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WO2024254536A1 - Méthodes de traitement de maladies inflammatoires - Google Patents

Méthodes de traitement de maladies inflammatoires Download PDF

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Publication number
WO2024254536A1
WO2024254536A1 PCT/US2024/033118 US2024033118W WO2024254536A1 WO 2024254536 A1 WO2024254536 A1 WO 2024254536A1 US 2024033118 W US2024033118 W US 2024033118W WO 2024254536 A1 WO2024254536 A1 WO 2024254536A1
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Prior art keywords
alkyl
compound
optionally substituted
hydroxyl
membered heterocyclyl
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Inventor
Mario G. Cardozo
Zuojun GUO
Robert Joseph MOREAU
Naomi S. RAJAPAKSA
Meera Rao
David C. Tully
Steffen GRESSIES
Kai Thede
Zachary K. Sweeney
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Interline Therapeutics Inc
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Interline Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings

Definitions

  • the present application relates to the fields of chemistry and biology, in particular to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof, and compositions comprising same. Also described are methods of treating the diseases and disorders disclosed herein, with the compounds of Formula (I), and pharmaceutically acceptable salts thereof, and the compositions comprising same.
  • Receptor interacting protein kinase 2 is a serine-threonine protein kinase, and is a signaling molecule downstream of nucleotide-binding oligomerization domain 1 (NODI), NOD2, and Toll-like receptors (TLRs).
  • the RIPK2 protein includes a kinase domain (KD), an intermediate domain (INTD), and a caspase activation and recruitment domain (CARD).
  • the CARD domain of RIPK2 mediates interaction with NODI and NOD2.
  • RIPK2 is expressed in the cytoplasm of antigen- presenting cells including dendritic cells and macrophages, and is also expressed in T cells and epithelial cells.
  • NOD receptors function in the innate immune system, detecting bacterial pathogens by binding to diaminopimelic acid or muramyl dipeptide residues present in bacterial peptidoglycans.
  • Interactions between RIPK2 and NODI, NOD2 and TLRs trigger the release of pro-inflammatory cytokines including TNF- ⁇ , IL-6, and IL- 12/23p40, and RIPK2-mediated induction of NF-kappa-B -dependent inflammatory responses.
  • Activation of RIPK2 and dysregulation of the RIPK2-NOD signaling pathways may also have a role in the pathogenesis of various inflammatory diseases.
  • RIPK2 has been reported to be a prognostic indicator and candidate therapeutic target for various cancers.
  • Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • X 1 is C-NR 1A -S(O 2 )C1-C6 alkyl, C-NR 1A -S(O 2 )5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, or N;
  • X 3 is CR 3 or N
  • X 4 is CH or N
  • R 1A is hydrogen or C1-C6 alkyl
  • R 2 is hydrogen, C1-C6 alkoxy, or -NR 2A R 2B ;
  • R 2A and R 2B are independently hydrogen or C1-C6 alkyl, or when X 3 is CR 3 , then R 2A is hydrogen and R 2B and R 3 with the atoms to which they are attached together form a 5 -membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • R 3 is hydrogen, halogen, C1-C6 alkoxy, -NR 3A R 3B , or , or R 3 and R 2 with the atoms to which they are attached together form a 5-membered heterocyclyl, 5-membered heteroaryl ring, or phenyl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • R 3A and R 3B are independently hydrogen or C1-C6 alkyl, or R 3A is hydrogen and R 3B and R 2 with the atoms to which they are attached together form a 5- membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • Ring A is phenyl, 5-10 membered heteroaryl, C4-C10 cycloalkyl, or 5-10 membered heterocyclyl; each R 3C is independently selected from the group consisting of:
  • R a3 is hydrogen or C1-C6 alkyl
  • R b3 is:
  • L is a bond, -O-, or -NH-;
  • Q is a bond, NH, or N(C1-C6 alkyl).
  • composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Also provided herein is a method of treating a RIPK2 -associated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • terapéuticaally effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease or disorder as described herein (e.g., a RIPK2-associated disease or disorder), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease or disorder, or (iii) delay the onset of one or more symptoms of the particular disease or disorder described herein.
  • a disease or disorder as described herein e.g., a RIPK2-associated disease or disorder
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder, diminishment of the extent of a neurological disorder, stabilized (i.e., not worsening) state of a disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease or disorder), and remission (whether partial or total), whether detectable or undetectable and can be determined by various clinical assessments including clinical evaluation and self- reporting. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • pharmaceutically acceptable excipient means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tarta
  • composition refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “pharmaceutically acceptable excipients”), such as stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or other excipients.
  • pharmaceutically acceptable excipients such as stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or other excipients.
  • pharmaceutical composition facilitates administration of the compound to an organism.
  • subject refers to an animal, including, but not limited to, a primate (e.g. , human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g. , human
  • monkey cow, pig, sheep, goat
  • horse dog, cat, rabbit, rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
  • halo refers to one of the halogens, group 17 of the periodic table.
  • the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine or chlorine.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched, containing the indicated number of carbon atoms.
  • Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, zz-hexyl.
  • alkenyl refers to an acyclic hydrocarbon radical that may be a straight chain or branched, containing the indicated number of carbon atoms and one or more carbon-carbon double bonds. Non-limiting examples include ethylenyl and allyl.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • hydroxyalkyl refers to an alkyl group as described herein, in which one or more hydrogen atoms is/are replaced with one or more hydroxyl groups, as described herein.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH 3 ).
  • thioalkyl refers to an alkyl group as described herein, which is attached to a molecule via a sulfur atom (e.g., -SCH 3 ).
  • haloalkoxy refers to a haloalkyl group which is attached to a molecule via an oxygen atom (e.g., -OCF 3 ).
  • alkoxyalkyl refers to an alkyl group as described herein, in which one or more hydrogen atoms is/are replaced with one or more alkoxy groups as described herein.
  • cyano refers to a -CN radical
  • hydroxyl refers to an -OH radical
  • amino refers to a -NH 2 radical.
  • heteroaryl refers to a 5-14 membered mono-, bi-, or tricyclic group wherein at least one ring in the system is aromatic; and wherein one or more carbon atoms in at least one ring in the system is/are replaced with an heteroatom independently selected from the group consisting of N, O, S, B, Si, and P.
  • heteroatom independently selected from the group consisting of N, O, S, B, Si, and P.
  • a heteroaryl may further contain one or more oxo, N-oxide, S-oxide, and/or S,S-dioxide groups, valence permitting.
  • heteroaryl groups include furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2, 3 -thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotri azole, thiadiazole, tetrazole, pyridine, 2-pyridone, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, triazine, 2,3 -di
  • heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by nonhydrogen substituents), such as one or more of pyridone (e.g., pyridazinone (e.g., pyrazinone (
  • cycloalkyl refers to a saturated or partially unsaturated mono-, bi-, or tricyclic carbon group having 3 to 20 carbon atoms.
  • Bicyclic and tricyclic cycloalkyl groups include fused, spiro, and bridged ring systems.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro [2.3] hexyl, and bicyclo[l.l. l]pentyl.
  • cycloalkoxy refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).
  • aryl refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system.
  • aromatic e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • heterocyclyl refers to a saturated or partially unsaturated hydrocarbon monocyclic, bicyclic, or tricyclic ring system having from 3 to 20 ring atoms, that is not aromatic, and having at least one heteroatom within the ring system selected from the group consisting of N, O, S, B, Si, and P.
  • Bicyclic and tricyclic heterocyclyl groups include fused, spiro, and bridged ring systems.
  • a heterocyclyl group may be denoted as a “5 to 10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom.
  • a heterocycle may further contain one or more oxo, thiocarbonyl, N-oxide, S-oxide, and/or S,S-dioxide groups, valence permitting, so as to make the definition include oxosystems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
  • a heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen.
  • heterocyclyl groups include, but are not limited to 1,3 -di oxolane, 1,4-di oxolane, maleimide, succinimide, dioxopiperazine, hydantoin, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2- oxopyrrolidine, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyr
  • saturated means only single bonds present between constituent atoms.
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • a group may be unsubstituted or substituted with one or more of the indicated substituents.
  • that substitution can include the sharing of a carbon atom between the parent group and the substitution to form a spiro ring.
  • an n-butyl group substituted with cyclopropyl includes both and , amongst others.
  • rings and cyclic groups e.g., carbocycle, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like described herein
  • rings and cyclic groups e.g., carbocycle, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms
  • any compound or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically enriched compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2 H, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • isotopically enriched compounds of the present disclosure for example those into which radioactive isotopes such as 13 C and 14 C are incorporated.
  • Such isotopically enriched compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • isotopically enriched compounds includes “deuterated” compounds described herein in which one or more hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. Such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Indeed, isotopically enriched compounds of this disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically enriched reagent for a non- isotopically enriched reagent.
  • Deuterium enriched compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index relative to the corresponding non-enriched compound.
  • DMPK drug metabolism and pharmacokinetics
  • the concentration of a heavier isotope, such as deuterium, may be defined by an isotopic enrichment factor.
  • the positions noted as “H” or “hydrogen” in the compounds described herein have hydrogen at its natural abundance isotopic composition.
  • the positions noted as “H” or “hydrogen” in the compounds described herein have hydrogen enriched in deuterium above its natural abundance isotopic composition, i.e., the compound is a deuterium enriched compound.
  • deurated groups in the compounds described herein include, but are not limited to deuteromethine monodeuteromethylene and dideuteromethylene trideuteromethyl ( trideuteromethoxy and the like.
  • Compounds of the present disclosure also include deuterium enriched compounds at the alpha position of an oxo group, such
  • a compound containing the moiety encompasses the tautomeric form containing the moiety:
  • a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • enantiomers e.g., R and S isomers
  • diastereomers e.g., R and S isomers
  • mixtures of enantiomers e.g., R and S isomers
  • a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.
  • a “RIPK2 inhibitor” as defined herein includes any compound exhibiting RIPK2 inhibition activity. In some embodiments, a RIPK2 inhibitor is selective for RIPK2.
  • Exemplary RIPK2 inhibitors can exhibit inhibition activity (IC50) against a RIPK2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as described herein.
  • a RIPK2 inhibitor can exhibit inhibition activity (IC50) against RIPK2 of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.
  • RIPK2 mediates inflammatory signaling via NODI, N0D2, and TLRs.
  • in vitro inhibition of RIPK2 kinase activity alone is not fully predictive of suppression of downstream cellular RIPK2 signaling. Rather, interfering with the interaction of RIPK2 and XIAP is necessary to robustly reduce inflammatory signaling.
  • potent inhibitors of RIPK2 kinase activity lack the ability to disrupt RIPK2/XIAP binding and thus lack the ability to completely block inflammatory signaling in cells or in human subjects.
  • the present disclosure is based, in part, on the discovery that selected compounds described herein exert RIPK2 inhibition via simultaneous inhibition of RIPK2 kinase activity and disruption of the RIPK2/XIAP interaction and thus reduce cellular inflammatory signaling.
  • X 1 is C-NR 1A -S(O 2 )C1-C6 alkyl, C-NR 1A -S(O 2 )5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, or N;
  • X 3 is CR 3 or N
  • X 4 is CH or N
  • R 1A is hydrogen or C1-C6 alkyl
  • R 2 is hydrogen, C1-C6 alkoxy, or -NR 2A R 2B ;
  • R 2A and R 2B are independently hydrogen or C1-C6 alkyl, or when X 3 is CR 3 , then R 2A is hydrogen and R 2B and R 3 with the atoms to which they are attached together form a 5 -membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • R 3 is hydrogen, halogen, C1-C6 alkoxy, -NR 3A R 3B , or or R 3 and R 2 with the atoms to which they are attached together form a 5-membered heterocyclyl, 5-membered heteroaryl ring, or phenyl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • R 3A and R 3B are independently hydrogen or C1-C6 alkyl, or R 3A is hydrogen and R 3B and R 2 with the atoms to which they are attached together form a 5- membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • Ring A is phenyl, 5-10 membered heteroaryl, C4-C10 cycloalkyl, or 5-10 membered heterocyclyl; each R 3C is independently selected from the group consisting of:
  • R a3 is hydrogen or C1-C6 alkyl
  • R b3 is:
  • L is a bond, -O-, or -NH-;
  • Q is a bond, NH, or N(C1-C6 alkyl).
  • X 1 is C- NH-S(O 2 )C1-C6 alkyl.
  • X 1 is C-NR 1A -S(O 2 )5-10 membered heteroaryl optionally substituted with C1-C6 alkyl.
  • X 1 is C-
  • X 1 is N.
  • X 3 is CR 3 .
  • X 3 is N.
  • X 4 is CH.
  • X 4 is N.
  • X 1 is N
  • X 3 is CR 3
  • X 4 is CH.
  • R 2 is hydrogen
  • R 2 is C1-C6 alkoxy. In some embodiments,
  • R 2 is methoxy
  • R 2 is -NR 2A R 2B . In some embodiments, R 2 is -NH 2 .
  • X 1 is N
  • R 2 is -NH 2
  • X 3 is CR 3
  • X 4 is CH.
  • R 3 is hydrogen
  • R 3 is halogen. In some embodiments, R 3 is fluoro or chloro. In some embodiments, R 3 is bromo.
  • R 3 is C1-C6 alkoxy. In some embodiments,
  • R 3 is methoxy
  • R 3 is -NR 3A R 3B . In some embodiments, R 3 is -NH 2 .
  • R 3 is and ring A is phenyl.
  • R 3 is and m is 3.
  • R 3 is , ring A is phenyl, and m is 3. [0074] In some embodiments, at least one R 3C is halogen. In some embodiments, one R 3C is halogen. In some embodiments, at least one R 3C is fluoro. In some embodiments, one R 3C is fluoro.
  • At least one R 3C is C1-C6 alkoxy. In some embodiments, one R 3C is C1-C6 alkoxy. In some embodiments, at least one R 3C is methoxy. In some embodiments, one R 3C is methoxy.
  • At least one R 3C is -NR a3 R b3 . In some embodiments, one R 3C is -NR a3 R b3 .
  • At least one R 3C is -NR a3 -S(O 2 )Cl-C6 alkyl. In some embodiments, one R 3C is -NR a3 -S(O 2 )Cl-C6 alkyl. In some embodiments, at least one R 3C is -N(H)-S(O 2 )C1-C6 alkyl or -N(CH 3 )-S(O 2 )C1-C6 alkyl. In some embodiments, one R 3C is -N(H)-S(O 2 )C1-C6 alkyl or -N(CH 3 )-S(O 2 )C1-C6 alkyl.
  • R 3 is , ring A is phenyl, and at least one R 3C is C1-C6 alkoxy. In some embodiments, R 3 is , ring A is phenyl, and one or two R 3C is C1-C6 alkoxy.
  • R 3 is ring A is phenyl, and at least one R 3C is -NR a3 -S(O 2 )Cl-C6 alkyl. In some embodiments, R 3 is
  • ring A is phenyl
  • one R 3C is -NR a3 -S(O 2 )Cl-C6 alkyl.
  • R 3 is , ring A is phenyl, m is
  • At least one R 3C is C1-C6 alkoxy, and at least one R 3C is -NR a3 -S(O 2 )Cl-C6 alkyl.
  • R 3 is , ring A is phenyl, m is 3, one R 3C is C1-C6 alkoxy, and one R 3C is -NR a3 -S(O 2 )Cl-C6 alkyl. [0081] In some embodiments, R 3 is selected from hydrogen, methoxy,
  • X 3 is CR 3
  • R 2 is -NR 2A R 2B
  • R 2A is hydrogen
  • R 2B and R 3 with the atoms to which they are attached together form a 5-membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 and optionally substituted with C1-C6 alkyl.
  • R 3 and R 2 with the atoms to which they are attached together form a 5-membered heterocyclyl, 5-membered heteroaryl ring, or phenyl ring fused to the ring comprising X 1 .
  • R 3 is -NR 3A R 3B , R 3A is hydrogen, and R 3B and R 2 with the atoms to which they are attached together form a 5 -membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 and optionally substituted with C1-C6 alkyl.
  • L is a bond
  • L is -NH-.
  • each R 5A and R 5B are each independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, C3-C6 cycloalkyl, or 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl.
  • R 5 is hydrogen
  • R 5 is phenyl. In some embodiments, R 5 is phenyl substituted with halogen. In some embodiments, R 5 is phenyl substituted with fluoro. In some embodiments, R 5 is phenyl substituted with C1-C6 alkoxy. In some embodiments, R 5 is phenyl substituted with methoxy.
  • R 5 is phenyl substituted with -N(H)-S(O) 2 C1-C6 alkyl or -N(CH 3 )-S(O) 2 C1-C6 alkyl.
  • R 5 is phenyl substituted with halogen, C1-C6 alkoxy, and -NR 5A -S(O) 2 C1-C6 alkyl.
  • R 5 is 4-8 membered heterocyclyl. In some embodiments, R 5 is 6-membered heterocyclyl.
  • R 5 is 4-8 membered heterocyclyl substituted with C1-C6 alkyl.
  • R 5A and R 5B are each independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, C3-C6 cycloalkyl, or 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl.
  • R 5 is 5-10 membered heteroaryl. In some embodiments, R 5 is 5-membered heteroaryl. In some embodiments, R 5 is 6-membered heteroaryl. In some embodiments, R 5 is 9-membered heteroaryl.
  • R 5 is 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl and -Q-(4-10 membered heterocyclyl).
  • R 5 is 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl and -Q-(4-10 membered heterocyclyl), wherein the 4-10 membered heterocyclyl is optionally substituted with C1-C6 alkyl, hydroxyl, oxo, - C(O)R a5 , or -C(O)NR b5 R c5 .
  • R 5 is selected from hydrogen
  • R 5 is selected from hydrogen
  • the compound of Formula (I) is of Formula (II-A), Formula (II-B), Formula (II-C), Formula (II-D), or Formula (II-E): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (II- A), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (II-B), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (II-C), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (II-D), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (II-E), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (III- A), Formula (III-B), Formula (III-C), Formula (III-D), or Formula (III-E):
  • the compound of Formula (I) is of Formula (III- A), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (III-B), or a pharmaceutically acceptable salt thereof.
  • each R 23 is C1-C6 alkyl; s is 0, 1, 2, 3, or 4; and t is 0, 1, 2, or 3.
  • the compound of Formula (I) is of Formula (IV-A), or a pharmaceutically acceptable salt thereof.
  • R e3 is C1-C6 alkyl optionally substituted with hydroxyl; u is 0, 1, or 2; and v is 0, 1, 2, 3, 4, or 5.
  • the phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, and -Q-(4-10 membered heterocyclyl), wherein the 4-10 membered heterocyclyl is optionally substituted with C1-C6 alkyl, hydroxyl, oxo, - C(O)R a5 , or -C(O)NR b5 R c5 ; each R a5 , R b5 , and R c5 is independently selected from hydrogen and C1-C6 alkyl;
  • R a5 , R b5 , and R c5 are each C1-C6 alkyl
  • the compound of Formula (I) is of Formula (V-A), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (V-B), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formula (V-C), or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I), and pharmaceutically acceptable salts thereof do not include the compounds exemplified in PCT Appl. No. PCT/US23/24988, or pharmaceutically acceptable salts thereof.
  • the compound is any of Examples 1-132 and pharmaceutically acceptable salts thereof.
  • the compounds of Examples 1-132 are in the free base form.
  • the compounds of Examples 1-132 are in salt form, e.g., pharmaceutically acceptable salt form.
  • the ability of test compounds to act as RIPK2 inhibitors may be demonstrated by the biological assays described herein. See, e.g., Tables Al and A.
  • Some embodiments provide a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: X 1 , R 1A , X 3 , CR 3 , X 4 , R 2 R 2A R 2B R 3 R 3A R 3B A R 3C R a3 R b3 R c3 R d3 m L R 5 R 5A R 5B R a5 R b5 Ring R c5 , and Q is as described with respect to Formula (I), and pharmaceutically acceptable salts thereof.
  • the compounds and compositions disclosed herein are effective for modulating the activity of RIPK2.
  • the compounds and compositions disclosed herein are RIPK2 inhibitors.
  • RIPK2-associated disease or disorder refers to diseases or disorders associated with or having a dysregulation of a RIPK2 gene, a RIPK2 protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a RIPK2 gene, a RIPK2 protein, a RIPK2 protein domain, or the expression or activity or level of any of the same described herein).
  • Some embodiments provide a method of treating a RIPK2- associated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating a RIPK2- associated disease or disorder in a subject in need thereof, comprising (a) determining that the subject is suffering from a RIPK2-associated disease or disorder; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating a RIPK2- associated disease or disorder in a subject previously identified or diagnosed as having a RIPK2-associated disease or disorder, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the RIPK2-associated disease or disorder is a cardiovascular disease, an allergic disorder, an autoimmune disease, an inflammatory disease, a cardiovascular disease, a fibrotic disease, or a disease associated with abnormal cell growth.
  • the RIPK2-associated disease or disorder is a Type I hypersensitivity (allergic) reaction.
  • the Type I hypersensitivity (allergic) reaction is allergic inflammation.
  • the allergic inflammation is allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic- and vernal keratoconjunctivitis, or atopic dermatitis.
  • the RIPK2-associated disease or disorder is an autoimmune disease.
  • the autoimmune disease is Crohn’s disease, ulcerative colitis, rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, psoriasis, lupus nephritis, immune thrombocytopenic purpura, Sjogren’s syndrome, ankylosing spondylitis, psoriatic arthritis, juvenile dermatomyositis, juvenile rheumatoid arthritis, juvenile spondyloarthopathy, nonradiographic spondyloarthopathy, Behcet’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, pemph
  • the autoimmune disease is Crohn’s disease, ulcerative colitis, inflammatory bowel disease, or multiple sclerosis. In some embodiments, the autoimmune disease is Crohn’s disease. In some embodiments, the autoimmune disease is ulcerative colitis. In some embodiments, the autoimmune disease is inflammatory bowel disease. In some embodiments, the autoimmune disease is multiple sclerosis.
  • the RIPK2-associated disease or disorder is a metabolic disease.
  • the metabolic disease is dysglycemia, type 2 diabetes, non-alcoholic fatty liver disease (including non-alcoholic steatohepatitis), or obesity.
  • the RIPK2-associated disease or disorder is an inflammatory disease.
  • the inflammatory disease is chronic lung inflammatory disease, osteoarthritis, inflammatory arthritis, asthma, early onset sarcoidosis, sarcoidosis, eczema, allergic eczema, uveitis, reactive arthritis, chronic inflammation, chronic prostatitis, inflammatory bowel disease, glomerulonephritis, bursitis, carpal tunnel syndrome, tendinitis, inflammation of the lung (e.g., chronic obstructive pulmonary disease), pelvic inflammatory disease, transplant rejection, vasculitis, regional enteritis, distal ileitis, regional ileitis, and terminal ileitis, central areolar choroidal dystrophy, macular degeneration, retinosis pigmentosa, adult vitelliform disease, pattern dystrophy, diabetic retinopathy, BEST disease, myopic degeneration, central serous retinopathy, Stargardt’s
  • the RIPK2-associated disease or disorder isgranulomatous inflammatory disease.
  • the granulomatous inflammatory disease is Wegener’s granulomatosis, Churg-Strauss syndrome, relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, primary biliary cirrhosis, hepatic granulomatous disease, Langerhan's granulomatosis, granulomatous enteritis, orofacial granulomatosis, or Peyronie’s disease.
  • the RIPK2-associated disease or disorder is a cardiovascular disease.
  • the cardiovascular disease is atherosclerosis, thrombosis, myocardial infarction, stroke, aortic aneurysm, arterial hypertension, sickle cell crisis, or ischemia-reperfusion injury.
  • the RIPK2-associated disease is lethal systemic inflammatory response syndrome, chronic gut and skin inflammation, or acute pancreatitis.
  • the RIPK2-associated disease or disorder is a fibrotic disease.
  • the fibrotic disease is scleroderma, asbestosis, or idiopathic pulmonary fibrosis.
  • the RIPK2-associated disease or disorder comprises neuroinflammation.
  • the RIPK2-associated disease or disorder is Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease, Lewy body disease, Niemann-Pick disease, type Cl (NPC1), Friedreich’s ataxia, spinal muscular atrophy, corticobasal degeneration, progress supranuclear palsy (PSP), or multiple system atrophy (MSA).
  • the RIPK2-associated disease or disorder is a disease related to abnormal cell growth.
  • the disease related to abnormal cell growth is cancer, including hematological malignancies and solid tumors.
  • Hematological malignancies include, but are not limited to leukemias, such as acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, and lymphomas and myelomas, such as B-cell lymphoma (e.g., mantle cell lymphoma), T-cell lymphoma (e.g., peripheral T-cell lymphoma), non-Hodgkin’s lymphoma, and multiple myeloma.
  • leukemias such as acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, and lymphomas and myelomas, such as B-cell lymphoma (e.g., mantle cell lymphoma), T-cell lymphoma (e.g., peripheral T-cell lymphoma), non-Hodgkin’
  • Solid tumors include lung cancer (small cell lung cancer and nonsmall cell lung cancer), pancreatic cancer, colon cancer, breast cancer, genitourinary cancer, skin cancer, bone cancer, prostate cancer, liver cancer, brain cancer, laryngeal cancer, gall bladder cancer, rectal cancer, parathyroid cancer, thyroid cancer, adrenal cancer, neural tissue cancer, bladder cancer, head and neck cancer, stomach cancer, gastric cancer, bronchial cancer, and kidney cancer (e.g., renal clear cell carcinoma), colorectal cancer, clear cell carcinoma, basal cell carcinoma, squamous cell carcinoma, esophageal cancer, metastatic skin carcinoma, osteosarcoma, Ewing’s sarcoma, reticulum cell sarcoma, Kaposi’s sarcoma, giant cell tumor, islet cell tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, medullary carcinoma, pheochromocytoma, mucosal neuromas
  • the RIPK2-associated disease or disorder is a disease related to abnormal cell growth that is a non-malignant proliferative disease.
  • the non-malignant proliferative disease is benign prostatic hypertrophy, restenosis, hyperplasia, synovial proliferation disorder, idiopathic plasmacytic lymphadenopathy, or retinopathy.
  • the RIPK2-associated disease or disorder is selected from the group consisting of: avascular necrosis, calcium pyrophosphate dihydrate crystal deposition disease (pseudo gout), Blau syndrome, Ehlers-Danlos syndrome, fibromyalgia, Fifth disease, giant cell arteritis, gout, Lyme disease, Marfan syndrome, myositis, osteoarthritis, osteogenesis imperfecta, osteoporosis, Paget’s disease, Raynaud’s phenomenon, reactive arthritis, reflex sympathetic dystrophy syndrome, spinal stenosis, and Still’s disease.
  • the RIPK2-associated disease or disorder is a cancer associated with chronic inflammation.
  • the cancer associated with chronic inflammation that can be treated include colitis-associated colorectal cancer, gastric cancer, gastric mucosal lymphoma, lung cancer, hepatocellular carcinoma, thyroid cancer, breast cancer, oral cancer, head and neck cancer, nasopharyngeal carcinoma, endometrial cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, esophageal cancer, skin cancer, and non-Hodgkin lymphoma.
  • Some embodiments provide a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating inflammatory bowel disease in a subject in need thereof, comprising (a) determining that the subject is suffering from inflammatory bowel disease; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating inflammatory bowel disease in a subject previously identified or diagnosed as having inflammatory bowel disease, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating Crohn’s disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating Crohn’s disease in a subject in need thereof, comprising (a) determining that the subject is suffering from Crohn’s disease; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a method of treating Crohn’s disease in a subject previously identified or diagnosed as having Crohn’s disease, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • Some embodiments provide a method for inhibiting RIPK2 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the mammalian cell comprises a RIPK2 protein.
  • the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is sufficient to inhibit RIPK2 activity in the cell. In some embodiments, the contacting is in vivo, wherein the method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a mammalian cell having RIPK2 activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is an cancer cell.
  • the RIPK2 activity is inhibited by about 10% to about 99%, for example, about 10% to about 50%, about 25% to about 75%, about 50% to about 99%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or any value in between.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting RIPK2 (e.g., a RIPK2 protein) with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a RIPK2 protein, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing a RIPK2 protein.
  • Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Embodiment 1 A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • X 1 is C-NR 1A -S(O 2 )C1-C6 alkyl, C-NR 1A -S(O 2 )5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, or N;
  • X 3 is CR 3 or N
  • X 4 is CH or N
  • R 1A is hydrogen or C1-C6 alkyl
  • R 2 is hydrogen, C1-C6 alkoxy, or -NR 2A R 2B ;
  • R 2A and R 2B are independently hydrogen or C1-C6 alkyl, or when X 3 is CR 3 , then R 2A is hydrogen and R 2B and R 3 with the atoms to which they are attached together form a 5 -membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • R 3 is hydrogen, halogen, C1-C6 alkoxy, -NR 3A R 3B , or or R 3 and R 2 with the atoms to which they are attached together form a 5-membered heterocyclyl, 5-membered heteroaryl ring, or phenyl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • R 3A and R 3B are independently hydrogen or C1-C6 alkyl, or R 3A is hydrogen and R 3B and R 2 with the atoms to which they are attached together form a 5- membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 optionally substituted with C1-C6 alkyl;
  • Ring A is phenyl, 5-10 membered heteroaryl, C4-C10 cycloalkyl, or 5-10 membered heterocyclyl; each R 3C is independently selected from the group consisting of: (i) halogen,
  • R a3 is hydrogen or C1-C6 alkyl
  • R b3 is:
  • L is a bond, -O-, or -NH-;
  • Q is a bond, NH, or N(C1-C6 alkyl).
  • Embodiment 2 The compound of Embodiment 1, wherein X 1 is C- NH-S(O 2 )C1-C6 alkyl.
  • Embodiment 3 The compound of Embodiment 1, wherein X 1 is C- NR 1A -S(O 2 )5-10 membered heteroaryl optionally substituted with C1-C6 alkyl.
  • Embodiment 4 The compound of Embodiment 1, wherein X 1 is C- NR 1A -S(O 2 )5-10 membered heteroaryl substituted with C1-C6 alkyl.
  • Embodiment 5 The compound of Embodiment 1, wherein X 1 is N.
  • Embodiment 6 The compound of any one of Embodiments 1-5, wherein X 3 is CR 3 .
  • Embodiment 7 The compound of any one of Embodiments 1-5, wherein X 3 is N.
  • Embodiment 8 The compound of any one of Embodiments 1-7, wherein X 4 is CH.
  • Embodiment 9 The compound of any one of Embodiments 1-7, wherein X 4 is N.
  • Embodiment 10 The compound of Embodiment 1, wherein X 1 is N, X 3 is CR 3 , and X 4 is CH.
  • Embodiment 11 The compound of any one of Embodiments 1-10, wherein R 2 is hydrogen.
  • Embodiment 12 The compound of any one of Embodiments 1-10, wherein R 2 is C1-C6 alkoxy.
  • Embodiment 13 The compound of any one of Embodiments 1-10, wherein R 2 is -NR 2A R 2B .
  • Embodiment 15 The compound of any one of Embodiments 1-6 and 8-14, wherein R 3 is hydrogen.
  • Embodiment 16 The compound of any one of Embodiments 1-6 and 8-14, wherein R 3 is halogen.
  • Embodiment 17 The compound of any one of Embodiments 1-6 and 8-14, wherein R 3 is C1-C6 alkoxy.
  • Embodiment 18 The compound of any one of Embodiments 1-6 and 8-14, wherein R 3 is -NR 3A R 3B .
  • Embodiment 19 The compound of any one of Embodiments 1-6 and
  • Embodiment 20 The compound of any one of Embodiments 1-6 and
  • Embodiment 21 The compound of any one of Embodiments 1-6 and
  • Embodiment 22 The compound of any one of Embodiments 1-6 and
  • Embodiment 23 The compound of any one of Embodiments 1-6, 8- 14, and 18-22, wherein at least one R 3C is halogen.
  • Embodiment 24 The compound of any one of Embodiments 1-6, 8-
  • R 3C is C1-C6 alkoxy.
  • Embodiment 25 The compound of any one of Embodiments 1-6, 8- 14, and 18-22, wherein at least one R 3C is -NR a3 R b3 .
  • Embodiment 26 The compound of any one of Embodiments 1-6, 8- 14, and 18-22, wherein at least one R 3C is -NR a3 -S(O 2 )Cl-C6 alkyl.
  • Embodiment 27 The compound of any one of Embodiments 1-6, 8- 14, and 18-22, wherein at least one R 3C is -N(H)-S(O 2 )C1-C6 alkyl or -N(CHs)- S(O 2 )C1-C6 alkyl.
  • Embodiment 28 The compound of any one of Embodiments 1-6 and
  • R is , ring A is phenyl, and at least one R is C1-C6 alkoxy.
  • Embodiment 29 The compound of any one of Embodiments 1-6 and
  • R 3 is , ring A is phenyl, and at least one R 3C is -NR a3 -
  • Embodiment 20 The compound of any one of Embodiments 1-6 and
  • R 3 is , ring A is phenyl, m is 3, at least one R 3C is C1-C6 alkoxy, and at least one R 3C is -NR a3 -S(O 2 )Cl-C6 alkyl.
  • Embodiment 33 The compound of any one of Embodiments 1-6 and 8-14, wherein R 3 and R 2 with the atoms to which they are attached together form a 5- membered heterocyclyl, 5 -membered heteroaryl ring, or phenyl ring fused to the ring comprising X 1 .
  • Embodiment 34 The compound of any one of Embodiments 1-6 and 8-14, wherein R 3 is -NR 3A R 3B , R 3A is hydrogen, and R 3B and R 2 with the atoms to which they are attached together form a 5-membered heterocyclyl or heteroaryl ring fused to the ring comprising X 1 and optionally substituted with C1-C6 alkyl.
  • Embodiment 35 The compound of any one of Embodiments 1-34, wherein L is a bond.
  • Embodiment 36 The compound of any one of Embodiments 1-34, wherein L is -NH-.
  • Embodiment 37 The compound of any one of Embodiments 1-36, wherein R 5 is hydrogen.
  • Embodiment 40 The compound of any one of Embodiments 1-36, wherein R 5 is phenyl.
  • Embodiment 41 The compound of any one of Embodiments 1-36, wherein R 5 is phenyl optionally substituted with halogen.
  • Embodiment 42 The compound of any one of Embodiments 1-36, wherein R 5 is phenyl optionally substituted with C1-C6 alkoxy.
  • Embodiment 43 The compound of any one of Embodiments 1-36, wherein R 5 is phenyl optionally substituted with -N(H)-S(O) 2 C1-C6 alkyl or - N(CH 3 )-S(O) 2 C1-C6 alkyl.
  • Embodiment 44 The compound of any one of Embodiments 1-36, wherein R 5 is phenyl optionally substituted with halogen, C1-C6 alkoxy, and -NR 5A - S(O) 2 C1-C6 alkyl.
  • Embodiment 45 The compound of any one of Embodiments 1-36, wherein R 5 is 4-8 membered heterocyclyl.
  • Embodiment 46 The compound of any one of Embodiments 1-36, wherein R 5 is 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • Embodiment 50 The compound of any one of Embodiments 1-36, wherein R 5 is 5-10 membered heteroaryl.
  • Embodiment 51 The compound of any one of Embodiments 1-36, wherein R 5 is 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl and - Q-(4-10 membered heterocyclyl).
  • Embodiment 52 The compound of any one of Embodiments 1-36, wherein R 5 is 5-10 membered heteroaryl optionally substituted with C1-C6 alkyl and - Q-(4-10 membered heterocyclyl), wherein the 4-10 membered heterocyclyl is optionally substituted with C1-C6 alkyl, hydroxyl, oxo, -C(O)R a5 , or -C(O)NR b5 R c5 .
  • Embodiment 53 The compound of any one of Embodiments 1-36,
  • Embodiment 55 The compound of any one of Embodiments 1-36,
  • Embodiment 56 The compound of any one of Embodiments 1-36,
  • Embodiment 57 A compound selected from the compounds of any of Examples 1-132, or a pharmaceutically acceptable salt of any of the foregoing.
  • Embodiment 58 A pharmaceutical composition comprising a compound of any one of Embodiments 1-57, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Embodiment 59 A method of treating a RIPK2-associated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 58.
  • Embodiment 60 The method of Embodiment 59, wherein the RIPK2-associated disease or disorder is a cardiovascular disease, an allergic disorder, an autoimmune disease, an inflammatory disease, a cardiovascular disease, a fibrotic disease, or a disease associated with abnormal cell growth.
  • the RIPK2-associated disease or disorder is a cardiovascular disease, an allergic disorder, an autoimmune disease, an inflammatory disease, a cardiovascular disease, a fibrotic disease, or a disease associated with abnormal cell growth.
  • Embodiment 61 The method of Embodiment 59 or 60, wherein the RIPK2-associated disease or disorder is an inflammatory disease.
  • Embodiment 62 The method of Embodiment 61, wherein the inflammatory disease is chronic lung inflammatory disease, osteoarthritis, inflammatory arthritis, asthma, early onset sarcoidosis, sarcoidosis, eczema, allergic eczema, uveitis, reactive arthritis, chronic inflammation, chronic prostatitis, inflammatory bowel disease, glomerulonephritis, bursitis, carpal tunnel syndrome, tendinitis, inflammation of the lung (e.g., chronic obstructive pulmonary disease), pelvic inflammatory disease, transplant rejection, vasculitis, regional enteritis, distal ileitis, regional ileitis, and terminal ileitis, central areolar choroidal dystrophy, macular degeneration, retinosis pigmentosa, adult vitelliform disease, pattern dystrophy, diabetic retinopathy, BEST disease, myopic degeneration, central serous retinopathy, Stargardt’s disease, Cone-
  • Embodiment 63 A method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of Embodiments 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 58.
  • Embodiment 64 A method of treating inflammatory bowel disease in a subject in need thereof, comprising (a) determining that the subject is suffering from inflammatory bowel disease; and (b) administering to the subject an effective amount of the compound of the compound of any one of Embodiments 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 58.
  • Embodiment 65 A method of treating inflammatory bowel disease in a subject previously identified or diagnosed as having inflammatory bowel disease, the method comprising administering to the subject an effective amount of the compound of the compound of any one of Embodiments 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 58.
  • Embodiment 66 A method of treating Crohn’s disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of the compound of any one Embodiments 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 58.
  • Embodiment 67 A method of treating Crohn’s disease in a subject in need thereof, comprising (a) determining that the subject is suffering from Crohn’s disease; and (b) administering to the subject an effective amount of the compound of the compound of any one of Embodiments 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 58.
  • Embodiment 68 A method of treating Crohn’s disease in a subject previously identified or diagnosed as having Crohn’s disease, the method comprising administering to the subject an effective amount of the compound of the compound of any one of Embodiments 1-57, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 58.
  • the reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000; March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th Ed., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry ' J. Chem. Educ., 74(11), 1297 (1997).
  • 6-amino-5-bromo-pyridine-3-carbohydrazide To a solution of methyl 6- amino-5-bromo-pyridine-3-carboxylate (5 g, 21.64 mmol, 1 eq) in EtOH (50 mL) was added hydrazine monohydrate (6.18 g, 104.93 mmol, 6 mL, 85% purity, 4.85 eq). The reaction mixture was stirred at 90 °C for 15 h before half of the solvent was removed under reduced pressure and the residue was poured into ice water (30 mL). The precipitate was filtered and washed with ice-cold EtOH (30 mL) to afford the title compound (4 g, 80% yield) as a yellow solid.
  • 6-amino-5- bromonicotinohydrazide (1.45 g, 1 eq, 6.28 mmol) and NN-carbonyldiimidazole (1.12 g, 1.1 eq, 6.90 mmol) was dissolved in THF (70 mL).
  • DIEA (1.62 g, 2.19 mL, 2 eq, 12.6 mmol) was added and the mixture was heated to 40 °C for 48 hours before the solvent was evaporated and water was added. The mixture was stirred and the precipitate was collected by filtration to give the title compound (725 mg, 45% yield).
  • 6-(bis(4-methoxybenzyl)amino)-5-bromo-N-hydroxynicotinimidamide A mixture of t-BuOK (1.28 g, 11.43 mmol, 3.5 eq) and NH 2 OH•HCl (680.61 mg, 9.79 mmol, 3 eq) in MeOH (15 mL) was stirred at 0 °C for 30 min, and then 6-(bis(4- methoxybenzyl)amino)-5-bromonicotinonitrile (1.5 g, 3.26 mmol, 1 eq) was added.
  • 6-amino-5-(3-fluoro-4-methoxy-5-(propylsulfonamido)phenyl)nicotinic acid To a solution of methyl 6-amino-5-(3-fluoro-4-methoxy-5- (propylsulfonamido)phenyl)nicotinate (20 mg, 40.26 ⁇ mol, 1 eq) in methanol (1 mL) and H 2 O (0.3 mL) was added LiOH• H 2 O (3.38 mg, 80.52 ⁇ mol, 2 eq).
  • ethyl 8-chloroimidazo[1,2-a]pyrazine-6-carboxylate To a solution of ethyl 5-amino-6-chloropyrazine-2-carboxylate (800 mg, 3.57 mmol, 1 eq) in MeCN (4 mL) was added 2-bromo-1,1-dimethoxyethane (1.21 g, 7.14 mmol, 838.34 ⁇ L, 2 eq). The mixture was stirred at 80 °C for 12 hours before the solids were removed by filtration.
  • ethyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-6-carboxylate To a solution of ethyl 8-chloroimidazo[1,2-a]pyrazine-6-carboxylate (250 mg, 997.20 ⁇ mol, 1 eq) in MeCN (5 mL) was added NBS (141.99 mg, 797.76 ⁇ mol, 0.8 eq) at 0 °C. The mixture was stirred at 0 °C for 3 hours before it was concentrated, diluted with saturated aqueous Na 2 SO 3 (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated.
  • ethyl 3-bromo-8-(methylamino)imidazo[1,2-a]pyrazine-6-carboxylate To a solution of ethyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-6-carboxylate (240 mg, 709.30 ⁇ mol, 1 eq) in EtOH (1 mL) was added DIEA (275.01 mg, 2.13 mmol, 370.63 ⁇ L, 3 eq) and MeNH 2 •HCl (110.63 mg, 1.06 mmol, 1.5 eq). The mixture was stirred at 80 °C for 12 hours before it was concentrated, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL).
  • 6-bromo-3-iodo-N-methylimidazo[1,2-a]pyrazin-8-amine To a solution of 6-bromo-3-iodo-8-(methylsulfonyl)imidazo[1,2-a]pyrazine (2.6 g, 5.82 mmol, 1 eq) in EtOH (26 mL) was added MeNH 2 •HCl (786.02 mg, 11.64 mmol, 2 eq) and DIEA (2.26 g, 17.46 mmol, 3.04 mL, 3 eq).
  • N-(5-(6-bromo-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl)-3-fluoro-2- methoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide A mixture of 6-bromo-3- iodo-N-methylimidazo[1,2-a]pyrazin-8-amine (500 mg, 1.27 mmol, 1 eq), N-(3-fluoro- 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H- pyrazole-4-sulfonamide (873.88 mg, 1.91 mmol, 1.5 eq), Pd(dppf)Cl 2 (93.29 mg, 127.49 ⁇ mol, 0.1 eq) and K3PO4 (811.88 mg, 3.82 mmol, 3 eq) in dioxane (5 mL) and
  • Example 60 N-(5-(5-(5-(4-acetylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-2-aminopyridin- 3-yl)-2,3-dimethoxyphenyl)-N-methylpropane-1-sulfonamide: To a mixture of N- (5-(5-(5-(4-acetylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-2-aminopyridin-3-yl)-2,3- dimethoxyphenyl)propane-1-sulfonamide (11 mg, 1 eq, 20 ⁇ mol) and K2CO3 (5.6 mg, 2 eq, 40 ⁇ mol) in DMF (0.5 mL) was added a solution of iodomethane (3.1 mg, 1.4 ⁇ L, 1.1 eq, 22 ⁇ mol) in DMF (0.1 mL).
  • N-(5-(2-amino-5-(5-morpholino-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-3- fluoro-2-methoxyphenyl)propane-1-sulfonamide To a stirred solution of N-(5-(2- (bis(4-methoxybenzyl)amino)-5-(5-morpholino-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-3- fluoro-2-methoxyphenyl)propane-1-sulfonamide (37 mg, 42.92 ⁇ mol, 1 eq) in DCM (3 mL) was added TFA (1 mL).
  • Example 62 N-(5-(2-amino-5-(1-methyl-3-morpholino-1H-pyrazol-5-yl)pyridin-3-yl)-3- fluoro-2-methoxyphenyl)propane-1-sulfonamide: To a solution of (6-amino-5-(3- fluoro-4-methoxy-5-(propylsulfonamido)phenyl)pyridin-3-yl)boronic acid (30 mg, 64.47 ⁇ mol, 1 eq) and 4-(5-bromo-1-methyl-1H-pyrazol-3-yl)morpholine (70.52 mg, 257.87 ⁇ mol, 4 eq) in dioxane (2 mL) and H 2 O (0.5 mL) was added Pd(dppf)Cl 2 (4.72 mg, 6.45 ⁇ mol, 0.1 eq) and K2CO3 (26.73 mg, 193.40 ⁇ mol, 3 eq).
  • Example 89 N-(5-(2-amino-5-(3-morpholino-1H-pyrazol-1-yl)pyridin-3-yl)-3-fluoro-2- methoxyphenyl)propane-1-sulfonamide: A mixture of 4-(1H-pyrazol-3- yl)morpholine (24.72 mg, 161.37 ⁇ mol, 3 eq), N-(5-(2-amino-5-bromopyridin-3-yl)-3- fluoro-2-methoxyphenyl)propane-1-sulfonamide (25 mg, 53.79 ⁇ mol, 1 eq), CuI (1.02 mg, 5.38 ⁇ mol, 0.1 eq), trans-N,N′-dimethyl-1,2-diaminocyclohexane (1.
  • Example 92 N-(5-(2-amino-5-(1-(cyclopropanecarbonyl)pyrrolidin-2-yl)pyridin-3-yl)- 3-fluoro-2-methoxyphenyl)propane-1-sulfonamide: To a mixture of N-(5-(2-amino- 5-bromopyridin-3-yl)-3-fluoro-2-methoxyphenyl)propane-1-sulfonamide (100 mg, 215.17 ⁇ mol, 1 eq) and (cyclopropanecarbonyl)-D-proline (51.25 mg, 279.72 ⁇ mol, 1.3 eq) in DMA (2 mL) was added Cs2CO3 (105.16 mg, 322.75 ⁇ mol, 1.5 eq), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (2.41 mg, 2.15 ⁇ mol, 0.01 eq) and NiCl 2 •dtbb
  • reaction mixture was stirred under a N 2 atmosphere and irradiated for 14 hours using a 10 W blue LED lamp (3 cm away) with water circulated to keep the reaction temperature at 25 °C.
  • Example 96 N-(3-fluoro-5-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)-2- methoxyphenyl)propane-1-sulfonamide: To a solution of N-(3-fluoro-2-methoxy-5- (1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)propane-1-sulfonamide (200 mg, 493.97 ⁇ mol, 1 eq) in DMF (2 mL) was added NIS (100.02 mg, 444.57 ⁇ mol, 0.9 eq).
  • N-(3-fluoro-2-methoxy-5-(3-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyridin-5- yl)phenyl)propane-1-sulfonamide To a solution of N-(3-fluoro-5-(3-iodo-1H- pyrazolo[3,4-b]pyridin-5-yl)-2-methoxyphenyl)propane-1-sulfonamide (100 mg, 203.96 ⁇ mol, 1 eq) and 4,4,5,5-tetramethyl-2-(oxetan-3-yl)-1,3,2-dioxaborolane (75.07 mg, 407.92 ⁇ mol, 2 eq) in DMF (2 mL) was added morpholine (26.65 mg, 305.94 ⁇ mol, 26.92 ⁇ L, 1.5 eq), Ir[dF(CF3)ppy]2(dtbpy
  • the reaction solution was pumped through a reactor at a flow rate of 300 ⁇ L/min (residence time of 0.5 hour), irradiating with a 450 nm LED lamp with a cooling fan present to keep the reaction temperature at 25 °C.
  • Example 97 was prepared following procedures analogous to that described for Example 96.
  • (5-bromo-2-fluoropyridin-3-yl)(morpholino)methanethione A mixture of (5-bromo-2-fluoropyridin-3-yl)(morpholino)methanone (260 mg, 809.41 ⁇ mol, 1 eq) and Lawesson’s reagent (654.76 mg, 1.62 mmol, 2 eq) in THF (2 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 40 °C for 2 hours under a N 2 atmosphere. The reaction mixture was diluted with H 2 O (40 mL) and extracted with EtOAc (3 x 20 mL).
  • N-(3-fluoro-2-methoxy-5-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5- yl)phenyl)propane-1-sulfonamide A mixture of 4-(5-bromo-1H-pyrazolo[3,4- b]pyridin-3-yl)morpholine (30 mg, 95.36 ⁇ mol, 1 eq), N-(3-fluoro-2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide (66.74 mg, 143.05 ⁇ mol, 1.5 eq), Pd(dppf)Cl 2 (6.98 mg, 9.54 ⁇ mol, 0.1 eq), K2CO3 (39.54 mg, 286.09 ⁇ mol, 3 eq) in dioxane (0.5 mL) was degassed and purged with N 2 three
  • Example 100 was obtained from the corresponding N- Boc intermediate after Boc group removal with TFA and purification of the final product.
  • Example 102 5-bromo-2-nitro-N-(oxetan-3-yl)pyridin-3-amine: To a solution of 5-bromo- 3-fluoro-2-nitropyridine (1 g, 4.53 mmol, 1 eq) and oxetan-3-amine (396.92 mg, 5.43 mmol, 1.2 eq) in MeCN (5 mL) was added Et3N (1.37 g, 13.58 mmol, 1.89 mL, 3 eq). The mixture was stirred at 80 °C for 4 hours before it was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL).
  • 5-bromo-N 3 -(oxetan-3-yl)pyridine-2,3-diamine A mixture of 5-bromo-2- nitro-N-(oxetan-3-yl)pyridin-3-amine (300 mg, 985.15 ⁇ mol, 1 eq), Fe powder (550.15 mg, 9.85 mmol, 10 eq) and NH4Cl (526.97 mg, 9.85 mmol, 10 eq) in EtOH (4.8 mL) and H 2 O (0.3 mL) was degassed and purged with N 2 three times.
  • N-(3-fluoro-2-methoxy-5-(1-(oxetan-3-yl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-6-yl)phenyl)propane-1-sulfonamide A mixture of 6-bromo- 1-(oxetan-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (30 mg, 105.52 ⁇ mol, 1 eq), N-(3-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)propane-1-sulfonamide (87.53 mg, 211.05 ⁇ mol, 2 eq), Pd(dppf)Cl 2 (7.72 mg, 10.55 ⁇ mol, 0.1 eq) and K2CO3 (43.75 mg, 316.57
  • Example 106 6-chloro-3-iodo-N-methylimidazo[1,2-b]pyridazin-8-amine: To a solution of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (110 mg, 276.26 ⁇ mol, 1 eq) in EtOH (3 mL) was added DIEA (107.11 mg, 828.77 ⁇ mol, 144.36 ⁇ L, 3 eq) and MeNH 2 •HCl (37.30 mg, 552.52 ⁇ mol, 2 eq). The mixture was stirred at 80 °C for 1 hour before it was concentrated under reduced pressure.
  • N-(5-(6-chloro-8-(methylamino)imidazo[1,2-b]pyridazin-3-yl)-2,3- dimethoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide A mixture of 6-chloro-3- iodo-N-methylimidazo[1,2-b]pyridazin-8-amine (50 mg, 145.86 ⁇ mol, 1 eq), N-(2,3- dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H- pyrazole-4-sulfonamide (89.18 mg, 189.62 ⁇ mol, 1.3 eq), Pd(dppf)Cl 2 (10.67 mg, 14.59 ⁇ mol, 0.1 eq) and K 2 CO 3 (60.48 mg, 437.59 ⁇ mol, 3 eq) in water (0.3 mL)
  • N-(2,3-dimethoxy-5-(8-(methylamino)imidazo[1,2-b]pyridazin-3- yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide To a solution of N-(5-(6-chloro-8- (methylamino)imidazo[1,2-b]pyridazin-3-yl)-2,3-dimethoxyphenyl)-1-methyl-1H- pyrazole-4-sulfonamide (30 mg, 56.49 ⁇ mol, 1 eq) in EtOH (2 mL) was added 10% Pd/C (60.12 mg, 56.49 ⁇ mol, 1 eq) under a N 2 atmosphere.
  • Example 107 3-bromo-N-methyl-8-(methylamino)imidazo[1,2-a]pyrazine-6- carboxamide: A mixture of 3-bromo-8-(methylamino)imidazo[1,2-a]pyrazine-6- carboxylic acid (90 mg, 298.82 ⁇ mol, 1 eq), MeNH 2 •HCl (60.53 mg, 896.45 ⁇ mol, 3 eq), HATU (227.24 mg, 597.63 ⁇ mol, 2 eq) and DIEA (115.86 mg, 896.45 ⁇ mol, 156.14 ⁇ L, 3 eq) in DMF (2 mL) was stirred at 25 °C for 12 hours under a N 2 atmosphere before it was diluted with water (5 mL) and extracted with EtOAc (2 x 10 mL).
  • Example 115 N-(3-fluoro-2-methoxy-5-(8-(methylamino)-6-(2-oxopyrrolidin-1- yl)imidazo[1,2-a]pyrazin-3-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide: A mixture of pyrrolidin-2-one (4.50 mg, 52.91 ⁇ mol, 4.06 ⁇ L, 1.5 eq), N-(5-(6-bromo-8- (methylamino)imidazo[1,2-a]pyrazin-3-yl)-3-fluoro-2-methoxyphenyl)-1-methyl-1H- pyrazole-4-sulfonamide (20 mg, 35.27 ⁇ mol, 1 eq), CuI (2.69 mg, 14.11 ⁇ mol, 0.4 eq), N 1 ,N 2 -dimethylethane-1,2-diamine (2.49 mg, 28.22 ⁇ mol, 3.04 ⁇ L,
  • Example 116 N-(2,3-dimethoxy-5-(6-methoxy-8-(methylamino)imidazo[1,2-a]pyrazin-3- yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide: A mixture of N-(5-(6-bromo-8- (methylamino)imidazo[1,2-a]pyrazin-3-yl)-2,3-dimethoxyphenyl)-1-methyl-1H- pyrazole-4-sulfonamide (30 mg, 51.69 ⁇ mol, 1 eq), t-BuONa (14.90 mg, 155.06 ⁇ mol, 3 eq) and t-BuBrettPhos Pd G3 (4.42 mg, 5.17 ⁇ mol, 0.1 eq) in dioxane (1 mL) and MeOH (0.6 mL) was degassed and purged with N 2 , and then the mixture was stirred at 80 °C for 2 hours
  • Example 119 N-(3-fluoro-2-methoxy-5-(8-(methylamino)-6-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)imidazo[1,2-a]pyrazin-3-yl)phenyl)-1-methyl-1H-pyrazole-4- sulfonamide: To 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (1.72 g, 11.79 mmol, 1.60 mL, 83.55 eq) was added N-(5-(6-bromo-8-(methylamino)imidazo[1,2-a]pyrazin- 3-yl)-3-fluoro-2-methoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide (80 mg, 141.08 ⁇ mol, 1 eq), Cs2CO3 (137.
  • N-(3-fluoro-5-(6-(2-hydroxyethoxy)-8-(methylamino)imidazo[1,2- a]pyrazin-3-yl)-2-methoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide To a solution of N-(3-fluoro-2-methoxy-5-(8-(methylamino)-6-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)imidazo[1,2-a]pyrazin-3-yl)phenyl)-1-methyl-1H-pyrazole-4- sulfonamide (10 mg, 15.64 ⁇ mol, 1 eq) in DCM (1 mL) was added TFA (191.88 mg, 1.68 mmol, 125.00 ⁇ L, 107.62 eq).
  • Example 120 N-(3-fluoro-2-methoxy-5-(8-(methylamino)-6- (methylsulfonyl)imidazo[1,2-a]pyrazin-3-yl)phenyl)propane-1-sulfonamide: A mixture of N-(5-(6-bromo-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl)-3-fluoro-2- methoxyphenyl)propane-1-sulfonamide (10 mg, 19.05 ⁇ mol, 1 eq), (2S,4R)-N-(2,6- dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide (223.22 ⁇ g, 9.53e-1 ⁇ mol, 0.05 eq), sodium methanesulfinate (2.92 mg, 28.58 ⁇ mol, 1.5 eq) and K3PO4 (4.04 mg, 19.05 ⁇ mol, 1 eq) in DMSO (1 mL) was degas
  • Example 121 was prepared following procedures analogous to that described for Example 120.
  • Example 122 N-(2,3-dimethoxy-5-(6-methyl-8-(methylamino)imidazo[1,2-a]pyrazin-3- yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide: A mixture of N-(5-(6-bromo-8- (methylamino)imidazo[1,2-a]pyrazin-3-yl)-2,3-dimethoxyphenyl)-1-methyl-1H- pyrazole-4-sulfonamide (30 mg, 51.69 ⁇ mol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (64.88 mg, 258.44 ⁇ mol, 72.26 ⁇ L, 5 eq), Pd(dppf)Cl 2 (3.78 mg, 5.17 ⁇ mol, 0.1 eq) and K2CO3 (21.43 mg, 155.06 ⁇ mol, 3 eq) in dioxane (0.5
  • Example 126 N-(2,3-dimethoxy-5-(8-(methylamino)-6-vinylimidazo[1,2-a]pyrazin-3- yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide: A mixture of N-(5-(6-bromo-8- (methylamino)imidazo[1,2-a]pyrazin-3-yl)-2,3-dimethoxyphenyl)-1-methyl-1H- pyrazole-4-sulfonamide (80 mg, 137.83 ⁇ mol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (25.47 mg, 165.40 ⁇ mol, 28.05 ⁇ L, 1.2 eq), Pd(dppf)Cl 2 (10.09 mg, 13.78 ⁇ mol, 0.1 eq) and K2CO3 (57.15
  • N-(5-(6-ethyl-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl)-2,3- dimethoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide To a solution of N-(2,3- dimethoxy-5-(8-(methylamino)-6-vinylimidazo[1,2-a]pyrazin-3-yl)phenyl)-1-methyl- 1H-pyrazole-4-sulfonamide (15 mg, 28.75 ⁇ mol, 1 eq) in MeOH (5 mL) was added 10% Pd/C (30.60 mg, 28.75 ⁇ mol, 1 eq) under a N 2 atmosphere.
  • N-(5-(6-(1-hydroxyethyl)-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl)-2,3- dimethoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide To a solution of N-(5-(6- formyl-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl)-2,3-dimethoxyphenyl)-1-methyl- 1H-pyrazole-4-sulfonamide (70 mg, 133.62 ⁇ mol, 1 eq) in THF (2 mL) was added MeMgBr (3 M, 133.62 ⁇ L, 3 eq) at 0 °C under a N 2 atmosphere.
  • N-(5-(6-(hydroxymethyl)-8-(methylamino)imidazo[1,2-a]pyrazin-3-yl)-2,3- dimethoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide A solution of methyl 3- (3,4-dimethoxy-5-((1-methyl-1H-pyrazole)-4-sulfonamido)phenyl)-8- (methylamino)imidazo[1,2-a]pyrazine-6-carboxylate (30 mg, 58.29 ⁇ mol, 1 eq) in THF (1 mL) was degassed and purged with N 2 three times before LiAlH4 (2.5 M, 116.57 ⁇ L, 5 eq) was added dropwise at 0 °C.
  • N-(5-(6-(2-hydroxypropan-2-yl)-8-(methylamino)imidazo[1,2-a]pyrazin-3- yl)-2,3-dimethoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide To a solution of methyl 3-(3,4-dimethoxy-5-((1-methyl-1H-pyrazole)-4-sulfonamido)phenyl)-8- (methylamino)imidazo[1,2-a]pyrazine-6-carboxylate (20 mg, 35.89 ⁇ mol, 1 eq) in THF (1 mL) was added MeMgBr (3 M, 71.78 ⁇ L, 6 eq) at 0 °C.
  • Biological Data RIPK2 binding competition assay The ability of selected compounds of Formula (I) to inhibit the binding of an Alexa647-labelled ATP-competitive kinase inhibitor to a GST-RIPK2 fusion protein was quantified employing the TR-FRET-based RIPK2 binding competition assay as described in the following paragraphs.
  • PR9115B was used as Alexa647-labelled ATP- competitive kinase inhibitor.
  • the resulting mixture was incubated 45 min at 22°C to allow the formation of a complex between the Tracer 199, the fusion protein and Anti-GST-Tb.
  • test compounds were tested on the same microtiter plate in 11 different concentrations in the range of 20 ⁇ M to 0.07 nM (20 ⁇ M, 5.7 ⁇ M, 1.6 ⁇ M, 0.47 ⁇ M, 0.13 ⁇ M, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, is the dilution series prepared separately before the assay on the level of the 100-fold concentrated solutions in DMSO by serial dilutions; exact concentrations may vary depending on pipettors used) in duplicate values for each concentration and IC50 values were calculated using Genedata ScreenerTM software.
  • Table A1 lists IC50 values of selected compounds of Formula (I) measured in the RIPK2 binding competition assay .
  • IC50 values “A” denotes an IC50 of ⁇ 1 nM; “B” denotes an IC50 of 1 nM ⁇ B ⁇ 2.5; “C” denotes an IC50 of 2.5 nM ⁇ C ⁇ 20; and “D” denotes an IC50 of 20 nM ⁇ D.
  • the fluorescence emissions at 520 nm and 665 nm after excitation at 337 nm were measured in a TR-FRET reader, e.g. a Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or an Envision (PerkinElmer).
  • the ratio of the emissions at 665 nm and at 520 nm was taken as the measure of the amount of the complex.
  • test compounds were tested on the same microtiter plate in 11 different concentrations in the range of 10 ⁇ M to 0.04 nM (10 ⁇ M, 2.86 ⁇ M, 0.82 ⁇ M, 0.23 ⁇ M, 67 nM, 19 nM, 5.4 nM, 1.6 nM, 0.4 nM, 0.1 nM and 0.04 nM, is the dilution series prepared separately before the assay on the level of the 100-fold concentrated solutions in DMSO by serial dilutions; exact concentrations may vary depending on pipettors used) in duplicate values for each concentration and IC50 values were calculated using Collaborative Drug Discovery software.
  • THP1 ⁇ DualTM cells (InvivoGen Cat# thpd-nfis) allow simultaneous assessment of the NF- ⁇ pathway, by monitoring the activity of secreted embryonic alkaline phosphatase (SEAP) as well as the IRF pathway, by assessing the activity of a secreted luciferase (Lucia). Cells were cultured according to manufacturers’ recommendations.
  • cell concentration was adjusted to 7.14 x 10 5 cells/mL in assay media (RPMI 1640, 2 mM L-Glutamine, 25 mM HEPES, 10% fetal bovine serum (heat-inactivated for 30 min at 56 °C), Pen-Strep (100 U/mL)) and 35 ⁇ L of cell suspension ( ⁇ 25,000 cells) per well were added to a flat bottom 384-well plate (white opaque). Plate was centrifuged at 300 g for 2 min, compounds were added in serial dilution series according to the plate layout (volumes ⁇ 500 nL – 0.0152 nL) and plate was incubated at 37 °C in 5% CO2 for 30 min.
  • assay media RPMI 1640, 2 mM L-Glutamine, 25 mM HEPES, 10% fetal bovine serum (heat-inactivated for 30 min at 56 °C), Pen-Strep (100 U/mL)
  • 35 ⁇ L of cell suspension ⁇ 25,000 cells
  • the optical density (OD) was measured at 620-655 nm using a microplate reader (PheraStar FS microplate reader with protocol for OD 620-655 nm).
  • a microplate reader PheraStar FS microplate reader with protocol for OD 620-655 nm.
  • the viability assay the cells remaining in the plate were used to assess cell viability. For this, CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate was allowed to equilibrate to room temperature and lyophilized CellTiter-Glo substrate was reconstituted according to the manufacturers’ recommendations.
  • Table A lists potency values of selected compounds of Formula (I) measured in the RIPK2/XIAP binding competition PPI assay and the THP-1 Dual cell SEAP and viability assays.
  • IC50 values “A” denotes an IC50 of ⁇ 1 nM; “B” denotes an IC50 of 1 nM ⁇ B ⁇ 5; “C” denotes an IC50 of 5 nM ⁇ C ⁇ 50; and “D” denotes an IC50 of 50 nM ⁇ D.
  • Amax values “A” denotes an Amax of ⁇ 80%; “B” denotes an Amax of 80% > B ⁇ 55; “C” denotes an Amax of 55% > C > 30; and “D” denotes an Amax of ⁇ 30%.
  • L18MDP THP-1 assay IC50 values “A” denotes an IC50 of ⁇ 50 nM; “B” denotes an IC50 of 50 nM ⁇ B ⁇ 250; “C” denotes an IC50 of 250 nM ⁇ C ⁇ 1,000; and “D” denotes an IC50 of 1,000 nM ⁇ D.
  • IC50 values For the IFNg THP-1 assay IC50 values, “A” denotes an IC50 of ⁇ 50 nM; “B” denotes an IC50 of 50 nM ⁇ B ⁇ 250; “C” denotes an IC50 of 250 nM ⁇ C ⁇ 1,000; and “D” denotes an IC50 of 1,000 nM ⁇ D. Table A. Potency Values

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Abstract

La présente invention concerne des composés de formule (I), tels que définis dans la description, et des sels pharmaceutiquement acceptables de ceux-ci, et des compositions les comprenant. L'invention concerne également des procédés de traitement des maladies et des troubles décrits ici, avec les composés de formule (I), et des sels pharmaceutiquement acceptables de ceux-ci, et les compositions les comprenant.
PCT/US2024/033118 2023-06-09 2024-06-07 Méthodes de traitement de maladies inflammatoires Pending WO2024254536A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018183633A1 (fr) * 2017-03-29 2018-10-04 University Of Houston System Compositions destinées à être utilisées dans des procédés d'inhibition de protéines kinases
WO2020139748A1 (fr) * 2018-12-28 2020-07-02 Cedars-Sinai Medical Center Méthodes de traitement de maladies intestinales inflammatoires ciblant la ripk2
WO2023239941A1 (fr) * 2022-06-10 2023-12-14 Interline Therapeutics Inc. Dérivés d'imidazo(1,2-a)pyridine utilisés en tant qu'inhibiteurs de ripk2

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018183633A1 (fr) * 2017-03-29 2018-10-04 University Of Houston System Compositions destinées à être utilisées dans des procédés d'inhibition de protéines kinases
WO2020139748A1 (fr) * 2018-12-28 2020-07-02 Cedars-Sinai Medical Center Méthodes de traitement de maladies intestinales inflammatoires ciblant la ripk2
WO2023239941A1 (fr) * 2022-06-10 2023-12-14 Interline Therapeutics Inc. Dérivés d'imidazo(1,2-a)pyridine utilisés en tant qu'inhibiteurs de ripk2

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* Cited by examiner, † Cited by third party
Title
"Handbook of PharmaceuticalAdditives", 2007
"March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2001, WILEY-INTERSCIENCE PUBLICATION
"Protecting Group Chemistry", 2000, OXFORD UNIVERSITY PRESS
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
"The Pharmaceutical Press and the American Pharmaceutical Association", 2009, CRC PRESS LLC
PETURSSION, S. ET AL.: "Protecting Groups in Carbohydrate Chemistry", J. CHEM. EDUC, vol. 74, no. 11, 1997, pages 1297

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