WO2023081730A1 - Dérivés de 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphtyridine-3-carboxamide utilisés en tant que modulateurs du récepteur cb2 cannabinoïde pour le traitement du cancer - Google Patents

Dérivés de 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphtyridine-3-carboxamide utilisés en tant que modulateurs du récepteur cb2 cannabinoïde pour le traitement du cancer Download PDF

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WO2023081730A1
WO2023081730A1 PCT/US2022/079183 US2022079183W WO2023081730A1 WO 2023081730 A1 WO2023081730 A1 WO 2023081730A1 US 2022079183 W US2022079183 W US 2022079183W WO 2023081730 A1 WO2023081730 A1 WO 2023081730A1
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μmol
oxo
hydroxy
naphthyridine
mixture
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PCT/US2022/079183
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English (en)
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Elfatih Elzein
Jiwen Liu
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Teon Therapeutics, Inc.
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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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for the treatment of conditions, diseases, or disorders that would benefit from reduction or inhibition of cannabinoid receptor CB2 activity.
  • Cannabinoid CB2 receptors modulate immune responses during inflammatory processes, in the tumor microenvironment.
  • Endogenous and exogenous cannabinoids exert immunosupressive properties in a variety of ways, including induction of apoptosis of T cells, NK cells and B cells; inhibition of T, NK and B cells proliferation; inhibition of immunostimulatory cytokine and chemokine production, and induction of immunosuppressive cytokine production and regulatory T cells. Therefore, CB 2 R antagonism should restore T, NK and B cells function and relieve innate and adaptive immunosuppression caused by the endocannabinoids.
  • Developing CB2 receptor antagonists constitute a novel approach to treat cancer by enhancing antitumor immune response.
  • the present disclosure in one embodiment, provides a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, selected from Table 1.
  • Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and solvates thereof, are CB2 receptor (CB 2 R) modulators.
  • the CB 2 R modulators are CB 2 R antagonists.
  • the CB 2 R modulators are CB 2 R inverse agonists.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • described herein is a method of modulating the activity of the cannabinoid 2 receptor (CB 2 R) in a mammal comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • CBD 2 R cannabinoid 2 receptor
  • described herein is a method of treating a disease or disorder in a mammal that is mediated by the action of the cannabinoid 2 receptor (CB 2 R) comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • CBD 2 R cannabinoid 2 receptor
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -C(O)NH 2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • C u-v indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • die term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • the term “about X” includes description of “X”.
  • the singular forms “a” and “the” include plural references unless tiie context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • Alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (ie., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., CM alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl, and 3-methylpentyl.
  • alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e.
  • -(CH 2 ) 3 CH 3 sec-butyl (i.e. -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e. -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e. -C(CH 3 ) 3 ); and “propyl” includes n-propyl (i.e. -(CH 2 ) 2 CH 3 ) and isopropyl (i.e. -CH(CH 3 ) 2 ).
  • Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (te., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl).
  • alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • Alkoxy refers to the group “alkyl-O-”.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.
  • alkylamine refers to -NH( alkyl), or -N(alkyl) 2 .
  • Alkylthio refers to the group “alkyl-S-.”
  • acyl refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR y R z and an “N- amido” group which refers to the group -NR y C(O)R z , wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
  • Amino refers to the group -NR y R z wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6 -n aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.
  • Azido refers to —Ns.
  • Carbamoyl refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NR y R z and an “N-carbamoyl” group which refers to the group -NR y C(O)OR z , wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
  • Carboxyl refers to -C(O)OH.
  • Carboxyl ester refers to both -OC(O)R and -C(O)OR, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Cyano or “carbonitrile” refers to the group -CN.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • the term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3- 10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl).
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Cycloalkylene refers to -cycloalkyl-, i.e., a cycloalkyl ring as defined herein which is bonded to two groups.
  • Deuteroalkyl refers to an alkyl group as defined herein, in which at least one H is replaced by an isotope of hydrogen, i.e., by deuterium ( 2 H) or tritium ( 3 H).
  • Deuteroalkoxy refers to an alkoxy group as defined herein, in which at least one H is replaced by an isotope of hydrogen, i.e., by deuterium ( 2 H) or tritium ( 3 H).
  • Hydrazino refers to -NHNH 2 .
  • Imino refers to a group -C(NR)R, wherein each R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Halogen or “halo” includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ).
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C 1 -C 6 fluoioalkyl.
  • Fluoroalkoxy refers to an alkoxy group as defined herein, in which at least one H is replaced by a fluorine atom.
  • Haloalkoxy refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • Heteroalkyl refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
  • the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, - S(O)-, -S(O) 2 -, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted.
  • R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted.
  • heteroalkyl groups include -OCH 3 , - CH 2 OCH 3 , -SCH 3 , -CH 2 SCH 3 , -NRCH 3 , and -CH 2 NRCH 3 , where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
  • heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (e.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from ni trogen, oxygen, and sulfur.
  • heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.
  • fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.
  • Heterocyclyl or “heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heteroalixyclic” refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro.
  • any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.
  • ring carbon atoms i.e., C 2-20 heterocyclyl
  • 2 to 12 ring carbon atoms i.
  • heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
  • bridged-heterocyclyl refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g. 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • bridged- heterocyclyl includes bicyclic and tricyclic ring systems.
  • spiro-heterocyclyl refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to tenmembered heterocyclyl.
  • spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1- azaspiro[3.3]heptanyl.
  • fused-heterocyclyl rings include, but are not limited to, 1, 2,3,4- tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine -2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl.
  • the sulfur atom in a heterocycloalkyl is not oxidized.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a Cr-C 10 heterocycloalkyl.
  • a heterocycloalkyl is a C4- C 10 heterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • Niro refers to the group -NO 2 .
  • “Sulfonyl” refers to the group -S(O) 2 R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methyl sulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • Alkylsulfonyl refers to the group -S(O) 2 R, where R is alkyl.
  • Alkylsulfinyl refers to the group -S(O)R, where R is alkyl.
  • Thiocyanate refers to the group -SCN.
  • Thiol refers to the group -SH.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
  • the term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
  • the term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. In some embodiments, “modulate” means to interact with a target either directly or indirectly so as to decrease or inhibit receptor activity,
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, or combinations thereof.
  • a modulator is an antagonist.
  • Receptor antagonists are inhibitors of receptor activity. Antagonists mimic ligands that bind to a receptor and prevent receptor activation by a natural ligand. Preventing activation may have many effects. If a natural agonist binding to a receptor leads to an increase in cellular function, an antagonist that binds and blocks this receptor decreases the function.
  • Tautomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), n C, 13 C, 14 C, 15 N, 1S F, 31 P, 32 P, 35 S, 36 Cl, and 125 I.
  • isotopically labeled compounds of the present disclosure are those into which radioactive isotopes such as 3 H and 14 C are incorporated.
  • isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single -photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single -photon emission computed tomography
  • the disclosure also includes “deuterated analogs” of compounds in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • deuterated analogs of compounds in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, mafic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH 2 (alkyl)), dialkyl amines (i.e., HN(alkyl) 2 ), trialkyl amines (i.e., N(alkyl)s), substituted alkyl amines (i.e., NH 2 (substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl);), tri(substituted alkyl) amines (i.e., N(substituted alkyl);), alkenyl amines (i.e., NH 2 (alkenyl)), dialkenyl amines (i.e., HN( alkenyl) 2), trialkenyl amines (i.e., N(alkenyl
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • substituted means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded.
  • the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidine, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms.
  • impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • substituted alkyl refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
  • the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyi, aryl, or heteroaryl, each of which is unsubstituted.
  • “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • a “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
  • R 1 is -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl containing 1-2 N atom and 0 or 1 O or S atom, or a C 3 -C 6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom;
  • L 1 is absent, C 1 -C 4 alkylene, or C 3 -C 5 cycloalkylene;
  • R 2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R a ;
  • R 3 is H or C 1 -C 4 alkyl
  • R 4 is -L 2 -R 5 ;
  • L 2 is absent or -CR 10 R n -;
  • R 5 is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R b ;
  • ring B is C 3 - C 12 cycloalkyl, C 2 -C 10 heterocycloalkyl, phenyl, naphthyl, or heteroaryl;
  • R 10 and R 11 are independently selected from H or -CH 3 ; or R 10 and R 11 are taken together with the carbon atom to which they are attached to form a C 1 -C 6 cycloalkyl;
  • R 7 is H, halogen, -CN, -OH, -N(R 13 ) 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 heteroalkyl or C 3 -C 6 heterocycloalkyl;
  • X 1 is N; and X 2 is CR 8 or N; or X 1 is CR 8 or N; and X 2 is N;
  • R 8 is H, halogen, -CN, -OH, -N(R 13 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 3 -C 6 cycloalkyl, C 1 -C 4 heteroalkyl or C 3 -C 6 heterocycloalkyl; each R 12 is independently selected from the group consisting of C 1 -C 4 alky 1, C 1 -C 4 deuteroalkyl, C 1 -Cbfluoroalkyl.
  • each R 13 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deutcioalkyl, C -Cbfluoroalkyl.
  • C 1 -C 4 heteroalkyl substituted or unsubstituted Ch- C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; provided that when R 6 is H, R 4 is not cyclohexyl, 4-methylcyclohexyl, or cycloheptyl.
  • R 1 is hydrogen, -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl, C 3 -C 6 cycloalkyl, C--C 6 heterocycloalkyl containing 1 N atom and 0 or 1 O or S atom, or a C 3 -C 6 heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom;
  • L 1 is absent, C 1 -C 4 alkylene, or C 3 -C 6 cycloalkylene;
  • R 2 is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R a ;
  • R 3 is H or C 1 -C 4 alkyl
  • R 4 u is 1 or 2; v is 1 or 2; or R 4 is -L 2 -R 5 ;
  • L 2 is absent or -CR 10 R n -;
  • R 10 is -CH 3 ;
  • R 11 is H or -CH 3 ; or R 10 and R 11 are taken together with the carbon atom to which they are attached to form a cyclopropyl- 1 , 1 -diyl;
  • each R c is independently selected from the group consisting of halogen, -CN, -OH,
  • R 7 is H, halogen, -CN, -OH, -N(R 13 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 heteroalkyl;
  • X 1 is N; and X 2 is CR 8 or N; or X 1 is CR 8 or N; and X 2 is N;
  • R 8 is H, halogen, -CN, -OH, -N(R 13 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C -C 4 heteroalkyl: each R 12 is independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 - C 6 cycloalkyl, substituted or unsubstituted -C 3 -heterocycioalkyl.
  • each R 13 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, C 1 -C 4 fluoroalkyl.
  • C 1 -C 4 heteroalkyl substituted or unsubstituted C 3 - C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl provided that when R 1 is H, R 4 is not cyclohexyl substituted by 0, 1, 2, 3 or 4 methyl groups.
  • R 1 is H
  • R 4 is not cyclohexyl substituted by 0, 1, 2, 3 or 4 methyl groups.
  • Treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g. , decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • a) inhibiting the disease or condition e.g. , decreasing one or more symptoms resulting from the disease
  • prevention means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal.
  • the subject is a human.
  • a therapeutically effective amount or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition associated with modulation of CB2 receptors.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
  • the methods described herein may be applied to cell populations in vivo or ex vivo.
  • “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual.
  • “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art.
  • the selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.
  • the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for the modulation of cannabinoid receptors.
  • the cannabinoid receptor modulated by the compounds and methods is the cannabinoid 2 receptor (CB 2 R).
  • CB 2 R cannabinoid 2 receptor
  • CB 2 R modulators that are useful for treating one or more diseases or disorders associated with or that would benefit from modulation of CB 2 R activity.
  • described herein are methods for treating a disease or disorder, wherein the disease or disorder is cancer, a hyperproliferative disorder, an autoimmune disorder, or inflammatory disorder.
  • provided herein is a method of modulating the activity of the cannabinoid 2 receptor (CB 2 R) in a mammal comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • CBD 2 R cannabinoid 2 receptor
  • provided herein is a method of treating a disease or disorder in a mammal that is mediated by the action of the cannabinoid 2 receptor (CB 2 R) comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate or stereoisomer thereof.
  • CBD 2 R cannabinoid 2 receptor
  • a CB 2 R modulator described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof reduces, ameliorates or inhibits immunosuppression and cell proliferation associated with cancers.
  • a method for treating cancer in a mammal comprising administering to the mammal a selective cannabinoid 2 receptor (CB 2 R) modulator.
  • the selective cannabinoid 2 receptor (CB 2 R) modulator is a selective cannabinoid 2 receptor (CB 2 R) antagonist.
  • the selective cannabinoid 2 receptor (CB 2 R) modulator is a selective cannabinoid 2 receptor (CB 2 R) inverse agonist.
  • cancer refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
  • Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias and lymphomas) at any stage of the disease with or without metastases.
  • solid tumors such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias and lymph
  • a mammal treated with a compound described herein has a disease or disorder that is or is associated with a cancer or tumor.
  • the mammal is a human that is an oncology patient.
  • diseases and disorders and cancers include carcinomas, sarcomas, benign tumors, primary tumors, tumor metastases, solid tumors, non-solid tumors, blood tumors, leukemias and lymphomas, and primary and metastatic tumors.
  • the CB2 receptor modulators described herein are used in the treatment of solid tumours.
  • a solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas.
  • Solid tumors may be benign (not cancer), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are carcinomas, sarcomas, and lymphomas.
  • Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder carcinoma, bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, renal cell carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma.
  • Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.
  • Leukemias include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias; c) chronic lymphocytic leukemias (CLL), including B-cell CLL, T-cell CLL prolymphocyte leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts).
  • Lymphomas include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma); Hodgkin's lymphoma; and the like.
  • Benign tumors include, e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.
  • hemangiomas e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas,
  • Primary and metastatic tumors include, e.g., lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain; kidney cancers; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs.
  • lung cancer e.g., breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain;
  • the cancer is a solid tumor.
  • the cancer is bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or skin cancer.
  • the cancer is prostate cancer, breast cancer, colon cancer, or lung cancer.
  • the cancer is a sarcoma, carcinoma, or lymphoma.
  • the mammal is a human.
  • the methods comprise administering at least one additional therapy to the mammal.
  • the methods comprise administering at least one immune checkpoint inhibitor to the mammal.
  • the immune checkpoint inhibitor is an anti-PD-1 agent or an anti-PD-Ll agent.
  • the anti-PD-1 agent or anti-PD-Ll agent is nivolumab, pembrolizumab, cemiplimab, labrolizumab, avelumab, durvalumab or atezolizumab.
  • a compound described herein i.e. a CB 2 R antagonist or inverse agonist
  • a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor.
  • Immune checkpoint inhibitors include, but are not limited to, anti-PD-1, anti-PD- Ll, or anti-ligand 2 of programmed cell death protein 1 (PD-L2) agents/inhibitors.
  • immune checkpoint inhibitors include, but are not limited to anti-PD-1, anti-PD-Ll, or anti-ligand 2 of programmed cell death protein 1 (PD-L2) antibodies.
  • PD-1 refers to the Programmed Death 1 (PD-1) receptor.
  • Other names include programmed cell death protein 1 and CD279 (cluster of differentiation 279).
  • PD-1 has two ligands, PD-L1 and PD-L2.
  • targeting PD-1 restores immune function in the tumor microenvironment.
  • PD-L1 refers to the programmed death ligand 1 (PD-L1).
  • P-L2 refers to the programmed death ligand 2 (PD-L2).
  • the anti-PD-1 or anti-PDL-1 agent is an antibody, a peptide, a small molecule or a nucleic acid.
  • a compound described herein i.e. a CBzR antagonist or inverse agonist
  • a pharmaceutically acceptable salt thereof is administered in combination with an anti-PD-1 or anti-PD-Ll agent.
  • the anti-PD-1 agent is an anti-PD-1 antibody.
  • the anti-PD-Ll agent is an anti-PD-Ll antibody.
  • the anti PD-1 agent for use in combination with compound described herein i.e. a CB 2 R antagonist or inverse agonist
  • a pharmaceutically acceptable salt thereof is nivolumab, pembrolizumab, atezolizumab, durvalumab, pidilizumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI- 754091, IBL3O8, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN- 2034, CSIOOI, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzum
  • Anti-PD- 1 antibody refers to an antibody directed towards programmed death protein 1 (PD1).
  • an anti-PD-1 antibody binds an epitope of PD-1 which blocks the binding of PD-1 to any one or more of its putative ligands.
  • an anti-PDl antibody binds an epitope of a PD-1 protein which blocks the binding of PD-1 to PD-L1 and/or PD-L2.
  • Exemplary anti-PD-1 antibodies include but are not limited to: nivolumab/MDX-1106/BMS- 9300/ONO1152, a fully human lgG4 anti-PD-1 monoclonal antibody; pidilizumab (MDV9300/CT-011), a humanized IgGl monoclonal antibody; pembrolizumab (MK-3475/ pembrolizumab/lambrolizumab), a humanized monoclonal IgG4 antibody; durvalumab (MEDI-4736) and atezolizumab.
  • the anti-PD-1 antibody is nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck), cemiplimab (Libtayo), labrolizumab (Merck), or BGB-A317.
  • the anti-PDl antibody is an antibody set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,617,546, 8,709,417, or WO2014/179664.
  • antibody and “antibodies” as used herein is inclusive of all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, that may be appropriate for the medical uses disclosed herein.
  • the antibodies may be monoclonal or polyclonal and may be of any species of origin, including, for example, mouse, rat, rabbit, horse, or human.
  • Antibody fragments that retain specific binding to the protein or epitope, for example, PD-L1 or PD-1, bound by the antibody used in the present disclosure are included within the scope of the term “antibody.”
  • the antibodies may be chimeric or humanized, particularly when they are used for therapeutic purposes. Antibodies and antibody fragments may be obtained or prepared using various methods.
  • the anti PD-1 agent for use in combination with a compound described herein is atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX- 072, BMS-936559, KN035, CK-301 (Checkpoint Therapeutics), AUNP12, CA-170 (Aurigene/Curis), MEDI4736, MSB0010718C, MDX 1105-01, and BMS-986189.
  • a compound described herein i.e. a CB 2 R antagonist or inverse agonist
  • the anti PD-L1 agent is an anti PD-L1 antibody.
  • Anti-PD-Ll antibody refers to an antibody directed towards programmed death ligand 1 (PD-L1).
  • Anti-PD-Ll antibodies for use in combination with a compound described herein include: avelumab; BMS- 936559, a fully human IgG4 antibody; atezolizumab (MPDL3280A/RG-7446), a human monoclonal antibody; MEDI4736; MSB0010718C, and MDX 1105-01.
  • the anti-PD-Ll antibody is avelumab (Bavencio®, Merck KGA/Pfizer), durvalumab (AstraZeneca) and atezolizumab (TECENTRIQ®, Roche).
  • Additional exemplary antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos. 8,217,149, 8,383,796, 8,552,154 and 8,617,546.
  • Peptide anti-PD-l/PD-Ll agents include AUNP12 (a 29-mer peptide by Aurigene and Laboratoires Pierre Fabre), CA-170 (Aurigene/Curis), BMS-986189 (a macrocyclic peptide by BMS).
  • Small molecule anti-PD-l/PD-Ll agents include those described in WO/2020/086556, WO/2020/014643, WO/2019/204609, WO/2019/160882, WO/2018/195321, WO2018026971, US20180044329, US20180044305, US20180044304, US20180044303, US20180044350, US20180057455, US20180057486, US20180045142, WO20180044963, WO2018044783, W02018009505, WO20180044329, WO2017066227, WO2017087777, US20170145025, WO2017079669, W02017070089, US2017107216, WO2017222976, US20170262253, WO2017205464, US20170320875, WO2017192961, WO2017112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO2017202273,
  • kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging.
  • a kit further includes instructions for use.
  • a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
  • articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container.
  • the container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
  • compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art.
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
  • Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”).
  • transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.
  • the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate.
  • Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the daily dosage may also be described as a total amount of a compound described herein administered per dose or per day.
  • Daily dosage of a compound of Formula I may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
  • the compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.
  • the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
  • Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.
  • reaction with ethyl 3-chloro-3-oxopropanoate provides compound 1-2 which can be cyclized in the presence of a base and a protic solvent to provide compound 1-3 which can be converted to compounds of Formula (I) and/or Formula (X).
  • suitable bases for the cyclization include sodium methoxide, sodium ethoxide and the like.
  • suitable solvents include methanol, ethanol and the like.
  • Scheme 2 shows a further embodiment for the preparation of compounds of Formula (I) and/or Formula (X).
  • reaction with dibenzyl malonate provides compound 2-2 which can be converted to compounds of Formula (I) and/or Formula (X).
  • Scheme 3 shows an embodiment for the preparation of compounds of Formula (X).
  • Coupling of compound 4-4 with compound 4-5 under any suitable amide coupling conditions provides compound 4-6.
  • R 4 in compound 4-5 is as defined herein.
  • Compound 4-6 is converted to compound 4-7 using any suitable borylating agent.
  • Each R” in compound 4-7 is independently H, C 1 -C 3 alkyl, or phenyl, or, the two R” together with the atoms to which they are attached, form a dioxaborolane ring.
  • Compound 4-7 is coupled with a suitable compound 4-8 to provide compounds of Formula (I) or Formula (X).
  • R 6 is as defined herein and LG” is any suitable leaving group (e.g., halo).
  • the coupling reaction between compounds 4- 7 and 4-8 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art.
  • Scheme 5 shows an embodiment wherein R 1 is H or OH, and compounds 1 -3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X).
  • Each R” in compound 5-1 is independently H, C 1 -C 3 alkyl, or phenyl, or, the two R” together with the atoms to which they are attached, form a dioxaborolane ring.
  • Compound 5-1 is coupled with a suitable compound 4-8 to provide a compound 5-2.
  • the coupling reaction between compounds 5-1 and 4-8 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art.
  • R 6 is as defined herein and LG” is any suitable leaving group (e.g., halo).
  • the ester in compound 5-2 is hydrolyzed to provide compound 5-3.
  • each R is independently H, C 1 -C 3 alkyl, or phenyl, or, the two R’ ’ together with the atoms to which they are attached, form a dioxaborolane ring.
  • the coupling reaction between compounds 6-2 and 6-3 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art.
  • Compound 6-4 is converted to an amide 6-5 via a reaction with compound 4-5, wherein R 4 is as defined herein.
  • the ketal in compound 6-5 is hydrolyzed under acidic conditions (e.g., HCl) to provide the aldehyde 6-6 which is aminated with compound 6-7 to provide compounds of Formula (I) and/or (X).
  • R 2 in compound 6-7 is as defined herein.
  • Scheme 7 shows an embodiment for preparation of compounds of Formula (I) and/or (X) wherein R 1 is alkyl.
  • Scheme 8 shows an embodiment for preparation of compounds of Formula (I) and/or (X) wherein R 1 is alkoxy.
  • the compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie or Sigma (St. Louis, Missouri, USA).
  • the compounds described herein may be prepared using the methods disclosed herein and/or by using methods described in PCT/US2021/030838, and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
  • Step 1 Preparation of ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate
  • Step 2 Preparation of ethyl 6-bromo-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl)- 1,2- dihydro- 1,8-naphthyridine-3-carboxylate
  • Step 4 Preparation of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl)-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide [0180] To a solution of ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl)- 1,2- dihydro- 1,8-naphthyridine-3-carboxylate (50 mg, 106.41 ⁇ mol.
  • Step 1 Preparation of 4-(2-chloroethyl)tetrahydro-2H-pyran
  • SOCk 548.31 mg, 4.61 mmol, 334.34 ⁇ L, 3 eq.
  • the mixture was stirred at 85°C for 12 h.
  • the mixture was concentrated to give 4-(2-chloroethyl)tetrahydro-2H-pyran (50 mg, 336.41 ⁇ mol, 21.90% yield), which was used into next step directly.
  • Step 1 Preparation of ethyl 1-((l,3-dioxan-2-yl)methyl)-6-(4-fluorophenyl)-4-hydroxy-2- oxo- 1 ,2-dihydro- 1 ,8-naphthyridine-3-carboxylate
  • Step 1 Preparation of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-((4-methyl- 1,3-dioxan-2- yl)methyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate
  • Step 2 Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-((4-methyl- 1,3-dioxan-2- yl)methyl)-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • Step 1 Preparation of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-((5-methyl- 1,3-dioxan-2- yl)methyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate [0260] To a solution of the diethyl acetal (100 mg, 225.00 ⁇ mol, 694.44 ⁇ L, 1 eq) in 2-methylpropane- 1, 3-diol (1.24 g, 13.80 mmol, 1.0 mL, 61.33 eq) was added 4-methylbenzenesulfonic acid (100.74 mg, 584.99 ⁇ mol, 2.6 eq). The mixture was stirred at 20°C for 10 h. The mixture was triturated with water (6 mL) and the mixture was filtered, and the filtrate cake was dried to give the desired product (70 mg, 158.21 ⁇ mol, 70.32% yield
  • Step 2 Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-((5-methyl- 1,3-dioxan-2- yl)methyl)-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • Step 2 Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(1-(hydroxymethyl)cyclohexyl)-2- oxo-1-(2-oxoethyl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • To a solution of 1-(2,2-diethoxyethyl)-6-(4-fluorophenyl)-4-hydroxy-N-(l- (hydroxymethyl)cyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide 5 mg, 9.48 ⁇ mol, 1 eq) in THF (0.1 mL) was added hydrochloric acid (2 M, 0.1 mL, 20 eq) at 20°C. The mixture was stirred at 20°C for 1 h. The mixture was concentrated to give the desired product (4 mg, 8.82 ⁇ mol, 93.08% yield).
  • Step 3 Preparation of 6-(4-fluorophenyl)-1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hydroxy-N- (1-(hydroxymethyl)cyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • Step 5 Preparation of N-(bicyclo[l.l.l]pentan-1-yl)-2-(6-bromo-4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridin-3-yl)acetamide
  • Step 6 Preparation of N-(bicyclo[l.l.l]pentan-1-yl)-2-(6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridin-3-yl)acetamide
  • Step 1 Preparation of 1-(6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2- dihydro- 1,8-naphthyridine-3-carboxamido)cyclohexane-1-carboxylic acid [0302] To a solution of Compound 27 (130 mg, 220.69 ⁇ mol, 1 eq, HO) in DMSO (1 mL) was added NaOH (2 M, 0.3 mL, 3 eq). The mixture was stirred at 25°C for 2 h.
  • the mixture was filtered, and the filter cake was washed with water and dried to give the desired carboxylic acid (100 mg, 185.68 ⁇ mol, 84.13% yield).
  • Step 2 Preparation of N-(l-carbamoylcyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholmoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • Step 2 Preparation of ethyl 4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxylate
  • Step 3 Preparation of ethyl 1-(2,2-diethoxyethyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate
  • Step 4 Preparation of ethyl 1-(2,2-diethoxyethyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate
  • Step 1 Preparation of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate
  • Step 1 Preparation of ethyl l-[(4-fluorophenyl) methyl]-4-hydroxy-2-oxo- 1, 8- naphthyridine-3-carboxylate
  • CS 2 CO 3 5.56 g, 17.08 mmol, 8 eq
  • (bromomethyl)-4-fluoro-benzene 807.08 mg, 4.27 mmol, 527.50 ⁇ L, 2 eq
  • Step 2 Preparation of 1-(4-fluorobenzyl)-4-hydroxy-N-(1-(hydroxymethyl)cyclohexyl)-2- oxo- 1 ,2-dihydro- 1 ,8-naphthyridine-3-carboxamide
  • Step 1 Preparation of ethyl l-allyl-4-hydroxy-2-oxo- 1, 8-naphthyridine-3-carboxylate
  • Step 2 Preparation of l-allyl-4-hydroxy-N-(4-methylcyclohexyl)-2-oxo- 1,8-naphthyridine- 3-carboxamide
  • ethyl l-allyl-4-hydroxy-2-oxo- 1,8-naphthyridine-3-carboxylate 3.5 g, 12.76 mmol, 1 eq
  • (cis)-4-methylcyclohexanamine (1.91 g, 12.76 mmol, 1 eq, HCl)
  • DIPEA 4.95 g, 38.28 mmol, 6.67 mL, 3 eq
  • the mixture was then heated to 110 °C and stirred for 24 h.
  • the reaction mixture was concentrated to obtain a residue, the residue was dissolved in EA (150 mL), then washed with water (50 mL *2), dried by Na 2 SO 4 , filtered and concentrated to obtain a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 40 g epaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) and concentrated to obtain desired product.
  • Step 3 Preparation of 1-(2,3-dihydroxypropyl)-4-hydroxy-N-(4-methylcyclohexyl)-2-oxo- l,8-naphthyridine-3-carboxamide
  • Step 5 Preparation of 1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hydroxy-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • the residue was purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25 mm* 10 ⁇ m; mobile phase: [water (FA) -ACN]; B%: 21%-51%, 10 min) and lyophilized to give crude product.
  • the crude product was second purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25 mm* 10pm;mobile phase: [water (FA) -ACN];B%: 21%-48%, 9 min) and lyophilized to give Compound 42 (5 mg, 9.69 ⁇ mol, 6.65% yield, 92.32% purity, FA salt).
  • the reaction mixture was concentrated to obtain a residue, the residue was dissolved in EA (80 mL), then washed with water (40 mL *2) and brine (40 mL), dried by Na2SOr, filtered and concentrated to obtain the crude product.
  • the crude product was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate/Petroleum ethergradient @ 50 mL/rnin) and concentrated to obtain desired product.
  • the product N-benzyl-3-methyl-cyclopentanamine (1.4 g, 7.40 mmol, 72.58% yield) was obtained.
  • the residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10pm; mobile phase: [water (FA) -ACN];B%: 23%-53%, 10 min) and lyophilized.
  • the crude product was second purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10 ⁇ m;mobile phase: [water (FA) -ACN];B%: 29%-49%, 8 min) and lyophilized to give Compound 45 (3.4 mg, 6.72 ⁇ mol, 4.62% yield, 96.59% purity, FA).
  • the mixture was stirred at 60 °C for 2 hr.
  • the combined organic layers were washed with brine (10 mL *2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10 ⁇ m;mobilc phase: [water (FA) -ACN];B%: 20%-50%, 10 min) and lyophilized.
  • the crude product was second purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* lOpimmobile phase: [water (FA) -ACN];B%: 18%-48%, 10 min) and lyophilized to give Compound 50 (25 mg, 56.75 ⁇ mol, 38.97% yield, 100% purity).
  • Step 1 Preparation of ((ls,4s)-1-amino-4-methylcyclohexyl)methanol
  • L1AIH 4 72.43 mg, 1.91 mmol, 3 eq
  • THF 3 mL
  • (ls,4s)-1-amino-4-methylcyclohexane-1- carboxylic acid 100 mg, 636.09 ⁇ mol, 1 eq
  • Step 2 Preparation of 1-(4-fluorobenzyl)-4-hydroxy-N-((ls,4s)-1-(hydroxymethyl)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridme-3-carboxamide
  • L1AIH 4 (144.85 mg, 3.82 mmol, 3 eq) was added in a 50 mL round-bottom flask under Ni at 0 °C, THF was added (8 mL), and (lr,4r)-1-amino-4-methyl-cyclohexanecarboxylic acid (200 mg, 1.27 mmol, 1 eq) was added in small portions as a solid. Upon completion addition, the mixture was heated to 80 °C for 16 h. The mixture was cooled to 0 °C, treated slowly with saturated Na2CO; solution (5 mL), warmed to 20 °C, and stirred for 2 h.
  • Step 2 Preparation of 1-(4-fhiorobenzyl)-4-hydroxy-N-((lr,4r)-1-(hydroxymethyl)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • reaction mixture was concentrated to obtain a residue.
  • residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10pm; mobile phase: [water(FA)-ACN];B%: 70%-100%,10min) and lyophilized to obtain desired product.
  • Compound 53 28 mg, 63.71 ⁇ mol, 36.35% yield was obtained.
  • Step 1 Preparation of ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3- carboxylate
  • Step 3 Preparation of l-allyl-6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-2- oxo-1, 8-naphthyridine-3-carboxamide
  • the reaction mixture was concentrated to obtain a residue, the residue was dissolved in EA (80 mL), then washed with water (50 mL *3), dried by Na 2 SO 4 . filtered and concentrated to obtain a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 5% Ethyl acetate/Petroleum ethergradient @50 mL/min) and concentrated to obtain desired product.
  • Step 4 Preparation of 1-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-4-hydroxy-N-(4- methylcyclohexyl)-2-oxo- 1,8-naphthyridine-3-carboxamide
  • the reaction mixture was concentrated to obtain a solution, then filtered, the filter cake was triturated with 10 mL THF/H 2 O (1:1), filtered and the filter cake was dried by reduced pressure to obtain desired product.
  • Step 5 Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1-(2- oxoethyl)- 1,8-naphthyridine-3-carboxamide
  • the reaction mixture was concentrated to obtain a residue.
  • the residue was purified by prep-HPLC (FA condition) and lyophilized to obtain crude product, the crude product was purified by prep-HPLC (HCl condition, column: 3_Phenomenex Luna C1875*30mm*3pm; mobile phase: [water(HCl)-ACN];B%: 47%-67%,7min) and lyophilized to obtain desired product.
  • Compound 56 25 mg, 47.66 ⁇ mol, 26.06% yield
  • Step 2 Preparation of l-allyl-N-(4, 4-difluorocyclohexyl) -4-hydroxy-2-oxo- 1, 8- naphthyridine-3-carboxamide
  • Step 4 Preparation of 4-hydroxy- N-(4, 4-difluorocyclohexyl) -4-hydroxy-2-oxo-1-(2- oxoethyl) -1, 8-naphthyridine-3-carboxamide
  • the reaction mixture was quenched by addition IM HCl (10 mL) at 25 °C, and then diluted with water (10 mL), and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL *2), dried over NtoSCL, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10pm; mobile phase: [water (FA) -ACN];B%: 17% -47%, 10 min) and lyophilized to obtained crude product.
  • Step 3 Preparation of l-allyl-N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-2-oxo- 1,8- naphthyridine-3-carboxamide
  • the reaction mixture was concentrated to obtain a residue, the residue was dissolved in 100 mL EA, then washed with brine (60 mL *2), dried by Na 2 SO 4 , filtered and concentrated to obtain the crude product.
  • the crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 5% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) and concentrated to obtain desired product.
  • Step 6 Preparation of N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-1-(2-morpholinoethyl)-2- oxo-1, 2-dihydro- 1,8-naphthyridine-3-carboxamide
  • Step 1 Preparation of methyl (lr,4r)-1-amino-4-methylcyclohexane-1-carboxylate
  • SOCb 328.00 mg, 2.76 mmol, 0.2 mL, 4.33 eq
  • Step 2 Preparation of methyl (lr,4r)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholmoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1- carboxylate
  • Step 2 Preparation of methyl (ls,4s)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1- carboxylate
  • the reaction mixture was concentrated to obtain a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-80% Ethyl acetate/Petroleum ethergradient @50 mL/min) and concentrated to obtain desired product.
  • Compound 70 (240 mg, 423.56 ⁇ mol. 39.99% yield) was obtained.
  • reaction mixture was purified by pre-HPLC (column: 3_Phenomenex Luna Cl 8 75*30mm*3pm; mobile phase: [water (HCl)- ACN]; B%: 32%-52%,min) and lyophilized to obtain desired product.
  • Compound 72 (8 mg, 14.50 ⁇ mol, 26.71% yield) was obtained.
  • reaction mixture was purified directly.
  • the residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10 ⁇ m; mobile phase: [water(FA)-ACN];B%: 24%- 44%,10min) and lyophilized to obtain desired product.
  • Compound 73 (14 mg, 24.75 ⁇ mol, 68.39% yield) was obtained.
  • the residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10 ⁇ m;mobile phase: [water(FA)-ACN];B%: 39%-59%,10min) and lyophilized to obtain a crude product
  • the crude product was purified by prep-HPLC (neutral condition, column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH 4 HCO 3 )-ACN];B%: 80%-100%,7min) and lyophilized to obtain desired product.
  • Compound 78 (5 mg, 11.00 ⁇ mol. 8.21% yield) was obtained.
  • Step 1 Preparation of ethyl 4-hydroxy-1-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]- 2-oxo- 1,8-naphthyridine-3-carboxylate
  • Step 2 Preparation of 1-(2,3-dihydroxypropyl)-N-(4,4-dimethylcyclohexyl)-4-hydroxy-2- oxo-1, 8-naphthyridine-3-carboxamide
  • Step 4 Preparation of N-(4,4-dimethylcyclohexyl)-1-(2-(4-fluoropiperidin-1-yl)ethyl)-4- hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • the filter cake was washed by water (100 mL), then dried by reduced pressure to obtain a residue.
  • the filter cake and residue were mixed, and 8, 8-dimethyl- 1,3-diazaspiro[4.5]decane-2, 4-dione (4 g, 20.38 mmol, 85.74% yield) was obtained and used into the next step without further purification.
  • LiAlH 4 (443.30 mg, 11.68 mmol, 5 eq) was placed in a 50 mL round-bottom flask under N2 atmosphere at 0 °C, and THF (20 mL) was added.
  • l-Amino-4,4-dimethyl-cyclohexanecarboxylic acid 400 mg, 2.34 mmol, 1 eq was added in small portions as a solid, and upon completion addition the mixture was heated to 80 °C for 16 h.
  • Step 4 Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(1-(hydroxymethyl)-4,4- dimethylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide
  • ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8- naphthyridine-3-carboxylate 50 mg, 113.26 ⁇ mol, 1 eq
  • (l-amino-4,4-dimethyl- cyclohexyl)methanol 21.37 mg, 135.92 ⁇ mol, 1.2 eq
  • DIPEA 73.19 mg, 566.31 ⁇ mol, 98.64 ⁇ L, 5 eq
  • reaction mixture was concentrated to obtain a residue.
  • residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10 ⁇ m; mobile phase: [water(FA)-ACN];B%: 25%-55%,10min) and lyophilized to obtain desired product.
  • Compound 82 (28 mg, 50.67 ⁇ mol, 44.73% yield) was obtained.
  • CBiR binding protocol involves the use of the same solution buffer used for both incubation and washing reaction (Tris-HCl, 50 mM; EDTA, 2.5 mM; MgCF. 2.5 mM; BSA, 0.5 mg/mL at pH 7.4), 0.4 nM for [ 3 H]CP-55,940, test compounds (concentrations from 0.001 to 10 ⁇ M), and finally
  • CB 2 R binding assays were carried out with two different buffers: incubation buffer (Tris-HCl, 50 mM; MgCh, 5 mM; CaCh 1 mM; BSA, 0.2% at pH 7.4) and washing buffer (Tris-HCl, 50 mM; NaCl 500 mM; BSA, 0.1% at pH 7.4).
  • the assay mixture contained incubation buffer, 0.4 nM [ 3 H]CP-55,940, test substances (concentrations from 0.001 to 10 ⁇ M), and 4 pg/sample membrane in a total assay volume of 200 ⁇ L.
  • Assays were performed in duplicate and incubated for 120 min at 37 °C. After the incubation, the assay mixture was filtered through 96 GF/C filter plates (Perkin Elmer #6005174) using Perkin Elmer Filtermate Harvester, and then washed four times with ice-cold washing buffer. The filters were dried for 1 hour at 50°C and [ 3 H] trapped on filter counted for radioactivity in Perkin Elmer Microscint 20 cocktail (#6013329) using Perkin Elmer MicroBeta2 Reader.
  • Example B-2 CB2 Receptor cAMP Assay
  • cAMP Hunter CHO-K-1 cell lines expressing human CB 2 receptor (Eurofins) are expanded from freezer stocks according to standard procedures. Cells are seeded in a total volume of 20 ⁇ L into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing. cAMP modulation in agonist, inverse agonist or antagonist format is determined using the DiscoverX HitHunter cAMP XS+ assay (Eurofins). For agonist determination, cells are incubated with sample in the presence of EC80 forskolin to induce response. Media is aspirated from cells and replaced with 15 ⁇ L 2:1 HBSS/lOmM Hepes: cAMP XS+ Ab reagent.
  • 4X sample 5 ⁇ L is added to cells and incubated at 37°C or room temperature for 30 or 60 minutes.
  • Final assay vehicle concentration is 1%.
  • cells are pre-incubated with sample followed by agonist challenge at the EC80 concentration.
  • Media is aspirated from cells and replaced with 10 ⁇ L 1:1 HBSS/Hepes: cAMP XS+ Ab reagent.
  • 5 ⁇ L of 4X compound is added to the cells and incubated at 37 °C or room temperature for 30 minutes.
  • 5 ⁇ L of 4X EC80 agonist is added to cells and incubated at 37 °C or room temperature for 30 or 60 minutes.
  • EC80 forksolin is included.
  • assay signal is generated through incubation with 20 ⁇ L cAMP XS+ ED/CL lysis cocktail for one hour followed by incubation with 20 ⁇ L cAMP XS+ EA reagent for three hours at room temperature.
  • Microplates are read following signal generation with a PerkinElmer Envision instrument for chemiluminescent signal detection.
  • Compound activity is analyzed using CBIS data analysis suite (Chemlnnovation, CA).
  • % Inverse Agonist Activity 100% x ((mean RLU of test sample - mean RLU of EC20 forskolin) / (mean RLU of forskolin positive control - mean RLU of EC20 control)).
  • percentage inhibition 100% x (mean RLU of test sample - mean RLU of EC80 control) / (mean RLU of forskolin positive control - mean RLU of EC80 control).
  • Data are analyzed and IC 50 is calculated using GraphPad Prism 5 and the model “log(inhibitor) vs. response - Variable slope”.
  • Example B-3 In vitro mixed lymphocyte reaction assay
  • DC Dendritic cells
  • monocytes isolated from freshly isolated human PBMC 3 using a monocyte purification kit (Miltenyi Biotec) in vitro for 7 days with 500 U/mL interleukin-4 (IL-4) and 250 U/mL GM-CSF (R&D Systems).
  • IL-4 interleukin-4
  • GM-CSF R&D Systems
  • CD 4+ T cells IxlO 5
  • IxlO 4 are co-cultured with or without CBjR antagonists and/or anti-PD-(L)-! antibody added at the initiation of the assay. After 5 days, IFNy secretion in culture supernatants is analyzed by ELISA (BD Biosciences).
  • Example B-4 In vitro T cell exhaustion assay
  • Freshly isolated human PBMC 3 from healthy donors are cultured for 3 days with or without CB 2 R antagonists and/or anti-PD-(L)-l antibodies at the initiation of the assay together with serial dilutions of staphylococcal enterotoxin B (SEB; Toxin Technology). IL-2 levels in culture supernatants are measured by ELISA analysis (BD Biosciences).
  • Example B-5 In vivo B16F10 tumor growth inhibition study
  • C57BL/6 inbred female mice aged at 8-9 week, are purchased from Charles River.
  • B16F10 cells are harvested, washed and counted. Cells are re-suspended as single cell solution in PBS at a concentration of 5xl0 6 cells/mL at the final step.
  • 5xl0 5 five hundred thousand of B16F10 cells suspended in 0.1 mL PBS are injected in the right flank of C57BL/6 mice subcutaneously using 27G needles.
  • tumors are measured by a caliper and tumor volumes (mm 3 ) are calculated by length x width x height x 0.5236.
  • MTV Median Tumor Volume
  • Example B-6 Combination with Anti-PD-l/anti-PD-Ll Agents
  • CB 2 receptor antagonists can be used in combination with other therapies that further enhance the antitumor immune response.
  • PD-1 and PD-L1 join together, they form a biochemical shield protecting tumor cells from being destroyed by the immune system.
  • CB 2 receptor antagonists are combined with anti-PD-l/anti-PD-Ll agents to treat cancer. Combination therapy is advantageous when efficacy is greater than either agent alone or when the dose required for either drug is reduced thereby improving the side effect profile.
  • Example B -7 In vivo PK
  • the dosing suspension for oral administration is formulated in 0.5% Methylcellulose as a 1 mg/mL suspension for the 5 mg/kg oral dose level (5 mL/kg dose volume).
  • Blood samples are collected from rats via jugular vein cannulation into EDTA-K2 tubes.
  • blood samples are collected pre-dose, at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose administration.
  • blood samples are collected predose, at 15 min, 30 min,, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose administration.
  • blood concentrations of the compound are determined using LC-MS/MS with a lower limit of quantitation of 10 ng/mL.
  • plasma concentrations of the compound are determined using LC-MS/MS with a lower limit of quantitation of 1 ng/mL.
  • the pharmacokinetic parameters are determined by non-compartmental analysis using WinNonlin.

Abstract

La présente invention concerne 82 dérivés de 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphtyridine-3-carboxamide spécifiques utilisés en tant que modulateurs des récepteurs cannabinoïdes CB2 pour le traitement du cancer, par exemple du 6-(4-fluorophényl)-4-hydroxy-1-(2-(4-méthylpipérazin-1-yl) éthyl)-2-oxo-N-(spiro[2,3]hexan-5-yl)-1,2-dihydro-1,8-naphtyridine-3-carboxamide (exemple 1, composé 1). La présente description concerne la synthèse et la caractérisation des 82 composés revendiqués ainsi que des dosages biologiques de ceux-ci.
PCT/US2022/079183 2021-11-03 2022-11-02 Dérivés de 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphtyridine-3-carboxamide utilisés en tant que modulateurs du récepteur cb2 cannabinoïde pour le traitement du cancer WO2023081730A1 (fr)

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