-tetrahydropyrimidine-5-carboxamide
  • Step 9 1- (4- (3-amino-4- (4-nitrophenyl) -1H-pyrazolo [3, 4-b] pyridin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-1-one
  • Step 10 1- (4- (3-amino-4- (4-aminophenyl) -1H-pyrazolo [3, 4-b] pyridin-6-yl) piperidin-1-yl) -2-methylpropan-1-one
  • Step 6 1- (4- (3-amino-1-methyl-4- (4-nitrophenyl) -1H-pyrazolo [3, 4-b] pyridin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) -2-methylpropan-1-one
  • Step 7 1- (4- (3-amino-4- (4-aminophenyl) -1-methyl-1H-pyrazolo [3, 4-b] pyridin-6-yl) piperidin-1-yl) -2-methylpropan-1-one
  • Step 8 N- (4- (3-amino-6- (1-isobutyrylpiperidin-4-yl) -1-methyl-1H-pyrazolo [3, 4-b] pyridin-4-yl) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
  • the mixture was diluted with 4M HCl (10.0 mL) and stirred at 25°C for 0.5 h, the mixture was filtered and the filter cake was the desired product compound 66-3 (660 mg, 2.66 mmol, 40.9%yield) as yellow solid.
  • Step 13 7- (3-amino-4- (4-aminophenyl) -1-methyl-1H-indazol-6-yl) hexahydroindolizin-3 (2H) -one
  • Compound 68-12 (160 mg) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm *30.0 mm, 10.0 um) ; mobile phase: [CO 2 -EtOH (0.100%NH 3 ⁇ H 2 O) ] ; 60.0%B isocratic elution mode) to give Compounds 68-12a, 68-12b, 68-12c and 68-12d.
  • Step 18 N- (4- (3-amino-1-methyl-6- ( (7R, 8aS) -3-oxooctahydroindolizin-7-yl) -1H-indazol-4-yl) phenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide, N- (4- (3-amino-1-methyl-6- ( (7S, 8aR) -3-oxooctahydroindolizin-7-yl) -1H-indazol-4-yl) phenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide, N- (4- (3-amino-1-methyl-6- ( (7R, 8aR) -3-oxooctahydroindolizin-7-yl) -1H-indazol-4-y
  • Step 1 (R) -2- (3-amino-4- (4-aminophenyl) -1-methyl-1H-indazol-6-yl) hexahydropyrrolo [1, 2-a] pyrazin-6 (2H) -one and (S) -2- (3-amino-4- (4-aminophenyl) -1-methyl-1H-indazol-6-yl) hexahydropyrrolo [1, 2-a] pyrazin-6 (2H) -one
  • the product (SFC: EW38424-143-P1A_D13) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm *30.0 mm, 10.0 um) ; mobile phase: [CO 2 -ACN/i-PrOH (0.100%NH 3 ⁇ H 2 O) ] ; B%: 60.0%, isocratic elution mode) .
  • Step 2 (R) -N- (4- (3-amino-1-methyl-6- (6-oxohexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) -1H-indazol-4-yl) phenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide and (S) -N- (4- (3-amino-1-methyl-6- (6-oxohexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) -1H-indazol-4-yl) phenyl) -4-ethoxy-1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide
  • the crude was purified by prep-HPLC (column: Waters Xbridge 150 *25.0 mm *5.00 um; mobile phase: [water (ammoniahydroxide v/v) -ACN] ; gradient: 23.0%-53.0%B over 9 min) .
  • Compound 70a (10.6 mg, 16.7 ⁇ mol, 100%yield, 99.8%purity) was obtained.
  • Compound 70b was prepared in similar way as Compound 70a except that compound 70-3b were used instead of compound 70-3a.
  • Step 8 3-cyano-4- (4-nitrophenyl) -6- (3-oxooctahydroindolizin-7-yl) pyridin-2-yl trifluoromethanesulfonate
  • Step 9 7- (3-amino-1-methyl-4- (4-nitrophenyl) -1H-pyrazolo [3, 4-b] pyridin-6-yl) hexahydroindolizin-3 (2H) -one
  • Step 10 7- (3-amino-4- (4-aminophenyl) -1-methyl-1H-pyrazolo [3, 4-b] pyridin-6-yl) hexahydroindolizin-3 (2H) -one
  • Compound 80 was prepared in similar way as compound 71 except that compound 67-2 was used instead of compound 71-17.
  • Step 1 1- (4- (3-amino-4- (4-aminophenyl) -1-methyl-1H-indazol-6-yl) piperazin-1-yl) -2-methylpropan-1-one
  • the crude was purified by prep-HPLC (column: Waters Xbridge 150 *25 mm *5 um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; gradient: 20%-50%B over 9 min) to get the desired product compound 72-3 (20.0 mg, 50.9 ⁇ mol, 8.08%yield, -purity) as white solid.
  • the crude was purified by HPLC (column: Waters Xbridge 150 *25 mm *5um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; gradient: 29%-59%B over 9 min) to get the desired product Compound 72 (8.25 mg, 12.56 ⁇ mol, 49.31%yield, 99.24%purity) .
  • Step 2 1- (4- (3-amino-4- (4-aminophenyl) -1-methyl-1H-pyrazolo [3, 4-b] pyridin-6-yl) piperazin-1-yl) -2-methylpropan-1-one
  • Compound 82 was prepared in similar way as Compound 73 except that compound 72-4 was used instead of compound 73-5.
  • Step 1 1- (4- (3-amino-1-methyl-4- (4-nitrophenyl) -1H-pyrazolo [3, 4-b] pyridin-6-yl) piperazin-1-yl) ethan-1-one
  • Step 2 1- (4- (3-amino-4- (4-aminophenyl) -1-methyl-1H-pyrazolo [3, 4-b] pyridin-6-yl) piperazin-1-yl) ethan-1-one
  • the crude product was purified by prep-HPLC (ammonia hydroxide condition; column: Waters Xbridge 150 *25.0 mm *5.00 um; mobile phase: [water (ammonia hydroxide v/v) -ACN] ; gradient: 19.0%-49.0%B over 9 min) . Then the mixture was concentrated under reduced pressure to remove MeCN. And the mixture was freezedried to give a product. Compound 75 (4.14 mg, 6.60 ⁇ mol, 23.2%yield, 97.4%purity) was obtained.

Abstract

La présente invention concerne des composés pyrazolopyridine utiles en tant qu'inhibiteurs de kinases TAM, en particulier en tant qu'intibiteurs de kinases AXL et MER, ainsi que des compositions pharmaceutiques comprenant ces composés et des procédés de traitement par administration de ces composés ou des compositions pharmaceutiques.
PCT/CN2023/076794 2022-02-17 2023-02-17 Composés de pyrazolopyridine utiles en tant qu'inhibiteurs de tam WO2023155886A1 (fr)

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WO2007144202A1 (fr) * 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Aminopyrazolopyridines substituées et leurs sels, leurs synthèses et les compositions pharmaceutiques les incluant
CN108250200A (zh) * 2016-12-28 2018-07-06 中国科学院上海药物研究所 一种具有Axl抑制活性的化合物及其制备和应用
CN109348715A (zh) * 2016-03-28 2019-02-15 因赛特公司 作为tam抑制剂的吡咯并三嗪化合物
CN110627796A (zh) * 2018-06-21 2019-12-31 北京越之康泰生物医药科技有限公司 含氮杂环类衍生物及其在医药上的应用
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CN113683629A (zh) * 2020-05-18 2021-11-23 北京范恩柯尔生物科技有限公司 取代的杂芳基化合物及其组合物和用途
CN113912628A (zh) * 2020-07-10 2022-01-11 北京范恩柯尔生物科技有限公司 三嗪类化合物及其组合物和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007144202A1 (fr) * 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Aminopyrazolopyridines substituées et leurs sels, leurs synthèses et les compositions pharmaceutiques les incluant
CN109348715A (zh) * 2016-03-28 2019-02-15 因赛特公司 作为tam抑制剂的吡咯并三嗪化合物
CN108250200A (zh) * 2016-12-28 2018-07-06 中国科学院上海药物研究所 一种具有Axl抑制活性的化合物及其制备和应用
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