WO2020198053A1 - Dérivés de 2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-6-yl)-4-méthylbenzamide et composés similaires utilisés en tant qu'inhibiteurs de ripk2 pour traiter par exemple des maladies auto-immunes - Google Patents

Dérivés de 2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-6-yl)-4-méthylbenzamide et composés similaires utilisés en tant qu'inhibiteurs de ripk2 pour traiter par exemple des maladies auto-immunes Download PDF

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WO2020198053A1
WO2020198053A1 PCT/US2020/023984 US2020023984W WO2020198053A1 WO 2020198053 A1 WO2020198053 A1 WO 2020198053A1 US 2020023984 W US2020023984 W US 2020023984W WO 2020198053 A1 WO2020198053 A1 WO 2020198053A1
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pyridin
methylpropan
imidazo
hydroxy
oxo
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Mallareddy Komandla
Joanne Miura
Haixia Wang
Xiaolun Wang
John David Lawson
John Tyhonas
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • 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
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Definitions

  • This invention relates to pyridine-fused imidazole and pyrrole derivatives which are selective inhibitors of receptor-interacting protein kinase 2 (RIPK2), to pharmaceutical compositions which contain them, and to their use to treat diseases, disorders, and conditions associated with RIPK2, including inflammatory bowel disease (IBD).
  • RIPK2 receptor-interacting protein kinase 2
  • Receptor-interacting protein kinase 2 (RIPK2) is a serine/threonine protein kinase which mediates a pro-inflammatory signaling cascade involving nucleotide-binding oligomerization domain-containing protein 1 and 2 (NODI and NOD2).
  • the cytosolic pattern recognition receptors (PPRs) NODI and NOD2 function in the innate immune system, detecting invasive bacteria via binding to diaminopimelic acid or muramyl dipeptide (MDP) residues present in bacterial peptidoglycan.
  • NODI and NOD2 associate with RIPK2, which subsequently undergoes autophosphorylation and polyubiquitination via interaction with XIAP and other E3 ligases.
  • the RIPK2-ubiquitin complex activates TAK1 and IKK kinases, which promote upregulation of the mitogen-activated protein kinase and NF-KB signaling pathways. See, e.g, P. Canning, Q. Ruan, T. Schwerd, et al. ,“Inflammatory signaling by NOD-RIPK2 is inhibited by clinically relevant Type II Kinase Inhibitors,” Chemistry & Biology 22: 1174-84 (2015) and M. Hrdinka, L. Scheuer, B. Dai, et al. ,“Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling,” The EMBO Journal 37: e99372 (2018) and references cited therein.
  • Inhibitors of RIPK2 are expected to be useful for treating inflammatory and autoimmune diseases, including IBD.
  • This invention provides pyridine-fused imidazole and pyrrole derivatives and pharmaceutically acceptable salts thereof.
  • This invention also provides pharmaceutical compositions that contain the pyridine-fused imidazole and pyrrole derivatives and provides for their use to treat diseases, disorders and conditions associated with RIPK2, including IBD and other gastrointestinal diseases, disorders and conditions.
  • One aspect of the invention provides compounds of Formula 1 :
  • a is a single bond
  • b is a double bond
  • X 1 is NR 1n
  • R 2 is oxo
  • a is a double bond
  • b is a single bond
  • X 1 is selected from N and CR 1C
  • R 2 is selected from hydrogen, Ci-4 alkyl, and Ci-4 alkoxy
  • R 1C is selected from hydrogen, halo, and Ci- 6 alkyl which is substituted with from 0 to 3
  • R 1N is selected from Ci-4 alkyl, C3-8 cycloalkyl-(CH2)n, C2-8 heterocyclyl-(CH2)n, and
  • Ci-9 heteroaryl -(CH2)n wherein each of the Ci-4 alkyl, C3-8 cycloalkyl,
  • C2-8 heterocyclyl, and C1-9 heteroaryl moieties is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, Ci-4 alkyl, Ci-4 alkoxy, and amino which is optionally substituted with one or two Ci-4 alkyl, and wherein the Ci-4 alkyl and Ci-4 alkoxy optional substituents are each
  • n is selected from 0, 1, 2, and 3;
  • R 3 is Ci- 6 alkyl which is substituted with from 0 to 3 optional substituents independently
  • R 3 selected from halo, hydroxy, cyano, Ci-4 alkoxy which is optionally substituted with Ci-4 alkoxy, and from amino which is optionally substituted with one or two Ci-4 alkyl, wherein one or more of the hydrogen atoms on R 3 may optionally be deuterium;
  • R 4 and R 5 are each independently selected from hydrogen, halo, and Ci-4 alkyl;
  • X 6 is selected from N and C(R 6 );
  • X 7 is selected from N and C(R 7 ); R 6 and R 7 are each independently from hydrogen, halo, Ci-4 alkyl, and Ci-4 alkoxy;
  • R 8 is selected from hydrogen, halo, Ci-4 alkyl, and Ci-4 alkoxy, wherein the Ci-4 alkyl and
  • Ci-4 alkoxy substituents are substituted with from 0 to 3 optional substituents independently selected from halo;
  • R 9 is selected from Ci- 6 alkyl, C3-8 cycloalkyl, C2-8 heterocyclyl, and C1-9 heteroaryl, each substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, oxo, Ci-4 alkyl, Ci-4 alkoxy, and amino which is optionally substituted with one or two Ci-4 alkyl, wherein the Ci-4 alkyl and Ci-4 alkoxy optional substituents are each independently substituted with from 0 to 3 optional substituents independently selected from halo; and
  • heterocyclyl and heteroaryl moieties independently has 1 to 4 ring
  • heteroatoms each of the heteroatoms independently selected from N, O, and S.
  • Another aspect of the invention provides a compound which is selected from the group of compounds described in the examples and their pharmaceutically acceptable salts.
  • a further aspect of the invention provides a pharmaceutical composition which includes a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph; and a pharmaceutically acceptable excipient.
  • An additional aspect of the invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • Another aspect of the invention provides a compound of Formula 1 or a
  • a further aspect of the invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof, for use in treating a disease, disorder or condition selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjogren’s syndrome, ankylosing spondylitis, Behcet’s disease, graft versus host disease, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, and thrombosis.
  • a disease, disorder or condition selected from allergic rhinitis, asthma, atopic dermatitis, rheuma
  • An additional aspect of the invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease, disorder or condition associated with RIPK2.
  • Another aspect of the invention provides a method for inhibiting RIPK2 in a subject, the method comprising administering to the subject a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof.
  • a further aspect of the invention provides a method for treating a disease, disorder or condition associated with RIPK2, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof.
  • An additional aspect of the invention provides a method for treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from Type I hypersensitivity reactions, autoimmune diseases, and inflammatory disorders, cancer, and non-malignant proliferative disorders
  • Another aspect of the invention provides a method for treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjogren’s syndrome, ankylosing spondylitis, Behcet’s disease, graft versus host disease, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, and thrombosis.
  • “Substituted,” when used about a chemical substituent or moiety means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided valence requirements are met and a chemically stable compound results from the substitution.
  • Alkyl refers to straight chain and branched saturated hydrocarbon groups, generally having a specified number of carbon atoms (e.g., Ci-4 alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, Ci- 6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, and so on).
  • alkyl groups include methyl, ethyl, «-propyl, /-propyl, «-butyl, 5-butyl, /-butyl, /-butyl, pent-l-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3- methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-l-yl, «-hexyl, and the like.
  • Alkanediyl refers to divalent alkyl groups, where alkyl is defined above, and generally having a specified number of carbon atoms (e.g., Ci-4 alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms, Ci- 6 alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, and so on).
  • alkanediyl groups include methylene, ethane- 1,1-diyl, ethane- 1,2-diyl, propane- 1, 3 -diyl, propane- 1,2-diyl, propane- 1,1-diyl, propane-2, 2-diyl, butane- 1,4-diyl, butane-1, 3-diyl, butane- 1,2-diyl, butane- 1, 1-diyl, isobutane-1, 3-diyl, isobutane- 1,1 -diyl, isobutane- 1,2-diyl, and the like.
  • alkenyl refers to straight chain and branched hydrocarbon groups having one or more carbon-carbon double bonds, and generally having a specified number of carbon atoms.
  • alkenyl groups include ethenyl, 1 -propen- 1-yl, l-propen-2-yl, 2-propen- 1-yl, 1- buten-l-yl, l-buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2-methyl- 1- propen-l-yl, 2-methyl -2-propen- 1-yl, 1,3-butadien-l-yl, l,3-butadien-2-yl, and the like.
  • Alkynyl refers to straight chain or branched hydrocarbon groups having one or more triple carbon-carbon bonds, and generally having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-l-yl, 2-propyn-l-yl, 1-butyn-l-yl, 3- butyn-l-yl, 3-butyn-2-yl, 2-butyn-l-yl, and the like.
  • Alkoxy refers to straight chain and branched saturated hydrocarbon groups attached through an oxygen atom, generally having a specified number of carbon atoms (e.g., Ci-4 alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms,
  • Ci-6 alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, and so on).
  • alkoxy groups include methoxy, ethoxy, //-propoxy, z-propoxy, //-butoxy, .v-butoxy, z-butoxy, Z-butoxy, pent-l-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-l-yloxy, 3-methylbut-2- yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-l-yloxy, //-hexoxy, and the like.
  • Halo “halogen” and“halogeno” may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.
  • Haloalkyl “haloalkenyl,” and“haloalkynyl,” refer, respectively, to alkyl, alkenyl, and alkynyl groups substituted with one or more halogen atoms, where alkyl, alkenyl, and alkynyl are defined above, and generally having a specified number of carbon atoms.
  • haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, di chi orom ethyl, tri chi orom ethyl, 1-fluoroethyl, 1, 1-difluoroethyl, 1- chloroethyl, 1,1-dichloroethyl, 1 -fluoro- 1-methylethyl, 1 -chloro- 1 -methyl ethyl, and the like.
  • Cycloalkyl refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms that comprise the ring or rings (e.g.,
  • C3-8 cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members).
  • Bicyclic hydrocarbon groups may include isolated rings (two rings sharing no carbon atoms), spiro rings (two rings sharing one carbon atom), fused rings (two rings sharing two carbon atoms and the bond between the two common carbon atoms), and bridged rings (two rings sharing two carbon atoms, but not a common bond).
  • the cycloalkyl group may be attached through any ring atom unless such attachment would violate valence requirements, and where indicated, may optionally include one or more non-hydrogen substituents unless such substitution would violate valence requirements.
  • Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-l-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, and the like.
  • bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3 2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1 Jdecanyl,
  • spiro cycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, and the like.
  • isolated bicyclic cycloalkyl groups include those derived from bi(cyclobutane),
  • Cycloalkanediyl refers to divalent cycloalkyl groups, where cycloalkyl is defined above, and generally having a specified number of carbon atoms (e.g., C3-4 cycloalkanediyl refers to a cycloalkanediyl group having 3 to 4 (i.e., 3 or 4) carbon atoms, C3-6
  • cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, and so on).
  • Examples of cycloalkanediyl groups include cyclopropan-l,l-diyl, cyclopropan-l,2-diyl, cyclobutan-l,l-diyl, cyclobutan-l,2-diyl, and the like.
  • Cycloalkylidene refers to divalent monocyclic cycloalkyl groups, where cycloalkyl is defined above, which are attached through a single carbon atom of the group, and generally having a specified number of carbon atoms that comprise the ring (e.g.,
  • C3-6 cycloalkylidene refers to a cycloalkylidene group having 3 to 6 carbon atoms as ring members). Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.
  • Cycloalkenyl refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms that comprise the ring or rings.
  • the bicyclic cycloalkenyl groups may include isolated, spiro, fused, or bridged rings.
  • the cycloalkenyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements.
  • cycloalkenyl groups include the partially unsaturated analogs of the cycloalkyl groups described above, such as cyclobutenyl (i.e., cyclobuten-l-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.
  • Aryl refers to fully unsaturated monocyclic aromatic hydrocarbons and to polycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms that comprise their ring members (e.g., C6-14 aryl refers to an aryl group having 6 to 14 carbon atoms as ring members).
  • the group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements.
  • aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl, biphenylenyl, fluorenyl, groups derived from cycloheptatriene cation, and the like.
  • Arylene refers to divalent aryl groups, where aryl is defined above. Examples of arylene groups include phenylene (i.e., benzene- 1,2-diyl).
  • Heterocycle and“heterocyclyl” may be used interchangeably and refer to saturated or partially unsaturated monocyclic or bicyclic groups having ring atoms composed of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring or rings (e.g., C2-8 heterocyclyl refers to a heterocyclyl group having 2 to 8 carbon atoms and 1 to 4 heteroatoms as ring members).
  • bicyclic heterocyclyl groups may include isolated rings, spiro rings, fused rings, and bridged rings in which at least one of the rings includes one or more heteroatoms.
  • the heterocyclyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.
  • heterocyclyl groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-l-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepany
  • Heterocycle-diyl refers to heterocyclyl groups which are attached through two ring atoms of the group, where heterocyclyl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C2-8 heterocycle-diyl refers to a heterocycle-diyl group having 2 to 8 carbon atoms and 1 to 4 heteroatoms as ring members).
  • heterocycle-diyl groups include the multivalent analogs of the heterocycle groups described above, such as morpholine-3, 4-diyl, pyrrolidine- 1,2-diyl, l-pyrrolidinyl-2- ylidene, l-pyridinyl-2-ylidene, l-(4 /)-pyrazolyl-5-ylidene, l-(3 /)-imidazolyl-2-ylidene, 3- oxazolyl-2-ylidene, l-piperidinyl-2-ylidene, l-piperazinyl-6-ylidene, and the like.
  • Heteroaromatic and“heteroaryl” may be used interchangeably and refer to unsaturated monocyclic aromatic groups and to polycyclic groups having at least one aromatic ring, each of the groups having ring atoms composed of carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both the monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., Ci- 9 heteroaryl refers to a heteroaryl group having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members) and may include any bicyclic group in which any of the above- listed monocyclic heterocycles are fused to a benzene ring.
  • the heteroaryl group may be attached through any ring atom (or ring atoms for fused rings), and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.
  • heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-l-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, l-oxa-2,3-diazolyl, l-oxa-2,4-diazolyl, l-oxa-2,5-diazolyl, l-oxa-3,4-diazolyl, l-thia-2,3-diazolyl, l-thia-2,4-diazolyl, l-thia-2,5- diazolyl, l-thia-3,4-diazolyl, tetrazolyl, pyridinyl,
  • heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1 //-indolyl, 3//-indolyf isoindolyl, 1 H- isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, l /-indazolyl, 2 /-indazolyl,
  • Heteroarylene refers to heteroaryl groups which are attached through two ring atoms of the group, where heteroaryl is defined above. They generally have a specified number of carbon atoms in their ring or rings (e.g., C3-5 heteroarylene refers to a
  • heteroarylene group having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members).
  • heteroarylene groups include the multivalent analogs of the heteroaryl groups described above, such as pyridine-2, 3-diyl, pyridine-3, 4-diyl, pyrazole-4,5-diyl, pyrazole-3,4- diyl, and the like.
  • Leaving group refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. Leaving groups may be nucleofugal, in which the group leaves with a pair of electrons that formerly served as the bond between the leaving group and the molecule, or may be electrofugal, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its base strength, with the strongest bases being the poorest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkyl sulfonates (e.g., mesylate),
  • fluoroalkyl sulfonates e.g., triflate, hexaflate, nonaflate, and tresylate
  • aryl sulfonates e.g., tosylate, brosylate, closylate, and nosylate
  • Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides.
  • Some stronger bases, such as NLb and OH can be made better leaving groups by treatment with an acid. Common electrofugal leaving groups include the proton, CO2, and metals.
  • Optesite enantiomer refers to a molecule that is a non-superimposable mirror image of a reference molecule, which may be obtained by inverting all the stereogenic centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Likewise, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.
  • Stepoisomer and“stereoisomers” of a compound with given stereochemical configuration refer to the opposite enantiomer of the compound and to any diastereoisomers, including geometrical isomers ( Z!E) of the compound.
  • Z!E geometrical isomers
  • stereoisomer refers to any one of the possible stereochemical configurations of the compound.
  • substantially pure stereoisomer and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 95% of the sample.
  • “Pure stereoisomer” and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 99.5% of the sample.
  • Subject refers to a mammal, including a human.
  • “Pharmaceutically acceptable” substances refer to those substances which are suitable for administration to subjects.
  • Treating refers to reversing, alleviating, inhibiting the progress of, or preventing a disease, disorder or condition to which such term applies, or to reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of such disease, disorder or condition.
  • Treatment refers to the act of“treating,” as defined immediately above.
  • drug “Drug,”“drug substance,”“active pharmaceutical ingredient,” and the like, refer to a compound (e.g., compounds of Formula 1, including subgeneric compounds and compounds specifically named in the specification) that may be used for treating a subject in need of treatment.
  • Effective amount of a drug refers to the quantity of the drug that may be used for treating a subject and may depend on the weight and age of the subject and the route of administration, among other things.
  • “Excipient” refers to any diluent or vehicle for a drug.
  • “Pharmaceutical composition” refers to the combination of one or more drug substances and one or more excipients.
  • “Drug product,”“pharmaceutical dosage form,”“dosage form,”“final dosage form” and the like refer to a pharmaceutical composition suitable for treating a subject in need of treatment and generally may be in the form of tablets, capsules, sachets containing powder or granules, liquid solutions or suspensions, patches, films, and the like.
  • Condition associated with RIPK2 relate to a disease, disorder or condition in a subject for which inhibition of RIPK2 may provide a therapeutic or prophylactic benefit.
  • Tris buffer (2-amino-2- hydroxymethyl -propane- 1 ,3-diol buffer).
  • this disclosure concerns compounds of Formula 1 and their pharmaceutically acceptable salts.
  • This disclosure also concerns materials and methods for preparing compounds of Formula 1, pharmaceutical compositions which contain them, and the use of compounds of Formula 1 and their pharmaceutically acceptable salts (optionally in combination with other pharmacologically active agents) for treating diseases, disorders or conditions associated with RIPK2.
  • the compounds of Formula 1 include those in which (1):
  • a is a single bond
  • b is a double bond
  • X 1 is NR 1n
  • R 2 is oxo
  • a is a double bond
  • b is a single bond
  • X 1 is selected from N and CR 1C
  • R 2 is selected from hydrogen, Ci-4 alkyl, and Ci-4 alkoxy
  • R 1C is selected from hydrogen, halo, and Ci-6 alkyl which is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, Ci-4 alkoxy, and amino which is optionally substituted with one or two Ci-4 alkyl;
  • R 1N is selected from Ci-4 alkyl, C3-8 cycloalkyl-(CH2)n, C2-8 heterocyclyl-(CH2)n, and Ci- 9 heteroaryl -(CH2)n, wherein each of the Ci-4 alkyl, C3-8 cycloalkyl, C2-8 heterocyclyl, and C1-9 heteroaryl moieties is substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, Ci-4 alkyl, Ci-4 alkoxy, and amino which is optionally substituted with one or two Ci-4 alkyl, and wherein the Ci-4 alkyl and Ci-4 alkoxy optional substituents are each independently substituted with from 0 to 3 optional substituents independently selected from halo; n is selected from 0, 1, 2, and 3;
  • R 3 is Ci - 6 alkyl which is substituted with from 0 to 3 optional substituents
  • R 3 independently selected from halo, hydroxy, cyano, Ci-4 alkoxy which is optionally substituted with Ci-4 alkoxy, and from amino which is optionally substituted with one or two Ci-4 alkyl, wherein one or more of the hydrogen atoms on R 3 may optionally be deuterium;
  • R 4 and R 5 are each independently selected from hydrogen, halo, and Ci-4 alkyl;
  • X 6 is selected from N and C(R 6 );
  • X 7 is selected from N and C(R 7 );
  • R 6 and R 7 are each independently from hydrogen, halo, Ci-4 alkyl, and Ci-4 alkoxy;
  • R 8 is selected from hydrogen, halo, Ci-4 alkyl, and Ci-4 alkoxy, wherein the
  • Ci-4 alkyl and Ci-4 alkoxy substituents are substituted with from 0 to 3 optional substituents independently selected from halo;
  • R 9 is selected from Ci-6 alkyl, C3-8 cycloalkyl, C2-8 heterocyclyl, and C1-9 heteroaryl, each substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, oxo, Ci-4 alkyl, Ci-4 alkoxy, and amino which is optionally substituted with one or two Ci-4 alkyl, wherein the Ci-4 alkyl and Ci-4 alkoxy optional substituents are each independently substituted with from 0 to 3 optional substituents independently selected from halo; and
  • each of the heterocyclyl and heteroaryl moieties independently has 1 to 4 ring members which are heteroatoms, each of the heteroatoms
  • the compounds of Formula 1 include those in which (2) a is a single bond, b is a double bond, X 1 is NR 1n , and R 2 is oxo.
  • the compounds of Formula 1 include those in which R 1N is selected from:
  • Ci-5 heteroaryl -(CH2)n wherein each of the Ci-4 alkyl, C 3 -8 cycloalkyl,
  • C2-8 heterocyclyl, and C1-9 heteroaryl moieties is substituted with from 0 to 3 optional substituents as defined in embodiment (1); (4) Ci-4 alkyl, C3-8 cycloalkyl-(CH2)n, C3-5 heterocyclyl-(CH2)n, and
  • Ci-5 heteroaryl -(CH2)n wherein each of the Ci-4 alkyl, Ci-4 alkoxy, C3-6 cycloalkyl, C3-5 heterocyclyl, and C1-5 heteroaryl moieties is substituted with from 0 to 3 optional substituents as defined in embodiment (1); or
  • Ci-4 alkyl C3-6 cycloalkyl-(CH2)n, C3-5 heterocyclyl-(CH2)n, and
  • Ci-5 heteroaryl -(CH2)n wherein each of the Ci-4 alkyl, C3-6 cycloalkyl,
  • the compounds of Formula 1 include those in which each of the 0 to 3 optional substituents of R 1N is independently selected from:
  • Ci-4 alkyl hydroxy, Ci-4 alkyl, Ci-4 alkoxy, and amino which is optionally substituted with one or two Ci-4 alkyl, wherein the Ci-4 alkyl and Ci-4 alkoxy optional substituents are each independently substituted with from 0 to 3 optional substituents independently selected from halo;
  • the compounds of Formula 1 include those in which (10) R 1N is Ci-4 alkyl which is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which the Ci-4 alkyl substituent of R 1N is selected from:
  • the compounds of Formula 1 include those in which the Ci-4 alkyl substituent of R 1N is:
  • the compounds of Formula 1 include those in which (20) R 1N is C3-6 cycloalkyl-(CH2)n in which the C3-6 cycloalkyl moiety is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which the C3-6 cycloalkyl moiety of R 1N is selected from:
  • the compounds of Formula 1 include those in which the C3-6 cycloalkyl moiety of R 1N is substituted with from 0 to 3 optional substituents independently selected from:
  • the compounds of Formula 1 include those in which (29) the C3-6 cycloalkyl moiety of R 1N is unsubstituted.
  • the compounds of Formula 1 include those in which (30) R 1N is C3-5 heterocyclyl-(CH2)n in which the C3-5 heterocyclyl moiety is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which the C3-5 heterocyclyl moiety of the R 1N substituent has:
  • (31) one or two heteroatoms as ring members, each of the heteroatoms independently selected from N, O and S; or
  • the compounds of Formula 1 include those in which (33) the C3-5 heterocyclyl moiety of the R 1N substituent is monocyclic.
  • the compounds of Formula 1 include those in which the C3-5 heterocyclyl moiety of the R 1N substituent is selected from:
  • the compounds of Formula 1 include those in which the C3-5 heterocyclyl moiety of R 1N is:
  • the compounds of Formula 1 include those in which (43) R 1N is C1-5 heteroaryl-(CH2)n in which the C1-5 heteroaryl moiety is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which (44) the C1-5 heteroaryl moiety of the R 1N substituent has one or two heteroatoms as ring members, each of the heteroatoms independently selected from N, O and S.
  • the compounds of Formula 1 include those in which (45) the C1-5 heteroaryl moiety of the R 1N substituent is monocyclic.
  • the compounds of Formula 1 include those in which the C1-5 heteroaryl moiety of the R 1N substituent is selected from:
  • the compounds of Formula 1 include those in which the C1-5 heteroaryl moiety of R 1N is:
  • (51) substituted with from 0 to 3 optional substituents independently selected from fluoro, chloro, hydroxy, methyl, methoxy, and amino which is optionally substituted with one or two methyl;
  • the compounds of Formula 1 include those in which:
  • n is selected from 0, 1, and 2;
  • n is selected from 0 and 1;
  • n 1;
  • compounds of Formula 1 include those in which (58) a is a double bond, b is a single bond, X 1 is N, and R 2 is selected from hydrogen, Ci-4 alkyl, and Ci-4 alkoxy.
  • compounds of Formula 1 include those in which (59) a is a double bond, b is a single bond, X 1 is CR 1C , and R 2 is selected from hydrogen,
  • Ci -4 alkyl Ci-4 alkoxy
  • the compounds of Formula 1 include those in which R 1C is selected from:
  • the compounds of Formula 1 include those in which R 1C is selected from:
  • compounds of Formula 1 include those in which R 1C is selected from:
  • the compounds of Formula 1 include those in which R 2 is selected from:
  • the compounds of Formula 1 include those in which R 3 is Ci-4 alkyl which is: (78) substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, Ci-4 alkoxy which is optionally substituted with Ci-4 alkoxy, and from amino which is optionally substituted with one or two Ci-4 alkyl;
  • the compounds of Formula 1 include those in which R 3 is selected from:
  • the compounds of Formula 1 include those in which R 4 and R 5 are each independently selected from:
  • the compounds of Formula 1 include those in which:
  • X 6 is C(R 6 ) and X 7 is C(R 7 ).
  • the compounds of Formula 1 include those in which R 6 and R 7 are each independently selected from:
  • the compounds of Formula 1 include those in which R 8 is selected from:
  • the compounds of Formula 1 include those in which R 9 is selected from:
  • Ci- 6 alkyl, C3-8 cycloalkyl, and C1-9 heteroaryl each substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, oxo, Ci-4 alkyl, Ci-4 alkoxy, and amino which is optionally substituted with one or two Ci-4 alkyl, wherein the Ci-4 alkyl and Ci-4 alkoxy optional substituents are each independently substituted with from 0 to 3 optional substituents independently selected from halo;
  • Ci-4 alkyl, C3-6 cycloalkyl, and C1-5 heteroaryl each substituted with from 0 to 3 optional substituents independently selected from halo, hydroxy, cyano, oxo, Ci-4 alkyl, Ci-4 alkoxy, and amino which is optionally substituted with one or two Ci-4 alkyl; wherein the Ci-4 alkyl and Ci-4 alkoxy optional substituents are each independently substituted with from 0 to 3 optional substituents independently selected from halo.
  • the compounds of Formula 1 include those in which each of the 0 to 3 optional substituents of R 9 is independently selected from:
  • the compounds of Formula 1 include those in which each of the R 9 substituents is substituted with from 0 to 1 optional substituents independently selected from:
  • the compounds of Formula 1 include those in which (108) each of the R 9 substituents is unsubstituted.
  • the compounds of Formula 1 include those in which (109) R 9 is Ci-4 alkyl which is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which R 9 is Ci-4 alkyl which is selected from:
  • the compounds of Formula 1 include those in which the Ci-4 alkyl substituent of R 9 is:
  • the compounds of Formula 1 include those in which (118) R 9 is C3-8 cycloalkyl which is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which (119) R 9 is C3-6 cycloalkyl which is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which R 9 is C3-6 cycloalkyl which is:
  • the compounds of Formula 1 include those in which the C3-6 cycloalkyl substituent of R 9 is:
  • the compounds of Formula 1 include those in which (129) R 9 is C2-8 heterocyclyl which is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which (130) R 9 is C3-5 heterocyclyl which is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which the heterocyclyl substituent of R 9 has:
  • the compounds of Formula 1 include those in which (133) the heterocyclyl substituent of R 9 is monocyclic.
  • the compounds of Formula 1 include those in which the heterocyclyl substituent of R 9 is:
  • the compounds of Formula 1 include those in which (140) R 9 is C1-9 heteroaryl which is substituted with from 0 to 3 optional substituents as defined in embodiment (1). [0110] In addition to embodiments (101) to (102), the compounds of Formula 1 include those in which (141) R 9 is C1-5 heteroaryl which is substituted with from 0 to 3 optional substituents as defined in embodiment (1).
  • the compounds of Formula 1 include those in which (142) the heteroaryl substituent of R 9 has one or two heteroatoms as ring members, each of the heteroatoms independently selected from N, O and S.
  • the compounds of Formula 1 include those in which (143) the heteroaryl substituent of R 9 is monocyclic.
  • the compounds of Formula 1 include those in which the heteroaryl substituent of R 9 is:
  • (145) selected from imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, and pyridinyl.
  • the compounds of Formula 1 include those in which the heteroaryl substituent of R 9 is:
  • Compounds of Formula 1 include embodiments (1) through (151) described in the preceding paragraphs and all compounds specifically named in the examples, and may exist as salts, complexes, solvates, hydrates, and liquid crystals. Likewise, compounds of
  • Formula 1 that are salts may exist as complexes, solvates, hydrates, and liquid crystals.
  • Compounds of Formula 1 may form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including di-acids) and base salts.
  • Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acids
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, alipha
  • Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate
  • Pharmaceutically acceptable base salts include salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
  • suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum.
  • suitable amines include arginine, A(A f '-di benzyl ethyl enedi am i ne,
  • chloroprocaine choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, /V-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-l,3-diol, and procaine.
  • acid addition and base salts see S. M. Berge et ak, J Pharm. Sci. (1977) 66: 1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).
  • salts may be prepared using various methods. For example, a compound of Formula 1 may be reacted with an appropriate acid or base to give the desired salt. Alternatively, a precursor of the compound of Formula 1 may be reacted with an acid or base to remove an acid- or base-labile protecting group or to open a lactone or lactam group of the precursor. Additionally, a salt of the compound of Formula 1 may be converted to another salt (or free form) through treatment with an appropriate acid or base or through contact with an ion exchange resin. Following reaction, the salt may be isolated by filtration if it precipitates from solution, or by evaporation to recover the salt. The degree of ionization of the salt may vary from completely ionized to almost non-ionized.
  • Compounds of Formula 1 may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • amorphous refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”).
  • crystalline refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (“melting point”).
  • Compounds of Formula 1 may also exist in unsolvated and solvated forms.
  • solvate describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol).
  • solvent molecules e.g., ethanol
  • hydrate is a solvate in which the solvent is water.
  • Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., D2O, aceton e-de, DMSO-r/r,).
  • a currently accepted classification system for solvates and hydrates of organic compounds is one that distinguishes between isolated site, channel, and metal-ion
  • Isolated site solvates and hydrates are ones in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound.
  • the solvent molecules lie in lattice channels where they are next to other solvent molecules.
  • metal-ion coordinated solvates the solvent molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non- stoichiometry will typically be observed.
  • Compounds of Formula 1 may also exist as multi-component complexes (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non- stoichiometric amounts.
  • Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions but could also be a complex of a neutral molecule with a salt.
  • Co crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together. See, e.g., O. Almarsson and M. J.
  • compounds of Formula 1 may exist in a mesomorphic state (mesophase or liquid crystal).
  • the mesomorphic state lies between the true crystalline state and the true liquid state (either melt or solution).
  • Mesomorphism arising as the result of a change in temperature is described as“thermotropic” and mesomorphism resulting from the addition of a second component, such as water or another solvent, is described as“lyotropic.”
  • Compounds that have the potential to form lyotropic mesophases are described as“amphiphilic” and include molecules which possess a polar ionic moiety (e.g., -COO Na + , -COO K + , -S03 ⁇ Na + ) or polar non-ionic moiety (such as -NTS1 + (CH3)3). See, e.g., N. H. Hartshome and A. Stuart, Crystals and the Polarizing Microscope (4th ed, 1970).
  • Each compound of Formula 1 may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically-labeled, may result from the administration of a prodrug, or form a metabolite following administration.
  • Prodrugs refer to compounds having little or no pharmacological activity that can, when metabolized in vivo , undergo conversion to compounds having desired pharmacological activity.
  • Prodrugs may be prepared by replacing appropriate functionalities present in pharmacologically active compounds with“pro-moieties” as described, for example, in H. Bundgaar, Design of Prodrugs (1985).
  • Examples of prodrugs include ester, ether or amide derivatives of compounds of Formula 1 having carboxylic acid, hydroxy, or amino functional groups, respectively.
  • prodrugs see e.g., T. Higuchi and V. Stella “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series 14 (1975) and E. B. Roche ed., Bioreversible Carriers in Drug Design (1987).
  • Methodabolites refer to compounds formed in vivo upon administration of
  • Compounds of Formula 1 may exist as stereoisomers that result from the presence of one or more stereogenic centers, one or more double bonds, or both.
  • the stereoisomers may be pure, substantially pure, or mixtures.
  • Such stereoisomers may also result from acid addition or base salts in which the counter-ion is optically active, for example, when the counter-ion is D-lactate or L-lysine.
  • Tautomeric isomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.
  • Compounds of Formula 1 may exhibit more than one type of isomerism.
  • Geometrical (cis/trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.
  • the resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, etc., and the appropriate diastereoisomer converted to the compound having the requisite stereochemical configuration.
  • chromatography fractional crystallization, etc.
  • diastereoisomer converted to the compound having the requisite stereochemical configuration.
  • Compounds of Formula 1 may possess isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • Isotopes suitable for inclusion in compounds of Formula 1 include, for example, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as u C, 13 C and 14 C; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 0, 17 0 and 18 0; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as 18 F; isotopes of chlorine, such as 36 C1, and isotopes of iodine, such as 123 I and 125 I.
  • isotopic variations may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3 H, or 14 C), which may be useful in drug and/or substrate tissue distribution studies.
  • positron emitting isotopes such as U C, 18 F, 15 0 and 13 N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds may be prepared by processes analogous to those described elsewhere in the disclosure using an appropriate isotopically-labeled reagent in place of a non-labeled reagent.
  • the compounds of Formula 1 may be prepared using the techniques described below. Some of the schemes and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation,
  • reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).
  • certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites.
  • Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound.
  • protecting group strategies a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).
  • the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78°C to 0°C). Any reference in the disclosure and claims to a stoichiometric range, a temperature range, a pH range, etc., whether expressly using the word“range,” also includes the indicated endpoints.
  • the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination.
  • Representative solvents include saturated aliphatic hydrocarbons (e.g., «-pentane, «-hexane, «-heptane, «-octane,
  • cyclohexane methylcyclohexane
  • aromatic hydrocarbons e.g., benzene, toluene, xylenes
  • halogenated hydrocarbons e.g., methylene chloride, chloroform, carbon tetrachloride
  • aliphatic alcohols e.g., methanol, ethanol, propan-l-ol, propan-2-ol, butan-l-ol, 2-methyl- propan-l-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-l-ol, 3-methyl-butan-l-ol, hexan-l-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2- ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, di-isopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-di ethoxy-ethane, l-methoxy-2-(2-methoxy- ethoxy)-ethane, l-ethoxy-2-(2-e
  • substituent identifiers (a, b, n, R 1C , R 1N , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X 1 , X 6 , X 7 ) are as defined above for Formula 1.
  • some of the starting materials and intermediates may include protecting groups, which are removed prior to the final product.
  • the substituent identifier refers to moieties defined in Formula 1 and to those moieties with appropriate protecting groups (unless explicitly shown).
  • a starting material or intermediate in the schemes may include X 1 substituent having a potentially reactive hydroxy group.
  • X 1 would include the moiety with or without, say, a TBS or Ac group attached to the oxygen atom.
  • Schemes A and B show general methods for preparing compounds of Formula 1.
  • a heteroaromatic halide (A-l in which, e.g., X is Cl, Br or I) is reacted with an aromatic (or heteroaromatic) boronic acid or ester (A-2 in which, e.g., each R 10 is H or Ci-4 alkyl) in the presence of a palladium catalyst (e.g., XPhos Pd G3, Pd(dppf)Cl2, PdCl2(dtbpf), etc.), a base (e.g., K2CO3, Na2CCb, KF, etc.) and one or more polar solvents (e.g., dioxane, DMF, water, etc.).
  • a palladium catalyst e.g., XPhos Pd G3, Pd(dppf)Cl2, PdCl2(dtbpf), etc.
  • a base e.g., K2CO
  • the palladium catalyzed cross-coupling reaction is carried out at elevated temperature (e.g., 80-130°C) and gives the compound of Formula 1 directly or indirectly, e.g., after removal of protecting groups, further elaboration of functional groups, etc.
  • Scheme C shows a general method for preparing heteroaromatic halide (C-l) and heteroaromatic boronic acid or ester (C-2) which correspond, respectively, to compounds (A- 1) and (B-l) when a is a single bond, b is a double bond, X 1 is NR 1n , and R 2 is oxo.
  • a 2-halo-3-nitropyridine (C-3) is reacted with an R 3 -substituted amine (C-4) in the presence of a base (e.g., DIPEA) and solvent (e.g., ACN, DMSO, etc.) at elevated temperature (e.g., 80°C) to give a 3-nitropyridin-2-amine (C-5).
  • a base e.g., DIPEA
  • solvent e.g., ACN, DMSO, etc.
  • elevated temperature e.g. 80°C
  • the amine (C-5) is subsequently reduced (via e.g., catalytic hydrogenation, treatment with iron metal and NFLCl in EtOH and water, etc.) to provide a pyridine-2, 3-diamine (C-6).
  • the diamine (C-6) is reacted with CDI in a polar solvent (e.g., THF) and at elevated temperature (e.g., 60-75°C) to afford the desired pyrido-fused imidazolidinone (C-7).
  • the imidazolidinone (C-7) is treated with base (e.g., NaH, K2CO3, etc.) in solvent (e.g., DMF, ACN, etc.) and then reacted with an alkyl halide (C-8, R 1N is optionally substituted alkyl, X is Br, I, etc.) at elevated temperature (80-130°C) to give the heteroaromatic halide (C-l).
  • the halide (C-l) may be reacted with diboronic acid or ester (C-9) in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, Pd(dppf)Ch.CH2Cl2, etc.), base (KOAc, potassium phenoxide, etc.) and solvent (e.g., dioxane) at elevated temperature (e.g., 80-100°C) to provide the heteroaromatic boronic acid or ester (C-2).
  • a palladium catalyst e.g., Pd(dppf)Cl2, Pd(dppf)Ch.CH2Cl2, etc.
  • base KOAc, potassium phenoxide, etc.
  • solvent e.g., dioxane
  • Scheme D shows a general method for preparing heteroaromatic halide (D-l) and heteroaromatic boronic acid or ester (D-2) which correspond, respectively, to compounds (A- 1) and (B-l) when a is a double bond, b is a single bond, and X 1 is N.
  • pyridine-2,3 -diamine (C-6) is reacted with an acid chloride (D-3, R 2 is Ci-4 alkyl) in the presence of a non-nucleophilic base (e.g., DIPEA) and a polar solvent (THF) with cooling (e.g., 0-15°C) to obtain an /V-(pyri din-3 -yl)alkylamide (D-4).
  • a non-nucleophilic base e.g., DIPEA
  • THF polar solvent
  • the amide (D-4) is
  • each R 11 is, e.g., methyl
  • C1-5 alkanoic acid HO Ac, propionic acid, butanoic acid, etc.
  • elevated temperature e.g., 100- 120°C
  • the pyridine- 2, 3-diamine (C-6) may be reacted with tetraalkyl orthocarbonate (D-6, each R 2 is Ci-4 alkoxy) and Ci-5 alkanoic acid (HO Ac, propionic acid, butanoic acid, etc.) at elevated temperature (e.g., 100-120°C) to afford the heteroaromatic halide (D-l, R 2 is Ci-4 alkoxy).
  • the diamine (C-6) may be reacted with an orthoester (HC(OR n )3) in the presence of a C1-5 alkanoic acid (e.g., HOAc) at elevated temperature (e.g., 80°C) to give the heteroaromatic halide (D-l, R 2 is H).
  • HC(OR n )3 a C1-5 alkanoic acid
  • elevated temperature e.g. 80°C
  • the halide (D-l) may be reacted with diboronic acid or ester (C-9) in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, etc.), base (e.g., KOAc, potassium phenoxide, etc.) and solvent (e.g., dioxane) at elevated temperature (e.g., 80-100°C) to provide the heteroaromatic boronic acid or ester (D-2).
  • a palladium catalyst e.g., Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, etc.
  • base e.g., KOAc, potassium phenoxide, etc.
  • solvent e.g., dioxane
  • Scheme E shows a general method for preparing heteroaromatic halide (E-l) and boronic acid or ester (E-2) which correspond, respectively, to compounds (A-l) and (B-l) when a is a double bond, b is a single bond, X 1 is CR 1C , and R 1C is hydrogen.
  • a 3-bromo-5-chloro-2-fluoropyridine (E-3) is reacted with an R 3 -substituted amine (C-4) in the presence of a base (e.g., DIPEA) and solvent (e.g., ACN, DMSO, etc.) at elevated temperature (e.g., 80°C) to give a 3-bromo-5-chloropyridin-2-amine (E-4).
  • a base e.g., DIPEA
  • solvent e.g., ACN, DMSO, etc.
  • the amine (C-5) is subsequently reacted with an organostannane (E-5, R 12 is, e.g., butyl) in the presence of a palladium catalyst (e.g., Pd(PPh3)4) and nonpolar solvent (e.g., toluene) at elevated temperature (e.g., 100°C).
  • a palladium catalyst e.g., Pd(PPh3)4
  • nonpolar solvent e.g., toluene
  • E-6 is treated with a strong base (e.g., NaO/-Bu, KO/-Bu, etc.) in a polar solvent (DMF) at RT or above (e.g., 60°C) to give the heteroaromatic halide (E-l).
  • a strong base e.g., NaO/-Bu, KO/-Bu, etc.
  • DMF polar solvent
  • the halide (E-l) may be reacted with diboronic acid or ester (C-9) in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, Pd(dppf)Ch.CH2Cl2, etc.), base (e.g., KOAc, potassium phenoxide, etc.) and solvent (e.g., dioxane) at elevated temperature (e.g., 80-100°C) to provide the heteroaromatic boronic acid or ester (E-2).
  • a palladium catalyst e.g., Pd(dppf)Cl2, Pd(dppf)Ch.CH2Cl2, etc.
  • base e.g., KOAc, potassium phenoxide, etc.
  • solvent e.g., dioxane
  • Scheme F shows a general method for preparing aromatic (or heteroaromatic) boronic acid or ester (A-2) or halide (B-2).
  • a carboxylic acid (F-l) is treated with thionyl chloride in a solvent (e.g., DMF) at elevated temperature (e.g., 60-80°C).
  • thionyl chloride in a solvent (e.g., DMF) at elevated temperature (e.g., 60-80°C).
  • the resulting acid chloride (F-2) is reacted with an R 9 -substituted amine (F-3) in a solvent (e.g., DCM) with cooling (0-15°C) to give the aromatic halide (B-2).
  • the carboxylic acid (F-l) may be reacted with the amine (F-3) using an amide coupling agent (e.g., HATU, DCC, EDC hydrochloride, T3P or 2-chloro-l-methylpyridin-l-ium iodide) in the presence of a non-nucleophilic base (e.g., Et3N, DIPEA) and one or more compatible polar solvents (e.g. DCM, DMA, DMF, THF).
  • a non-nucleophilic base e.g., Et3N, DIPEA
  • compatible polar solvents e.g. DCM, DMA, DMF, THF.
  • the amide coupling may be carried out at temperatures which range from room temperature to about 80°C. HOBt may be used to facilitate the reaction.
  • the halide (B-2) may be reacted with diboronic acid or ester (C-9) in the presence of a palladium catalyst (e.g., Pd(dppf)Ch, Pd(dppf)Cl2.CH2Cl2, etc.), base (e.g., KOAc, potassium phenoxide, etc.) and solvent (e.g., dioxane) at elevated temperature (e.g., 80-100°C) to provide the heteroaromatic boronic acid or ester (A-2).
  • a palladium catalyst e.g., Pd(dppf)Ch, Pd(dppf)Cl2.CH2Cl2, etc.
  • base e.g., KOAc, potassium phenoxide, etc.
  • solvent e.g., dioxane
  • Scheme F The methods depicted in the schemes may be varied as desired.
  • protecting groups may be added or removed, and intermediates or products may be further elaborated via, for example, alkylation, acylation, halogenation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynation, transition metal catalyzed cross-coupling reactions, and the like to give the desired final product.
  • any intermediate or final product which comprises mixture of stereoisomers may be optionally purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with optically-pure reagents as described above to give a desired stereoisomer.
  • Compounds of Formula 1, which include compounds named above, and their pharmaceutically acceptable complexes, salts, solvates and hydrates, should be assessed for their biopharmaceutical properties, such as solubility and solution stability across pH, permeability, and the like, to select an appropriate dosage form and route of administration.
  • Compounds that are intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying, or radio frequency drying.
  • Compounds of Formula 1 may be administered alone or in combination with one another or with one or more pharmacologically active compounds which are different than the compounds of Formula 1. Generally, one or more of these compounds are administered as a pharmaceutical composition (a formulation) in association with one or more
  • excipients are pharmaceutically acceptable excipients.
  • the choice of excipients depends on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, among other things.
  • Useful pharmaceutical compositions and methods for their preparation may be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).
  • Compounds of Formula 1 may be administered orally. Oral administration may involve swallowing in which case the compound enters the bloodstream via the
  • oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration) such that the compound enters the bloodstream through the oral mucosa.
  • mucosal administration e.g., buccal, sublingual, supralingual administration
  • Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges which may be liquid-filled; chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal or mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs.
  • Such formulations may be employed as fillers in soft or hard capsules (made, e.g., from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifying agents, suspending agents or both.
  • a carrier e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agents e.g., ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • Liquid formulations may also be prepared by the reconstitution of a solid (e.g., from a sachet).
  • Compounds of Formula 1 may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11 (6):981 -986.
  • the active pharmaceutical ingredient may comprise from about 1 wt% to about 80 wt% of the dosage form or more typically from about 5 wt% to about 60 wt% of the dosage form.
  • tablets may include one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, anti oxidants, colorants, flavoring agents, preservatives, and taste-masking agents.
  • disintegrants examples include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, Ci- 6 alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate.
  • the disintegrant will comprise from about 1 wt% to about 25 wt% or from about 5 wt% to about 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation.
  • Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch,
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • Tablets may also include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from about 0.2 wt% to about 5 wt% of the tablet, and glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.
  • Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate.
  • Lubricants may comprise from about 0.25 wt% to about 10 wt% or from about 0.5 wt% to about 3 wt% of the tablet.
  • Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. If desired, prior to blending one or more of the components may be sized by screening or milling or both.
  • the final dosage form may comprise one or more layers and may be coated, uncoated, or encapsulated.
  • Exemplary tablets may contain up to about 80 wt% of API, from about 10 wt% to about 90 wt% of binder, from about 0 wt% to about 85 wt% of diluent, from about 2 wt% to about 10 wt% of disintegrant, and from about 0.25 wt% to about 10 wt% of lubricant.
  • Consumable oral films for human or veterinary use are pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive.
  • a typical film includes one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity-modifying agents, and solvents.
  • Other film ingredients may include anti-oxidants, colorants, flavorants and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants, and taste-masking agents.
  • Some components of the formulation may perform more than one function.
  • the amount of API in the film may depend on its solubility. If water soluble, the API would typically comprise from about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film or from about 20 wt% to about 50 wt% of the solutes in the film. A less soluble API may comprise a greater proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and typically comprises from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80 wt% of the film.
  • Film dosage forms are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper, which may be carried out in a drying oven or tunnel (e.g., in a combined coating-drying apparatus), in lyophilization equipment, or in a vacuum oven.
  • Useful solid formulations for oral administration may include immediate release formulations and modified release formulations.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.
  • suitable modified release formulations see US Patent No. 6,106,864.
  • Other useful release technologies such as high energy dispersions and osmotic and coated particles, see Verma et al, Pharmaceutical Technology On-line (2001) 25(2): 1-14.
  • Compounds of Formula 1 may also be administered directly into the blood stream, muscle, or an internal organ of the subject.
  • Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • Suitable devices for parenteral administration include needle injectors, including microneedle injectors, needle-free injectors, and infusion devices.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (e.g., pH of from about 3 to about 9).
  • excipients such as salts, carbohydrates and buffering agents (e.g., pH of from about 3 to about 9).
  • compounds of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions may be readily accomplished using standard pharmaceutical techniques.
  • solubility of compounds which are used in the preparation of parenteral solutions may be increased through appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.
  • compounds of Formula 1 may be formulated as a suspension, a solid, a semi-solid, or a thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(DL-lactic-coglycolic)acid (PGLA) microspheres.
  • Compounds of Formula 1 may also be administered topically, intradermally, or transdermally to the skin or mucosa.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions.
  • Liposomes may also be used.
  • Typical carriers may include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Topical formulations may also include penetration enhancers. See, e.g., Finnin and Morgan, J. Pharm. Sci.
  • Topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g.
  • Formulations for topical administration may be formulated to be immediate or modified release as described above.
  • Compounds of Formula 1 may also be administered intranasally or by inhalation, typically in the form of a dry powder, an aerosol spray, or nasal drops.
  • An inhaler may be used to administer the dry powder, which comprises the API alone, a powder blend of the API and a diluent, such as lactose, or a mixed component particle that includes the API and a phospholipid, such as phosphatidylcholine.
  • the powder may include a bioadhesive agent, e.g., chitosan or cyclodextrin.
  • a pressurized container, pump, sprayer, atomizer, or nebulizer may be used to generate the aerosol spray from a solution or suspension comprising the API, one or more agents for dispersing, solubilizing, or extending the release of the API (e.g., EtOH with or without water), one or more solvents (e.g., 1, 1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) which serve as a propellant, and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • An atomizer using electrohydrodynamics may be used to produce a fine mist.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is usually comminuted to a particle size suitable for delivery by inhalation (typically 90% of the particles, based on volume, having a largest dimension less than 5 microns). This may be achieved by any appropriate size reduction method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.
  • Capsules, blisters and cartridges made, for example, from gelatin or
  • hydroxypropylmethyl cellulose for use in an inhaler or insufflator may be formulated to contain a powder mixture of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or monohydrated.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from about 1 pg to about 20 mg of the API per actuation and the actuation volume may vary from about 1 pL to about 100 pL.
  • a typical formulation may comprise one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl.
  • Alternative solvents, which may be used instead of propylene glycol, include glycerol and polyethylene glycol.
  • Formulations for inhaled administration, intranasal administration, or both may be formulated to be immediate or modified release using, for example, PGLA.
  • Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to formulations intended for inhaled/intranasal administration.
  • the dosage unit is determined by means of a valve that delivers a metered amount.
  • Units are typically arranged to administer a metered dose or“puff’ containing from about 10 pg to about 1000 pg of the API.
  • the overall daily dose will typically range from about 100 pg to about 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the active compounds may be administered rectally or vaginally, e.g., in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal or vaginal administration may be formulated to be immediate or modified release as described above.
  • Compounds of Formula 1 may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable implants (e.g. absorbable gel sponges, collagen), non- biodegradable implants (e.g. silicone), wafers, lenses, and particulate or vesicular systems, such as niosomes or liposomes.
  • the formulation may include one or more polymers and a preservative, such as benzalkonium chloride.
  • Typical polymers include crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, cellulosic polymers (e.g.,
  • heteropolysaccharide polymers e.g., gelan gum
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular or aural administration may be formulated to be immediate or modified release as described above.
  • compounds of Formula 1 may be combined with soluble macromolecular entities, including cyclodextrin and its derivatives and polyethylene glycol-containing polymers.
  • soluble macromolecular entities including cyclodextrin and its derivatives and polyethylene glycol-containing polymers.
  • API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer.
  • Alpha-, beta- and gamma-cyclodextrins are commonly used for these purposes. See, e.g., WO 91/11172, WO 94/02518, and
  • one or more compounds of Formula 1, including compounds specifically named above, and their pharmaceutically active complexes, salts, solvates and hydrates, may be combined with each other or with one or more other active
  • the active compounds may be combined in a single dosage form as described above or may be provided in the form of a kit which is suitable for coadministration of the compositions.
  • the kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1; and (2) a device for separately retaining the two pharmaceutical compositions, such as a divided bottle or a divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets or capsules.
  • the kit is suitable for administering different types of dosage forms (e.g., oral and parenteral) or for administering different pharmaceutical compositions at separate dosing intervals, or for titrating the different pharmaceutical compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a memory aid.
  • the total daily dose of the claimed and disclosed compounds is typically in the range of about 0.1 mg to about 3000 mg depending on the route of administration.
  • oral administration may require a total daily dose of from about 1 mg to about 3000 mg
  • an intravenous dose may only require a total daily dose of from about 0.1 mg to about 300 mg.
  • the total daily dose may be administered in single or divided doses and, at the physician’s discretion, may fall outside of the typical ranges given above. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) whose mass falls outside of this weight range.
  • the compounds of Formula 1 may be used to treat diseases, disorders or conditions for which inhibition of RIPK2 is indicated.
  • diseases, disorders or conditions generally relate to any unhealthy or abnormal state in a subject for which the inhibition of RIPK2 provides a therapeutic benefit.
  • diseases, disorders or conditions may involve the immune system and inflammation, including Type I hypersensitivity (allergic) reactions (allergic rhinitis, allergic asthma, and atopic dermatitis); autoimmune diseases (rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, lupus nephritis, immune thrombocytopenic purpura, Sjogren’s syndrome, ankylosing spondylitis, and Behcet’s disease); inflammatory bowel disease; inflammation of the lung (chronic obstructive pulmonary disease), atherosclerosis, thrombosis, and myocardial infarction.
  • the compounds of Formula 1 may also be used to treat diseases, disorders or conditions related to abnormal cell growth, including hematological
  • malignancies such as acute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-cell lymphoma (e.g., mantle cell lymphoma), T-cell lymphoma (e.g., peripheral T-cell lymphoma), and multiple myeloma, as well as epithelial cancers (i.e., carcinomas), such as lung cancer (small cell lung cancer and non-small cell lung cancer), pancreatic cancer, and colon cancer.
  • B-cell chronic lymphocytic leukemia such as acute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-cell lymphoma (e.g., mantle cell lymphoma), T-cell lymphoma (e.g., peripheral T-cell lymphoma), and multiple myeloma
  • epithelial cancers i.e., carcinomas
  • lung cancer small cell lung cancer and non-small cell lung cancer
  • pancreatic cancer pancreatic cancer
  • the compounds of Formula 1 may also be used to treat other types of cancer, including leukemia (chronic myelogenous leukemia and chronic lymphocytic leukemia); breast cancer, genitourinary cancer, skin cancer, bone cancer, prostate cancer, and liver cancer; brain cancer; cancer of the larynx, gall bladder, rectum, parathyroid, thyroid, adrenal, neural tissue, bladder, head, neck, stomach, bronchi, and kidneys; basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteosarcoma, Ewing’s sarcoma, veticulum cell sarcoma, and Kaposi’s sarcoma; myeloma, giant cell tumor, islet cell tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, medullary carcinoma, pheochromocytoma, muco
  • the compounds of Formula 1 may also be used to treat other diseases, disorders or conditions related to abnormal cell growth, including non-malignant proliferative diseases such as benign prostatic hypertrophy, restinosis, hyperplasia, synovial proliferation disorder, idiopathic plasmacytic lymphadenopathy, retinopathy or other neovascular disorders of the eye, among others.
  • non-malignant proliferative diseases such as benign prostatic hypertrophy, restinosis, hyperplasia, synovial proliferation disorder, idiopathic plasmacytic lymphadenopathy, retinopathy or other neovascular disorders of the eye, among others.
  • the compounds of Formula 1 may also be used to treat autoimmune diseases, disorders or conditions in addition to those listed above.
  • diseases, disorders or conditions include Crohn’s disease, dermatomyositis, diabetes mellitus type 1, Goodpasture’s syndrome, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s disease, mixed connective tissue damage, myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, temporal arteritis, ulcerative colitis, vasculitis, and Wegener’s granulomatosis, among others.
  • the compounds of Formula 1 may be used to treat inflammatory diseases, disorders or conditions including asthma, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases (ulcerative colitis in addition to Crohn’s disease), pelvic inflammatory disease, reperfusion injury, transplant rejection, vasculitis, and systemic inflammatory response syndrome.
  • inflammatory diseases, disorders or conditions including asthma, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases (ulcerative colitis in addition to Crohn’s disease), pelvic inflammatory disease, reperfusion injury, transplant rejection, vasculitis, and systemic inflammatory response syndrome.
  • the compounds of Formula 1 may also be used to treat specific diseases or conditions that may fall within one or more general disorders described above, including arthritis.
  • arthritis In addition to rheumatoid arthritis, Sjogren’s syndrome, systemic lupus
  • compounds of Formula 1 may also be used to treat other arthritis diseases, including ankylosing spondylitis, avascular necrosis, Behcet’s disease, bursitis, calcium pyrophosphate dihyrate crystal deposition disease (pseudo gout), carpal tunnel syndrome, Ehlers-Danlos syndrome, fibromyalgia, Fifth disease, giant cell arteritis, gout, juvenile dermatomyositis, juvenile rheumatoid arthritis, juvenile
  • spondyloarthopathy Lyme disease, Marfan syndrome, myositis, osteoarthritis, osteogenesis imperfect, osteoporosis, Paget’s disease, psoriatic arthritis, Raynaud’s phenomenon, reactive arthritis, reflex sympathetic dystrophy syndrome, scleroderma, spinal stenosis, Still’s disease, and tendinitis, among others.
  • the claimed and disclosed compounds may be combined with one or more other pharmacologically active compounds or therapies for the treatment of one or more diseases, disorders or conditions for which RIPK2 is indicated, including those involving the immune system, inflammation, and abnormal cell growth.
  • compounds of Formula 1, which include compounds specifically named in the examples, and their pharmaceutically acceptable complexes, salts, solvates and hydrates may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating arthritis, including rheumatoid arthritis and osteoarthritis, or for treating cancer, including hematological malignancies, such as acute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, multiple myeloma, and carcinomas, such as lung cancer, pancreatic cancer, and colon cancer.
  • Such combinations may offer significant therapeutic advantages, including fewer side effects, improved ability to treat underserved patient populations, or synergistic activity.
  • the compounds of Formula 1 when used to treat arthritis, may be combined with one or more nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids, biological response modifiers, and protein-A immunoadsorption therapy.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • analgesics corticosteroids
  • corticosteroids biological response modifiers
  • protein-A immunoadsorption therapy when used to treat arthritis, the compounds of Formula 1 may be combined with one or more nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids, biological response modifiers, and protein-A immunoadsorption therapy.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Formula 1 may be combined with one or more disease modifying antirheumatic drugs (DMARDs), and when treating osteoarthritis, the compounds of Formula 1 may be combined with one or more osteoporosis agents.
  • DMARDs disease modifying antirheumatic drugs
  • NSAIDs include apazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylates, salsalate, and sulindac.
  • Representative analgesics include acetaminophen and morphine sulfate, as well as codeine, hydrocodone, oxycodone, propoxyphene, and tramadol, all with or without acetaminophen.
  • Representative corticosteroids include betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.
  • Representative biological response modifiers include TNF-a inhibitors, such as adalimumab, etanercept, and infliximab; selective B-cell inhibitors, such as rituximab; IL-1 inhibitors, such as anakinra, and selective costimulation modulators, such as abatacept.
  • TNF-a inhibitors such as adalimumab, etanercept, and infliximab
  • selective B-cell inhibitors such as rituximab
  • IL-1 inhibitors such as anakinra
  • selective costimulation modulators such as abatacept.
  • Representative DMARDs include auranofm (oral gold), azathioprine, chlorambucil, cyclophosamide, cyclosporine, gold sodium thiomalate (injectable gold),
  • osteoporosis agents include bisphosphonates, such as alendronate, ibandronate, risedronate, and zoledronic acid; selective estrogen receptor modulators, such as droloxifene,
  • lasofoxifene, and raloxifene include hormones, such as calcitonin, estrogens, and parathyroid hormone; and immunosuppressant agents such as azathioprine, cyclosporine, and rapamycin.
  • Particularly useful combinations for treating rheumatoid arthritis include a compound of Formula 1 and methotrexate; a compound of Formula 1 and one or more biological response modifiers, such as lefluonomide, etanercept, adalimumab, and infliximab; or a compound of Formula 1, methotrexate, and one or more biological response modifiers, such as lefluonomide, etanercept, adalimumab, and infliximab.
  • biological response modifiers such as lefluonomide, etanercept, adalimumab, and infliximab.
  • the compounds of Formula 1 may be combined with one or more cardiovascular agents such as calcium channel blockers, statins, fibrates, beta-blockers, ACE inhibitors, and platelet aggregation inhibitors.
  • cardiovascular agents such as calcium channel blockers, statins, fibrates, beta-blockers, ACE inhibitors, and platelet aggregation inhibitors.
  • the compounds of Formula 1 may also be combined with one or more compounds or therapies for treating cancer.
  • chemotherapeutic agents i.e., cytotoxic or antineoplastic agents
  • alkylating agents antibiotics, antimetabolic agents, plant- derived agents, and topoisomerase inhibitors
  • molecularly targeted drugs which block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression.
  • Molecularly targeted drugs include both small molecules and biologies.
  • Representative alkylating agents include bischloroethylamines (nitrogen mustards, e.g., chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, and uracil mustard); aziri dines (e.g., thiotepa); alkyl alkone sulfonates (e.g., busulfan); nitrosoureas (e.g., carmustine, lomustine, and streptozocin); nonclassical alkylating agents (e.g., altretamine, dacarbazine, and procarbazine); and platinum compounds (e.g., carboplatin, cisplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate).
  • nitrogen mustards e.g., chlorambucil, cyclophosphamide, ifos
  • antibiotic agents include anthracyclines (e.g., aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin); anthracenediones (e.g., mitoxantrone and pixantrone); and streptomyces (e.g., actinomycin, bleomycin, dactinomycin, mitomycin C, and plicamycin).
  • anthracyclines e.g., aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, and zorubicin
  • anthracenediones e.g., mitoxantrone and pixantrone
  • streptomyces e.g., actin
  • Representative antimetabolic agents include dihydrofolate reductase inhibitors (e.g., aminopterin, methotrexate, and pemetrexed); hymidylate synthase inhibitors (e.g., raltitrexed and pemetrexed); folinic acid (e.g., leucovorin); adenosine deaminase inhibitors (e.g., pentostatin); halogenated/ribonucleotide reductase inhibitors (e.g., cladribine, clofarabine, and fludarabine); thiopurines (e.g., thioguanine and mercaptopurine); thymidylate synthase inhibitors (e.g., fluorouracil, capecitabine, tegafur, carmofur, and floxuridine); DNA polymerase inhibitors (e.g., cytarabine); ribonu
  • Representative plant-derived agents include vinca alkaloids (e.g., vincristine, vinblastine, vindesine, vinzolidine, and vinorelbine), podophyllotoxins (e.g., etoposide and teniposide), and taxanes (e.g., docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel).
  • vinca alkaloids e.g., vincristine, vinblastine, vindesine, vinzolidine, and vinorelbine
  • podophyllotoxins e.g., etoposide and teniposide
  • taxanes e.g., docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel.
  • Representative type I topoisom erase inhibitors include camptothecins, such as belotecan, irinotecan, rubitecan, and topotecan.
  • Representative type II topoisomerase inhibitors include amsacrine, etoposide, etoposide phosphate, and teniposide, which are derivatives of epipodophyllotoxins.
  • cytokines include interleukin-2 (IL-2, aldesleukin), interleukin 4 (IL-4), interleukin 12 (IL-12), and interferon, which includes more than 23 related subtypes.
  • cytokines include granulocyte colony stimulating factor (CSF) (e.g., filgrastim) and granulocyte macrophage colony stimulating factor (GM-CSF or CSF2) (e.g., sargramostim, namimulab).
  • CSF granulocyte colony stimulating factor
  • GM-CSF or CSF2 granulocyte macrophage colony stimulating factor
  • immuno-modulating agents include bacillus Calmette- Guerin, levamisole, and octreotide; monoclonal antibodies against tumor antigens, such as trastruzumab and rituximab; and cancer vaccines, which induce an immune response to tumors.
  • EGF epiderma
  • Specific molecularly targeted drugs include selective estrogen receptor modulators, such as tamoxifen, toremifene, fulvestrant, and raloxifene; antiandrogens, such as
  • bicalutamide, nilutamide, megestrol, and flutamide include agents which inhibit signal transduction, such as imatinib, dasatinib, nilotinib, trastuzumab, gefitinib, erlotinib, cetuximab, lapatinib, panitumumab, and temsirolimus; agents that induce apoptosis, such as bortezomib; agents that block angiogenesis, such as bevacizumab, sorafenib, and sunitinib; agents that help the immune system destroy cancel cells, such as rituximab and alemtuzumab; and monoclonal antibodies which deliver toxic molecules to cancer cells, such as gemtuzumab ozogamicin, tositumomab,
  • a LanthaScreen® Eu Kinase Binding Assay (Invitrogen®) is optimized to screen the compounds of Formula 1 for RIPK2 inhibition.
  • LanthaScreen® Eu Kinase Binding Assays are based on the binding and displacement of a proprietary ATP-competitive kinase inhibitor scaffold (kinase- 199 tracer) to a kinase of interest.
  • the assay detects binding of the Kinase Tracer- 199, which is labeled with Alexa Fluor® 647, to RIPK2 using a europium-labeled anti-tag antibody, which binds to the RIPK2 kinase.
  • Simultaneous binding of both the tracer and the antibody to RIPK2 results in a high degree of fluorescence resonance energy transfer (FRET) from the europium (Eu) donor fluorophore to the Alexa Fluor® 647 acceptor fluorophore on the kinase tracer.
  • FRET fluorescence resonance energy transfer
  • Binding of a test compound to RIPK2 competes for binding with the tracer, resulting in a loss of FRET.
  • the compound screening assay is carried out using Complete Binding Assay Buffer: 50 mM HEPES, lOO mM NaCl, I mM DTT, lO mM MgCk, 1.15 mM CHEGA11, 0.1 mg/mL BSA, 2 nM RIPK2, 50nM Kinase Tracer-199, and 2nM Eu-Anti-His Antibody at pH 7.3.
  • the Eu-Anti-His Antibody and Kinase Tracer-199 are purchased from Invitrogen, and human RIPK2 protein (8-317 aa, N-terminal His-tag, R171C, 38.3KDa) may be obtained as described below.
  • RIPK2 DNA encoding residues 8-317 of the human protein is cloned into pFastBac vector (Invitrogen®) which incorporates a 6-histidine tag at the N-terminus followed by a rTEV cleavage site.
  • a R171C mutant is generated by site-directed mutagenesis.
  • Recombinant baculovirus incorporating the RIPK2 construct is generated by transposition using the Bac-to- Bac system (Invitrogen®).
  • High-titer viral stock is generated by infection of Spodoptera frugiperda Sf9 cells; the expression of recombinant protein is carried out by infection of Spodoptera frugiperda Sf9 (Invitrogen®) for 48 hours in a wave bag.
  • Recombinant RIPK2 protein is isolated from cellular extracts by binding with Probond Nickel resin (Life Technology®). The resin is washed with buffer containing 25 mM HEPES pH 7.6, 0.5 M NaCl and 20 mM imidazole, and then eluted with the elution buffer 50 mM HEPES pH 7.6, 250 mM imidazole, 150 mM NaCl, 5% glycerol and 0.5 mM TCEP. Partially purified protein is then dephosphorylated by adding 0.05 mM MnCk and l- phosphatase and incubating in room temperature for 4 hours.
  • the dephosphorylated RIPK2 protein is then purified through a Superdex® 75 column in the buffer containing 10 mM HEPES pH 7.5, 150 mM NaCl, 5% glycerol, 2 mM DTT, 1 mM TCEP, 5 mM L-Arg, and 5 mM L-Glu.
  • the protein is stored at -80°C in small aliquots.
  • Test compounds are prepared in 100% DMSO and are dispensed in duplicate to individual wells of a multiplate, starting at 10 mM with 2.5 x series dilution. Next 10 pL of Complete Binding Assay Buffer is added to each of the test compounds using a MultidropTM Combi Reagent Dispenser. The wells are covered with aluminum sealer, shaken for 2 minutes at 900 rpm, spun down for 10 seconds at 1000 rpm, incubated at RT for 60 minutes, shaken for 2 minutes at 900 rpm, and spun down for 10 seconds at 1000 rpm before reading. Samples are read on an instrument capable of measuring fluorescent polarization.
  • the ratio 665 nM/620 nM is determined using a PHERAstar plate reader. Test compound inhibition is expressed as percent (%) inhibition of internal assay controls. For concentration response experiments, normalized data are fit and pIC50s determined using conventional techniques. The pIC50s are averaged to determine a mean value for a minimum of two experiments.
  • products of certain preparations and examples are purified by mass-triggered HPLC, flash chromatography, preparative TLC or SFC.
  • Reverse phase chromatography is typically carried out on a column (e.g., GeminiTM 5pm C18 1 IOA, AxiaTM, 30 x 75 mm, 5 pm) under acidic conditions (“acid mode”) eluting with ACN and water mobile phases containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively, or under basic conditions (“basic mode”) eluting with water and 20/80 (v/v) water/acetonitrile mobile phases, both containing 10 mM NH4HCO3.
  • acid mode acidic conditions
  • basic mode basic conditions
  • Preparative TLC is typically carried out on silica gel 60 F254 plates.
  • the preparations and examples may employ SFC to separate enantiomers.
  • the solvent is removed and the product is obtained by drying in a centrifugal evaporator (e.g., GeneVacTM), rotary evaporator, evacuated flask, etc.
  • Reactions in an inert (e.g., nitrogen) or reactive (e.g., Eh) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).
  • PREPARATION 4 /V-cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2- di oxab orol an-2-y l)b enzami de
  • PREPARATION 5 5-bromo-/V 2 -(l-((/er/-butyldimethylsilyl)oxy)-2-methylpropan- 2-yl)pyridine-2, 3 -diamine
  • PREPARATION 6 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl acetate
  • PREPARATION 7 2-(6-bromo-2-oxo-l,2-dihydro-3iT-imidazo[4,5-Z>]pyridin-3-yl)- 2-methylpropyl acetate
  • PREPARATION 8 5-bromo-/V 2 -(l-((/er/-butyldimethylsilyl)oxy)propan-2- yl)pyridine-2, 3 -diamine
  • PREPARATION 9 5-bromo-/V 2 -(2-((/er/-butyldimethylsilyl)oxy)ethyl)pyridine- 2, 3-diamine
  • PREPARATION 10 6-bromo-3 -(1 -hydroxy -2-methylpropan-2-yl)- 1,3 -dihydro-2i7- imidazo[4,5-/>]pyridin-2-one
  • PREPARATION 11 2-(6-bromo-2-methyl-3iT-imidazo[4,5-Z>]pyridin-3-yl)-2- methylpropyl acetate
  • PREPARATION 12 6-bromo-3-(l-((/er/-butyldimethylsilyl)oxy)-2-methylpropan- 2-yl)-2-methoxy-3iT-imidazo[4,5-Z>]pyridine
  • PREPARATION 13 2-(6-bromo-2-oxo-l,2-dihydro-3i7-imidazo[4,5-/>]pyridin-3- yl)-2-methylpropyl-l, ⁇ -di acetate
  • PREPARATION 14 2-(5-bromo-liT-pyrrolo[2,3-Z>]pyridin-l-yl)-2-methylpropan- l-ol
  • STEP 2 5-bromo-2-((l-hydroxy-2-methylpropan-2-yl)amino)nicotinaldehyde
  • PREPARATION 15 2-(5-chloro-2-methyl-liT-pyrrolo[2,3-Z>]pyridin-l-yl)-2- methylpropan- 1 -ol
  • STEP 3 2-((5-chloro-3-(prop-l-yn-l-yl)pyridin-2-yl)amino)-2-methylpropyl acetate
  • STEP 4 2-(5-chloro-2-methyl-liT-pyrrolo[2,3-/ ]pyridin-l-yl)-2-methylpropan-l-ol
  • PREPARATION 16 6-bromo-3-(l-((/er/-butyldimethylsilyl)oxy)-2-methylpropan- 2-yl)-2-ethoxy-3iT-imidazo[4,5-Z>]pyridine
  • PREPARATION 17 6-bromo-3-(l-((/er/-butyldimethylsilyl)oxy)propan-2-yl)-2- methoxy-3i7-imidazo[4,5-/>]pyridine
  • PREPARATION 18 6-bromo-3-(2-((/er/-butyldimethylsilyl)oxy)ethyl)-2-methoxy- 3iT-imidazo[4,5-Z>]pyridine
  • PREPARATION 19 2-(6-bromo-3i7-imidazo[4,5-/>]pyridin-3-yl)-2-methylpropyl acetate
  • PREPARATION 20 /V-cycl opropyl -4-methyl -3 -(4,4, 5,5-tetramethyl- l ,3,2- di oxab orol an-2-y l)b enzami de
  • PREPARATION 21 2-(5-bromo-liT-pyrrolo[2,3-Z>]pyridin-l-yl)ethan-l-ol
  • PREPARATION 22 2-((3-amino-5-bromopyridin-2-yl)amino)ethyl acetate
  • PREPARATION 23 2-(6-bromo-3i7-imidazo[4,5-Z>]pyridin-3-yl)ethyl acetate
  • PREPARATION 24 2-(6-bromo-2-methoxy-3iT-imidazo[4,5-Z>]pyridin-3-yl)-2- methylpropyl acetate
  • PREPARATION 25 2-((3-amino-5-bromo-4-methylpyridin-2-yl)amino)-2- methylpropyl acetate
  • PREPARATION 26 2-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)-2- methylpropyl acetate
  • PREPARATION 27 2-(6-bromo-7-methyl-2-oxo-l,2-dihydro-3iT-imidazo[4,5- Z>]pyri din-3 -yl)-2-methylpropyl acetate
  • PREPARATION 28 2-(6-bromo-5-methyl-2-oxo-l,2-dihydro-3iT-imidazo[4,5- Z>]pyri din-3 -yl)-2-methylpropyl acetate
  • PREPARATION 29 2-amino-2-(methyl-£3 ⁇ 4)propan-3,3,3-£3 ⁇ 4-l-ol
  • PREPARATION 30 2-(6-bromo-2-oxo-l,2-dihydro-3iT-imidazo[4,5-b]pyridin-3- yl)-2-(methyl -i/r)propyl-3,3, 3 -ch acetate
  • PREPARATION 32 A f ,4-di methyl -3 -(4,4,5, 5-tetramethyl- l ,3,2-dioxaborolan-2- yl)benzamide
  • PREPARATION 33 2-(6-bromo-l-(2-fluoroethyl)-2-oxo-l,2-dihydro-3J7- imidazo[4,5-Z>]pyridin-3-yl)-2-methylpropyl acetate
  • PREPARATION 34 2-(l-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2-dihydro-3i7-imidazo[4,5-Z>]pyridin-3-yl)-2-methylpropyl acetate
  • PREPARATION 36 3 -bro o-A-cy cl opropy 1 -4-fl uorobenza i de
  • PREPARATION 37 4-bromo-A-cyclopropyl -5-methyl pi col inamide
  • PREPARATION 39 3-bromo-/V-cyclopropyl-5-fluoro-4-methylbenzamide
  • PREPARATION 40 3-chloro-/V-cyclopropyl-5-iodo-4-methylbenzamide
  • PREPARATION 43 3-bromo-4-methyl-/V-(l-((2-(trimethylsilyl)ethoxy)methyl)- 1 //-py razol -3 -y 1 )benzam i de
  • PREPARATION 44 5-bromo-2-fluoro-A f , 4-dimethylbenzamide
  • PREPARATION 45 l-(tetrahydro-2iT-pyran-2-yl)-liT-pyrazol-3 -amine
  • PREPARATION 46 5-bromo-2-fluoro-4-methyl-/V-(l-(tetrahydro-2i7-pyran-2-yl)- 1 //-py razol -3 -y 1 )benzam i de
  • PREPARATION 47 5 -bro o-2-fl uoro-4-m ethyl -N-( 1 -m ethyl - 1 //-py razol -3 - yl)benzamide
  • PREPARATION 48 2-chloro-/V-cyclopropyl-5-iodo-4-methylbenzamide
  • PREPARATION 49 3-bromo-4-methyl-A-((lS,2S)-2- methy 1 cy cl opropy l)b enzami de
  • PREPARATION 50 5-bromo-/V-cyclopropyl-2,4-difluorobenzamide
  • PREPARATION 51 3 -bro o-A-cy cl opropy 1 -4-(tri fl uoro ethyl )benzam i de
  • PREPARATION 53 /V-(bicyclo[l .1. l]pentan-2-yl)-3-bromo-4-methylbenzamide
  • PREPARATION 54 3-bromo-/V-cyclopropyl-4-(fluoromethyl)benzamide
  • PREPARATION 55 3-bromo-4-methyl-A-((lS,2A)-2- methy 1 cy cl opropy l)b enzami de
  • PREPARATION 59 2-(6-(5 -carbarn oyl-2-methylphenyl)- 1 -(2-fluoroethyl)-2-oxo- 1 , 2-di hydro-3 //-i mi dazo[4,5-/>]pyridin-3-yl)-2-methyl propyl ace t a t e
  • reaction mixture was stirred at 90°C for 5 hours under N2 atmosphere, then concentrated in vacuo and purified by column chromatography (S1O2) eluting with a gradient of 33-50% EtOAc in petroleum ether to give the title compound as a yellow solid (550 mg, 92%).
  • PREPARATION 61 A-(isoxazol-3-yl)-4-methyl-3-(4,4,5,5-tetramethyl-l,3,2- di oxab orol an-2-y l)b enzami de
  • PREPARATION 63 2-(6-bromo-l-ethyl-2-oxo-l,2-dihydro-3iT-imidazo[4,5- Z>]pyridin-3-yl)-2-methylpropyl acetate
  • PREPARATION 64 2-(l-ethyl-2-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l,2-dihydro-3iT-imidazo[4,5-Z>]pyridin-3-yl)-2-methylpropyl acetate
  • PREPARATION 65 3-bromo-4-methyl-A-( l -(tetrahydro-2//-pyran-2-yl )-!//- py razol -3 -yl)b enzami de
  • PREPARATION 66 3 -bro o-4-methy 1 -N-( 1 -m ethyl - 1 //-py razol -3 -y 1 )benzami de
  • PREPARATION 67 3-bromo-4-methyl-A-( l -methyl - l//-pyrazol-5-yl)benzamide
  • PREPARATION 68 5-bromo-2-fluoro-/V-(isoxazol-3-yl)-4-methylbenzamide
  • PREPARATION 69 2-methyl-2-(l-methyl-2-oxo-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2-dihydro-3i7-imidazo[4,5-/>]pyridin-3-yl)propyl acetate
  • STEP 2 2-methyl-2-(l-methyl-2-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l,2-dihydro-3iT-imidazo[4,5-Z>]pyridin-3-yl)propyl acetate
  • PREPARATION 70 2-(6-bromo-l-(2,2-difluoroethyl)-2-oxo-l,2-dihydro-3tf- imidazo[4,5-Z>]pyridin-3-yl)-2-methylpropyl acetate
  • PREPARATION 71 2-fluoro-A,4-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2- di oxab orol an-2-y l)b enzami de
  • PREPARATION 72 2-(6-bromo-l-(2-fluoroethyl)-2-oxo-l,2-dihydro-3tf- imidazo[4,5-/ ]pyridin-3-yl)-2-methylpropyl-l,l-ifc acetate
  • PREPARATION 73 2-fl uoro-A-(isoxazol -3-yl)-4-methyl -5-(4 , 4 , 5 , 5-tetram ethyl - l,3,2-dioxaborolan-2-yl)benzamide
  • PREPARATION 74 2-(l-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- 1 ,2-dihydro-3iT-imidazo[4,5 -Z>]pyridin-3-yl)-2-methylpropyl- 1,1 -ck acetate
  • PREPARATION 75 3 -bro o-N-( ⁇ sothi azol -3 -y 1 )-4-m ethy 1 benzam i de
  • PREPARATION 76 5-bromo-2-fluoro-/V-(isothiazol-3-yl)-4-methylbenzamide
  • PREPARATION 77 tert- butyl 3-(2-fhioro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzamido)- l //-pyrazole-l -carboxyl ate
  • PREPARATION 78 2-(6-bromo-l-ethyl-2-oxo-l,2-dihydro-3iT-imidazo[4,5- Z>]pyridin-3 -yl)-2-methylpropyl- 1,1 -di acetate
  • PREPARATION 79 2-(l-ethyl-2-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)- 1 ,2-dihydro-3iT-imidazo[4,5-Z>]pyridin-3 -yl)-2-methylpropyl- 1,1 -ck acetate
  • STEP 2 6-bromo-3-(/er/-butyl)-l,3-dihydro-2iT-imidazo[4,5-Z>]pyridin-2-one
  • PREPARATION 81 3-(3-(/er/-butyl)-l-methyl-2-oxo-2, 3-dihydro- liT-imidazo[4, 5- Z>]pyridin-6-yl)-4-methylbenzoic acid
  • PREPARATION 82 6-bromo-3 -(1 -hydroxy -2-methylpropan-2-yl)- 1 -methyl -1,3- dihydro-2//-imidazo[4,5-/>]pyridin-2-one
  • PREPARATION 83 6-bromo-3-(l-hydroxy-2-methylpropan-2-yl)-l-(2- hydroxy ethyl )- 1 , 3 -di hy dro-2//-i m i dazo[4, 5 -/>]py ri di n-2-one
  • PREPARATION 84 6-bromo-l-ethyl-3-(l-hydroxy-2-methylpropan-2-yl)-l,3- dihydro-2//-imidazo[4,5-/>]pyridin-2-one
  • EXAMPLE 1 /V-cyclopropyl-2-fluoro-5-(l-(2-fluoroethyl)-3-(l-hydroxy-2- methylpropan-2-yl)-2-oxo-2,3-dihydro-liT-imidazo[4,5-/>]pyridin-6-yl)-4-methylbenzamide
  • STEP 1 2-(6-(5-(cyclopropylcarbamoyl)-4-fluoro-2-methylphenyl)-l-(2- fluoroethyl)-2-oxo-l,2-dihydro-3i7-imidazo[4,5-Z>]pyridin-3-yl)-2-methylpropyl acetate
  • STEP 2 /V-cyclopropyl-2-fluoro-5-(l-(2-fluoroethyl)-3-(l-hydroxy-2- methylpropan-2-yl)-2-oxo-2,3-dihydro-li7-imidazo[4,5-/>]pyridin-6-yl)-4-methylbenzamide
  • EXAMPLE 3 /V-cyclopropyl-2-fluoro-5-(3-(l-hydroxy-2-methylpropan-2-yl)-2- methoxy-37/-imidazo[4,5-/>]pyridin-6-yl)-4-methylbenzamide
  • EXAMPLE 4 /V-cyclopropyl-2-fluoro-5-(3-(l-hydroxy-2-methylpropan-2-yl)-l-(2- hydroxyethyl)-2-oxo-2,3-dihydro-li7-imidazo[4,5-/>]pyridin-6-yl)-4-methylbenzamide
  • STEP 2 2-(6-(5-(cyclopropylcarbamoyl)-4-fluoro-2-methylphenyl)-l-(2- hydroxyethyl)-2-oxo-l,2-dihydro-3iT-imidazo[4,5-Z>]pyridin-3-yl)-2-methylpropyl acetate
  • EXAMPLE 5 /V-cyclopropyl-2-fluoro-5-(l-(2-fluoroethyl)-3-(l-hydroxy-2- methylpropan-2-yl-l, l-i3 ⁇ 4)-2-oxo-2, 3-dihydro- li/-imidazo[4, 5-0]pyridin-6-yl)-4- methylbenzamide
  • STEP 1 2-(6-(5-(cyclopropylcarbamoyl)-4-fluoro-2-methylphenyl)-l-(2- fluoroethyl)-2-oxo- 1 ,2-di hydro-3//-i mi dazo[4,5-/>]pyri din-3 -yl)-2-methylpropyl- 1,1 -di acetate
  • STEP 2 /V-cyclopropyl-2-fluoro-5-(l-(2-fluoroethyl)-3-(l-hydroxy-2- methylpropan-2-yl-l, l-ife)-2-oxo-2, 3-dihydro- li7-imidazo[4,5-/>]pyridin-6-yl)-4- methylbenzamide
  • EXAMPLE 6 2-fluoro-5-(l-(2-fluoroethyl)-3-(l-hydroxy-2-methylpropan-2-yl-l, l- £fe)-2-oxo-2,3-dihydro-li7-imidazo[4,5-/>]pyridin-6-yl)-/V-(isoxazol-3-yl)-4-methylbenzamide
  • EXAMPLE 7 3-(l-(2-fluoroethyl)-3-(l-hydroxy-2-methylpropan-2-yl-l,l-ifc)-2- oxo-2, 3-dihydro-liT-imidazo[4,5-Z>]pyridin-6-yl)-/V-(isoxazol-3-yl)-4-methylbenzamide
  • STEP 1 2-(l-(2-fluoroethyl)-6-(5-(isoxazol-3-ylcarbamoyl)-2-methylphenyl)-2- oxo- 1 ,2-dihydro-3i7-imidazo[4, 5-£]pyri din-3 -yl)-2-methylpropyl- 1, 1 -di acetate
  • STEP 2 3-(l-(2-fluoroethyl)-3-(l-hydroxy-2-methylpropan-2-yl-l,l-ifc)-2-oxo-2,3- dihydro-l/7-imidazo[4,5-/>]pyridin-6-yl)-/V-(isoxazol-3-yl)-4-methylbenzamide
  • EXAMPLE 8 2-fluoro-5-(l-(2-fluoroethyl)-3-(l-hydroxy-2-methylpropan-2-yl-l,l- ⁇ 72)-2-oxo-2,3-dihydro-177-imidazo[4,5-Z>]pyridin-6-yl)-4-methyl-/V-(lH-pyrazol-3- yl)benzamide
  • EXAMPLE 9 3-(l-(2-fluoroethyl)-3-(l-hydroxy-2-methylpropan-2-yl-l,l-ife)-2- oxo-2,3-dihydro-liT-imidazo[4,5-Z>]pyridin-6-yl)-/V-(isothiazol-3-yl)-4-methylbenzamide
  • STEP 1 2-(l-(2-fluoroethyl)-6-(5-(isothiazol-3-ylcarbamoyl)-2-methylphenyl)-2- oxo- 1 ,2-dihydro-3i7-imidazo[4, 5-£]pyri din-3 -yl)-2-methylpropyl- 1,1 -di acetate
  • STEP 2 3-(l-(2-fluoroethyl)-3-(l-hydroxy-2-methylpropan-2-yl-l,l-ifc)-2-oxo-2,3- di hydro- 1 //-i mi azo[4,5-/i]pyridin-6-yl)-A -(i sothi azol -3-yl)-4-methylbenza ide
  • EXAMPLE 10 2-fluoro-5-(l-(2-fluoroethyl)-3-(l-hydroxy-2-methylpropan-2-yl- 1, 1-72)-2-OXO-2, 3-dihydro- liT-imidazo[4,5-Z>]pyridin-6-yl)-/V-(isothiazol-3-yl)-4- methylbenzamide

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Abstract

La présente invention concerne des composés de formule 1, et des sels pharmaceutiquement acceptables de ceux-ci, dans la formule, α, β, R2, R3, R4, R5, R8, R9, X1, X6 et X7 sont définis dans la description. Les composés de formule 1 sont des inhibiteurs de protéine kinase 2 interagissant avec le récepteur (RIPK2) pour traiter, par exemple, des réactions d'hypersensibilité de type I, des maladies auto-immunes, de troubles inflammatoires, le cancer et des troubles prolifératifs non malins, tels que par exemple la rhinite allergique, l'asthme, la dermatite atopique, la polyarthrite rhumatoïde, la sclérose en plaques, le lupus érythémateux disséminé, la néphropathie lupique, le psoriasis, le purpura thrombocytopénique immunitaire, la maladie intestinale inflammatoire, la maladie pulmonaire obstructive chronique, le syndrome de Sjögren, la spondylarthrite ankylosante, la maladie de Behcet, la réaction du greffon contre l'hôte, le pemphigus vulgaris, la lymphadénopathie plasmatique idiopathique, l'athérosclérose, l'infarctus du myocarde et la thrombose. La présente invention concerne la préparation de composés donnés à titre d'exemple ainsi que des données pharmacologiques de ceux-ci (par exemple, pages 107 à 208 ; exemples 1 à 109 ; tableau 1). Un exemple de composé est, par exemple, le N-cyclopropyl-2-fluoro-5-(l-(2-fluoroéthyl)-3-(l-hydroxy-2-méthylpropan-2-yl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-6-yl)-4-méthylbenzamide (exemple 1).
PCT/US2020/023984 2019-03-22 2020-03-20 Dérivés de 2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-6-yl)-4-méthylbenzamide et composés similaires utilisés en tant qu'inhibiteurs de ripk2 pour traiter par exemple des maladies auto-immunes Ceased WO2020198053A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2022178559A1 (fr) * 2021-02-22 2022-08-25 The Trustees Of Princeton University Bicyclo[1.1.1]pentanes 2-substitués

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Publication number Priority date Publication date Assignee Title
WO2022178559A1 (fr) * 2021-02-22 2022-08-25 The Trustees Of Princeton University Bicyclo[1.1.1]pentanes 2-substitués

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