Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• Receptor interacting protein kinase 2 (RIPK2) is associated with promoting infiltration of immune cells into the central nervous system.
• RIPK2 mediates pro-inflammatory signaling from nucleotide-binding oligomerization domain containing proteins 1 and 2 (NODI and NOD2), and is implicated in numerous autoinflammatory disorders.
• NODI and NOD2 nucleotide-binding oligomerization domain containing proteins 1 and 2
• Autoinflammatory disorders such as inflammatory bowel disease (IBD) can be debilitating and sometimes lead to life-threatening complications. In 2011, studies showed that approximately 1.6 million Americans suffered from IBD. Accordingly, inhibition of RIPK2 is useful for treating certain diseases and disorders associated with autoinflammatory disorders.
• the present application provides technologies useful for inhibiting RIPK2.
• provided technologies are useful for, among other things, treating and/or preventing inflammatory disorders such as inflammatory bowel disease.
• the present application provides compounds having a structure as set forth in Formula I:
• R 1 is a 4- to 7-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9- to 10- membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 1 is substituted with (R 2 )p;
• each R 2 is independently halogen, optionally substituted Ci- 6 aliphatic, -OR, -N(R)2, -C(0)R, -C(0)0R, -SO2R, or an optionally substituted 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen, optionally substituted Ci- 6 aliphatic, or an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
• each R 3 is independently halogen, CN, -N(R)2, -OR, or optionally substituted Ci- 6 aliphatic; p is 0-4; and
• the present application provides compounds having a structure as set forth in Formula G :
• R 1 is a 4- to 7-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9- to 10- membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 1 is substituted with (R 2 )p; each R 2 is independently halogen, optionally substituted Ci- 6 aliphatic, -OR, -N(R)2, -C(0)R, -C(0)OR, -SO2R, or an optionally substituted 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen, optionally substituted Ci- 6 aliphatic, or an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
• each R 3 is independently halogen, CN, -N(R)2, -OR, or optionally substituted Ci- 6 aliphatic;
• X is hydrogen or halogen
• p 0-4;
• Aliphatic refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as“cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
• aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., Ci- 6 ).
• aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2).
• cycloaliphatic refers to a monocyclic C3-8 hydrocarbon or a bicyclic C7-10 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
• Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.
• a preferred aliphatic group is Ci- 6 alkyl.
• Alkyl refers to a saturated, optionally substituted straight or branched chain or cyclic hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., Ci-12, Ci-10, Ci- 8 , Ci- 6 , Ci-4, Ci-3, or C1-2).
• Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
• the term“cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms.
• Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• Alkylene refers to a bivalent alkyl group.
• “alkylene” is a bivalent straight or branched alkyl group.
• an "alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
• An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein.
• two substituents of the alkylene group may be taken together to form a ring system.
• two substituents can be taken together to form a 3- to 7- membered ring.
• the substituents can be on the same or different atoms.
• Alkenyl refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
• alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
• cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
• exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
• Alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
• exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
• Aryl refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members (e.g., C5-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
• the term “aryl” may be used interchangeably with the term“aryl ring”.
• “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified,“aryl” groups are hydrocarbons.
• biological sample typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein.
• a source of interest comprises an organism, such as an animal or human.
• a biological sample is or comprises biological tissue or fluid.
• a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell- containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc.
• a biological sample is or comprises cells obtained from an individual.
• obtained cells are or include cells from an individual from whom the sample is obtained.
• a sample is a“primary sample” obtained directly from a source of interest by any appropriate means.
• a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
• sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi- permeable membrane.
• a“processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
• Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
• carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
• carriers are or include one or more solid components.
• Combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents).
• the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
• “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
• combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
• composition may be used to refer to a discrete physical entity that comprises one or more specified components.
• a composition may be of any form - e.g., gas, gel, liquid, solid, etc.
• Dosage form or unit dosage form may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject.
• an active agent e.g., a therapeutic or diagnostic agent
• each such unit contains a predetermined quantity of active agent.
• such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (z.e., with a therapeutic dosing regimen).
• the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.
• Dosing regimen or therapeutic regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
• a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
• a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
• individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
• all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (z.e., is a therapeutic dosing regimen).
• Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.
• suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
• Heteroaryl The terms“heteroaryl” and“heteroar-”, used alone or as part of a larger moiety, e.g.,“heteroaralkyl”, or“heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6, 10, or 14 pP electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
• Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl.
• heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
• Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, AH quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, and benzoisoxazolyl.
• a heteroaryl group may be mono- or bicyclic.
• the term“heteroaryl” may be used interchangeably with the terms“heteroaryl ring”, “heteroaryl group”, or“heteroaromatic”, any of which terms include rings that are optionally substituted.
• the term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
• Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
• Heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”,
• heterocyclic radical and“heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
• nitrogen includes a substituted nitrogen.
• the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N- substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
• a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
• heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.
• bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, and
• a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
• heterocyclic ring systems include and
• Inhibitory agent refers to an entity, condition, or event whose presence, level, or degree correlates with decreased level or activity of a target.
• an inhibitory agent may act directly (in which case it exerts its influence directly upon its target, for example, by binding to the target); in some embodiments, an inhibitory agent may act indirectly (in which case it exerts its influence by interacting with and/or otherwise altering a regulator of the target, so that level and/or activity of the target is reduced).
• an inhibitory agent is one whose presence or level correlates with a target level or activity that is reduced relative to a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known inhibitory agent, or absence of the inhibitory agent in question, etc.).
• oral administration and“administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.
• parenteral administration and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracap sular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
• Partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms.
• the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
• Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g, mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
• animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
• a patient is a human.
• a patient or a subject is suffering from or susceptible to one or more disorders or conditions.
• composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
• the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
• compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
• oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
• compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• composition As used herein, the term
• “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
• Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
• compositions that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 66: 1-19 (1977).
• pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• nontoxic acid addition salts which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
• Prevent or prevention when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
• the term“specific”, when used herein with reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities or states.
• an agent is said to bind“specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets.
• specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of the binding agent for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding agent. In some embodiments, specificity is evaluated relative to that of a reference non-specific binding agent.
• the agent or entity does not detectably bind to the competing alternative target under conditions of binding to its target entity.
• a binding agent binds with higher on-rate, lower off-rate, increased affinity, decreased dissociation, and/or increased stability to its target entity as compared with the competing alternative target(s).
• Substituted or optionally substituted As described herein, compounds of the invention may contain“optionally substituted” moieties.
• the term“substituted,” whether preceded by the term“optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.“Substituted” applies to one or more
• an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
• the term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein.
• Groups described as being“substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being“optionally substituted” may be unsubstituted or be“substituted” as described above.
• Suitable monovalent substituents on R° are independently halogen, -(CH 2 )O-2R ⁇ , -(haloR*), -(CH 2 )o-20H, -(CH 2 )O- 2 OR ⁇ , -(CH 2 )O-
• Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -0(CR * 2 ) 2-3 0-, wherein each independent occurrence of R * is selected from hydrogen, Ci- 6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R * include halogen, -
• Suitable substituents on a substitutable nitrogen of an“optionally substituted” group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ ,
• each R ⁇ is independently hydrogen, Ci- 6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -
• therapeutic agent in general refers to any agent that elicits a desired pharmacological effect when administered to an organism.
• an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population.
• the appropriate population may be a population of model organisms.
• an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc.
• a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
• a“therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans.
• a“therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
• Treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
• Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
• treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
• the following structure is intended to encompass both
• TM w refers to a point of attachment between two atoms.
• the invention provides the compounds of Formula I or Formula F, or a pharmaceutically acceptable salt thereof, in the form of a solvate.
• the solvent may be water, in which case the solvate is termed a hydrate.
• the solvent may be an organic solvent.
• compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like.
• this invention also includes any compound provided herein that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D).
• the compounds of the invention may contain chiral centers, which, unless specified otherwise, may be either of the (R) or (S) configuration, or which may comprise a mixture thereof. Accordingly, the present application includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present application. DETAILED DESCRIPTION
• Autoinflammatory disorders are diseases characterized by systemic and organic- specific inflammation due to abnormalities in the innate immune system. These abnormalities are associated with numerous inflammatory disorders such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis. These disorders affect millions of people.
• NODI and NOD 2 are among the most prominent members of the NLR (NOD-LRR) family, which represent important components of the mammalian innate immune system, serving as intracellular receptors for pathogens and for endogenous molecules elaborated by tissue injury.
• NLR NLR
• Heredity polymorphisms in the genes encoding NODI and NOD2 have been associated with inflammatory disorders. Once activated, NOD signaling leads to activation of NF-KB and MAP kinases, resulting in the transcription of pro-inflammatory kinases and the induction of autophagy.
• Nachbur et al. , Nature Communication , 6:6442 (2015).
• RIPK2 Receptor-interacting protein kinase 2
• RIPK2 mediates pro-inflammatory signaling from NODI and NOD2. Canning, et al. , Chemistry & Biology , 22(9): 1174-1184 (17 Sept. 2015).
• RIPK2 is critical for NF-KB activation and cytokine production.
• inhibition of RIPK2 resolves abnormal inflammation states such as intestinal inflammation. Salla, et al. , J. Pharmacol. Exp. Ther ., 365:354-367 (May 2018).
• inhibitors of RIPK2 have potential to act as therapeutic agents, for example, to reduce or resolve inflammation for inflammatory disorders such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• inflammatory disorders such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• the present application provides certain compounds and/or compositions that act as RIPK2 inhibitory agents, and technologies relating thereto.
• the present application provides a compound of Formula I:
• R 1 is a 4- to 7-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9- to 10- membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 1 1-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 1 is substituted with (R 2 )p;
• each R 2 is independently halogen, optionally substituted Ci-6 aliphatic, -OR, -N(R)2, -C(0)R, -C(0)0R, -SO2R, or an optionally substituted 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen, optionally substituted Ci-6 aliphatic, or an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
• each R 3 is independently halogen, -CN, -N(R)2, -OR, or optionally substituted Ci-6 aliphatic; p is 0-4; and
• the present application provides compounds having a structure as set forth in Formula G :
• R 1 is a 4- to 7-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9- to 10- membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 1 is substituted with (R 2 )p;
• each R 2 is independently halogen, optionally substituted Ci- 6 aliphatic, -OR, -N(R)2, -C(0)R, -C(0)0R, -SO2R, or an optionally substituted 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen, optionally substituted Ci- 6 aliphatic, or an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
• each R 3 is independently halogen, CN, -N(R)2, -OR, or optionally substituted Ci- 6 aliphatic;
• X is hydrogen or halogen
• p 0-4;
• R 1 is a 4- to 7-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9- to 10-membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 1 is substituted with (R 2 )p.
• R 1 is a 4- to 7-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is a 4-membered monocyclic saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is a 5-membered monocyclic saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is a 6-membered monocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is a 5-membered monocyclic partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is a 6-membered monocyclic partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is piperidinyl substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is partially unsaturated piperdinyl substituted with 0, 1, 2, 3, or 4 R 2 groups. In some embodiments, R 1 is 1,2,3,6-tetrahydropyridinyl. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups. In some embodiments, R 1 is 1,2,3,6- tetrahydropyridinyl substituted with 1 or 2 R 2 groups.
• R 1 is a 7-membered monocyclic saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups. [0061] In some embodiments, R 1 is a 7-membered monocyclic partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is azepanyl or 2,3,4,7-tetrahydro-lH-azepinyl. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups. In some such embodiments, R 1 is 2,3,6,7-tetrahydro-lH-azepinyl. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is a 9- to 10-membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups. In some embodiments, R 1 is a 10-membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups. In some embodiments, R 1 is a 10-membered bicyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is
• R 1 is
• R 1 is a 7- to 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups. In some embodiments, R 1 is a 7-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is an 8-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is a 9-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is a 10-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is an 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 1 is substituted with 0, 1, 2, 3, or 4 R 2 groups.
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• R 1 is
• each R 2 is independently optionally substituted Ci- 6 aliphatic, -OR, -N(R)2, -C(0)R, -C(0)OR, -SO2R, or an optionally substituted 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• a substituent on an optionally substituted carbon atom of an optionally substituted R 2 group is selected from: oxo, halogen, -(CH2)o-4R°, -(CH2)o-40R°, and -(CH2)O-4N(R°)2; wherein R° is hydrogen, Ci- 6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• a substituent on an optionally substituted carbon atom of an optionally substituted R 2 group is selected from: oxo, halogen, -(CH2)o-40R°, and -(CH2)o- 4N(R°)2; wherein R° is hydrogen or Ci-6 aliphatic.
• R 2 is optionally substituted Ci-6 aliphatic.
• R 2 is Ci-6 aliphatic optionally substituted with a group selected from halogen, -(CH 2 )O-40R°, or -(CH2)O-4N(R°)2.
• R° is hydrogen or Ci-6 aliphatic optionally substituted with -OR * wherein R * is Ci-4 aliphatic.
• R 2 is Ci-4 aliphatic optionally substituted with a group selected from halogen, -(CH2)o-40R°, or -(CH2)o- 4N(R°)2.
• R 2 is Ci-4 alkyl optionally substituted with a group selected from halogen, -(CH2)o-40R°, or -(CH2)o-4N(R°)2. In some embodiments, R 2 is C1-2 alkyl optionally substituted with a group selected from halogen, -(CH2)o-40R°, or -(CH2)o-4N(R°)2. In some embodiments, R 2 is C1-2 alkyl optionally substituted with a group selected from halogen, -OR°, or -N(R°)2. In some embodiments, R 2 is C1-2 alkyl optionally substituted with halogen. In some embodiments, R 2 is selected from -CH2CH2F, -CH2CHF2, and -CH2CF3.
• R 2 is C1-3 alkyl substituted with -OR° or -N(R°)2. In some such embodiments, R° is hydrogen. In some embodiments, R 2 is -CH2CH2OH. In some embodiments, R 2 is -CH2CH2NH2 or -CH2CH2CH2NH2. In some embodiments, R 2 is C1-2 alkyl substituted with -OR° or -N(R°)2, wherein R° is Ci-4 aliphatic. In some embodiments, R 2 is C1-2 alkyl substituted with -OR° or -N(R°)2, wherein R° is C1-2 aliphatic.
• R 2 is Ci-2 alkyl substituted with -OR°, wherein R° is -CFb or -CH2CH3. In some embodiments, R 2 is -CH2CH2OCH3 or -CH2CH2OCH2CH3.
• R 2 is Ci- 6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is isopropyl.
• R 2 is -OR. In some embodiments, R 2 is -OR, wherein R is Ci-4 aliphatic. In some embodiments, R 2 is -OR, wherein R is C1-2 aliphatic. In some embodiments, R 2 is -OCH3.
• R 2 is -N(R)2. In some embodiments, R 2 is -N(R)2, wherein each R is independently hydrogen or Ci-4 aliphatic. In some embodiments, R 2 is
• R 2 is -N(R)2, wherein each R is independently hydrogen or C1-2 aliphatic.
• R 2 is -N(R)2, wherein each R is independently hydrogen or C1-2 alkyl.
• R 2 is -N(03 ⁇ 4)2.
• R 2 is -NH(03 ⁇ 4).
• R 2 is -C(0)R. In some embodiments, R 2 is -C(0)R, wherein R is optionally substituted Ci- 6 aliphatic. In some embodiments, R 2 is -C(0)R, wherein R is Ci-4 aliphatic optionally substituted with -(CH2)o-40R°, wherein R° is Ci-4 aliphatic. In some embodiments, R 2 is -C(0)R, wherein R is optionally substituted Ci-4 aliphatic. In some embodiments, R 2 is -C(0)R, wherein R is optionally substituted C1-2 aliphatic. In some embodiments, R 2 is -C(0)R, wherein R is optionally substituted C1-2 alkyl. In some embodiments, R 2 is -C(0)R, wherein R is methyl (e.g., R 2 is -C(0)CH3).
• R 2 is -C(0)R, wherein R is Ci- 6 aliphatic optionally substituted with -(CH2)o-40R°, wherein R° is Ci-4 aliphatic.
• R 2 is - C(0)R, wherein R is Ci-4 aliphatic optionally substituted with -(CH2)o-40R°, wherein R° is C1-2 aliphatic.
• R 2 is -C(0)R, wherein R is Ci-4 aliphatic optionally substituted with -(CH 2 )O-40R°, wherein R° is Ci-4 alkyl.
• R 2 is -C(0)R, wherein R is Ci-4 aliphatic optionally substituted with -(CH2)o-40R°, wherein R° is methyl.
• R 2 is -C(0)CH20CH3.
• R 2 is -C(0)OR. In some embodiments, R 2 is -C(0)OR, wherein R is Ci- 6 aliphatic. In some embodiments, R 2 is -C(0)OR, wherein R is Ci-4 aliphatic. In some embodiments, R 2 is -C(0)OR, wherein R is Ci-4 alkyl. In some embodiments, R 2 is - C(0)OR, wherein R is methyl. In some embodiments, R 2 is -C(0)OR, wherein R is ethyl. In some embodiments, R 2 is -C(0)OR, wherein R is propyl. In some embodiments, R 2 is - C(0)OR, wherein R is isopropyl.
• R 2 is -C(0)OR, wherein R is butyl. In some embodiments, R 2 is -C(0)OR, wherein R is t-butyl (i.e., R 2 is -C(0)0C(CH 3 ) 3 ).
• R 2 is -SO2R. In some embodiments, R 2 is -SO2R, wherein
• R is Ci-4 aliphatic.
• R 2 is -SO2R, wherein R is C1-2 aliphatic.
• R 2 is -SO2CH3.
• R 2 is a 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R 2 is oxetanyl. In some embodiments, R 2 is a 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• R 2 is a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6- membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a 6-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• each R is independently hydrogen, optionally substituted Ci-6 aliphatic, or an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on a nitrogen atom, together with the atoms to which they are attached, form a 4- to 6- membered heterocyclic ring having 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• a substituent on an optionally substituted carbon atom of an optionally substituted R group is selected from: oxo, halogen, -(CH2)o-4R°, -(CH2)O-40R°, and -(CH2)O-4N(R°)2; wherein R° is hydrogen, Ci-6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• a substituent on an optionally substituted carbon atom of an optionally substituted R group is selected from: oxo, halogen, -(CH2)o-40R° and -(CH2)o- 4N(R°)2; wherein R° is hydrogen or Ci-6 aliphatic.
• R is hydrogen
• R is an optionally substituted Ci-6 aliphatic. In some embodiments, R is an optionally substituted Ci-4 aliphatic. In some embodiments, R is an optionally substituted C1-2 aliphatic. In some embodiments, R is an optionally substituted C1-2 alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is is isopropyl. In some embodiments, R is butyl. In some embodiments, R is t-butyl.
• R is a Ci-6 aliphatic optionally substituted with a group selected from halogen, -(CH2)o-40R°, or -(CH2)o-4N(R°)2.
• R° is hydrogen or Ci-6 aliphatic optionally substituted with -OR * wherein R * is Ci- 4 aliphatic.
• R is Ci-4 aliphatic optionally substituted with a group selected from halogen, -(CH2)o-40R°, or -(CH2)o-4N(R°)2.
• R° is hydrogen or Ci- 6 aliphatic optionally substituted with -OR * wherein R * is Ci-4 aliphatic.
• R is C1-2 aliphatic optionally substituted with a group selected from halogen, - (CH 2 )O-40R°, or -(CH2)O-4N(R°)2.
• R° is hydrogen or Ci- 6 aliphatic optionally substituted with -OR * wherein R * is Ci-4 aliphatic.
• R is C1-2 alkyl optionally substituted with a group selected from halogen, -(CH2)o-40R°, or -(O3 ⁇ 4)o- 4N(R°)2.
• R° is hydrogen or Ci- 6 aliphatic optionally substituted with -OR * wherein R * is Ci-4 aliphatic.
• R is Ci- 6 aliphatic optionally substituted with a group selected from halogen, -OR°, or -N(R°)2. In some such embodiments, R° is hydrogen or Ci- 6 aliphatic optionally substituted with -OR * wherein R * is Ci-4 aliphatic. In some embodiments, R is Ci-4 aliphatic optionally substituted with a group selected from halogen, -OR°, or -N(R°)2. In some such embodiments, R° is hydrogen or Ci- 6 aliphatic optionally substituted with -OR * wherein R * is Ci-4 aliphatic.
• R is C1-2 aliphatic optionally substituted with a group selected from halogen, -OR°, or -N(R°)2. In some such embodiments, R° is hydrogen or Ci- 6 aliphatic optionally substituted with -OR * wherein R * is Ci-4 aliphatic. In some embodiments, R is C1-2 alkyl optionally substituted with a group selected from halogen, -OR°, or -N(R°)2. In some such embodiments, R° is hydrogen or Ci- 6 aliphatic optionally substituted with -OR * wherein R * is Ci-4 aliphatic.
• R is an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6- membered saturated heterocyclic ring having 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• two R groups on a nitrogen atom, together with the atoms to which they are attached form a 4- to 6-membered heterocyclic ring having 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• two R groups on a nitrogen atom, together with the atoms to which they are attached form a 4- membered heterocyclic ring.
• two R groups on a nitrogen atom, together with the atoms to which they are attached form a 5-membered heterocyclic ring.
• two R groups on a nitrogen atom, together with the atoms to which they are attached form a 6-membered heterocyclic ring having 0 or 1 additional heteroatom selected from nitrogen, oxygen, and sulfur.
• R 1 is piperidinyl and R 2 is methyl. In some embodiments,
• R 1 is piperidinyl, ,
• R 1 is selected from:
• each R 3 is independently halogen, -CN, -N(R)2, -OR, or optionally substituted Ci- 6 aliphatic.
• a substituent on an optionally substituted carbon atom of an optionally substituted R 3 group is selected from: oxo, halogen, -(CH2)o-4R°, -(CH2)o-40R°, and -(CH2)O-4N(R°)2; wherein R° is hydrogen, Ci- 6 aliphatic or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• a substituent on an optionally substituted carbon atom of an optionally substituted R 3 group is selected from: halogen, -(CH2)o-4R°, -(CH2)o-40R°, and -(CH2)O-4N(R°)2; wherein R° is hydrogen, Ci- 6 aliphatic, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 3 is halogen. In some embodiments, R 3 is selected from bromo, chloro, or fluoro. In some embodiments, R 3 is bromo. In some embodiments, R 3 is chloro. In some embodiments R 3 is fluoro. In some embodiments, R 3 is optionally substituted Ci- 6 aliphatic. In some embodiments, R 3 is optionally substituted Ci-4 aliphatic. In some embodiments, R 3 is optionally substituted C1-2 aliphatic. In some embodiments, R 3 is optionally substituted C1-2 alkyl. In some embodiments, R 3 is methyl.
• p is 0-4. In some embodiments, p is 0, 1, 2, 3, or 4.
• p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.
• q is 0-4. In some embodiments, q is 0, 1, 2, 3, or 4.
• q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.
• X is hydrogen or halogen. In some embodiments, X is hydrogen. In some embodiments, X is halogen. In some such embodiments, X is fluoro or chloro. In some embodiments, X is fluoro.
• R 1 and R 3 are as defined above and described herein.
• the present application provides compounds of Formula
• the present application provides compounds of Formula
• R 1 and R 3 are as defined above and described herein.
• the present application provides compounds of Formula
• the present application provides compounds of Formula
• R 1 and R 3 are as defined above and described herein.
• the present application provides compounds of Formula
• the compound of Formula I or Formula F is selected from:
• the compound of Formula I or Formula F is:
• the compound of Formula I is:
• the compound of Formula I is:
• the compound of Formula I is:
• the compound of Formula I is:
• the compound of Formula I is:
• the compound of Formula I is:
• X and Y are leaving groups (e.g., halogen, including bromo, chloro, and iodo), and can be the same or different, and“Het” is an 9-membered heteroaryl substituted by (R 3 )q, wherein R 1 , R 3 and q are as defined above and described herein.
• X and Y are each halogen.
• X is selected from bromo, chloro, and iodo.
• X is bromo.
• X is chloro.
• X is iodo.
• Y is selected from bromo, chloro, and iodo. In some embodiments, Y is bromo. In some embodiments, Y is chloro. In some embodiments, Y is iodo. In some embodiments, X is chloro and Y is iodo.
• “Het” is benzothiazolyl substituted with 0-4 R 3 groups. In some embodiments,“Het” is benzothiazoyl substituted with 1 R 3 group. In some embodiments, “Het” is benzothiazolyl substituted with 2 R 3 groups. In some embodiments, “Het” is benzothiazolyl substituted with 3 R 3 groups.
• “Het” is benzothiazolyl substituted with 4 R 3 groups.
• R 3 is halogen.
• each R 3 is independently selected from bromo, chloro, of fluoro.
• R 3 is bromo.
• R 3 is chloro.
• R 3 is fluoro.
• “Het” is:
• “Het” is:
• “Het” is:
• Compound D is prepared by contacting Intermediate 3 with Compound B in the presence of a first palladium catalyst and a first base.
• the first palladium catalyst is Pd(OAc)2.
• the first base is CS2CO3.
• Compound B is selected from:
• R 3 is halogen.
• each R 3 is independently selected from bromo, chloro, of fluoro.
• R 3 is bromo.
• R 3 is chloro.
• R 3 is fluoro.
• Compound B is:
• Intermediate 3 is prepared by contacting Intermediate 1 with Compound C in the presence of a second palladium catalyst and a second base, wherein R 1 is as defined above and described herein.
• the second palladium catalyst is Pd(dppf)Cl2.
• the second base is t-BuONa.
• Intermediate 1 is prepared by reacting Compound A with
• X2 in the presence of a third base.
• the third base is lithium diisopropylamide.
• X2 is I2.
• Compound D is prepared by contacting Intemediate 2 with
• Compound C in the presence of a fourth palladium catalyst and a fourth base wherein R 1 is as defined above and described herein.
• the fourth palladium catalyst is Pd2(dba)3.
• the fourth base is KOH.
• Intermediate 2 is prepared by contacting Intermediate 1 with Compound B in the presence of an acid.
• the acid is />-TsOH.
• Compound B is selected from:
• R 3 is halogen.
• each R 3 is independently selected from bromo, chloro, of fluoro.
• R 3 is bromo.
• R 3 is chloro.
• R 3 is fluoro.
• Compound B is:
• compounds reported herein may be provided in a composition (e.g., in combination) with one or more other components.
• compositions that comprise and/or deliver compounds reported herein (e.g., compounds of formula I, G, II, IF, III, IIG, IV, and/or IV’), or an active metabolite thereof, e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include RIPK2 activity; in some embodiments, administration of such a composition to the system or environment achieves inhibition of RIPK2 activity as described herein.
• compounds reported herein e.g., compounds of formula I, G, II, IF, III, IIG, IV, and/or IV
• an active metabolite thereof e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include RIPK2 activity
• administration of such a composition to the system or environment achieves inhibition of RIPK2 activity as described herein.
• a provided composition as described herein may be a pharmaceutical composition in that it comprises an active agent (e.g., a compound of formula I, G, II, IF, III, IIF, IV, and/or IV’) and one or more pharmaceutically acceptable excipients; in some such embodiments, a provided pharmaceutical composition comprises and/or delivers a compound reported herein (e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV’), or an active metabolite thereof to a relevant system or environment (e.g., to a subject in need thereof) as described herein.
• an active agent e.g., a compound of formula I, G, II, IF, III, IIF, IV, and/or IV’
• a provided pharmaceutical composition comprises and/or delivers a compound reported herein (e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV’), or an active metabolite thereof to a
• one or more compounds reported herein e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV’
• a pharmaceutically acceptable salt form e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV.
• compositions comprising a compound reported herein (e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV’), or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• a compound reported herein e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV’
• a pharmaceutically acceptable carrier, adjuvant, or vehicle e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV’
• a pharmaceutically acceptable carrier, adjuvant, or vehicle e.g., a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• the amount of compound in provided compositions is such that is effective to measurably inhibit RIPK2 in a biological sample or in a patient.
• a provided compound or composition is formulated for administration to a patient in need of such composition.
• dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the provided compounds and compositions will be decided by the attending physician within the scope of sound medical judgment.
• the specific effective dose level for any particular patient or organism will vary from subject to subject, depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed and its route of administration; the species, age, body weight, sex and diet of the patient; the general condition of the subject; the time of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and the like.
• compositions may be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracisternally or via an implanted reservoir, depending on the severity of the condition being treated.
• the compositions are administered orally, intraperitoneally or intravenously.
• provided compounds are administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
• parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
• Sterile injectable forms of provided compositions may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• Suitable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or di-glycerides.
• Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• the rate of compound release can be controlled.
• biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
• compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
• the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• additional substances other than inert diluents e.g., lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings (i.e. buffering agents) and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
• Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• the oral compositions can also include adj
• compositions described herein may be administered in the form of suppositories for rectal or vaginal administration.
• suppositories for rectal or vaginal administration.
• suitable non-irritating excipients or carriers that are solid at room temperature but liquid at body (e.g. rectal or vaginal) temperature and therefore will melt in the rectum or vaginal cavity to release the active compound.
• suitable non-irritating excipients or carriers that are solid at room temperature but liquid at body (e.g. rectal or vaginal) temperature and therefore will melt in the rectum or vaginal cavity to release the active compound.
• Such materials include cocoa butter, a suppository wax (e.g., beeswax) and polyethylene glycols.
• compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract.
• Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
• Dosage forms for topical or transdermal administration of a provided compound include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of this application.
• the present application contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
• Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin.
• compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
• Carriers for topical administration of compounds of this application include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
• provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzyl alkonium chloride.
• the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
• compositions of this application may also be administered by nasal aerosol or inhalation.
• Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
• compositions of this application are formulated for oral administration.
• the present application provides a variety of uses and applications for compounds and/or compositions as described herein, for example in light of their activities and/or characteristics as described herein.
• such uses may include therapeutic and/or diagnostic uses.
• such uses may include research, production, and/or other technological uses.
• the present application provides methods comprising administering one of more compounds of the present application (e.g., a compound of formula I, G, II, IF, III, IIG, IV, and/or IV’) to a subject, e.g., to treat, prevent, or reduce the risk of developing a disorder associated with NODI, NOD2, and/or RIPK2 (e.g., an inflammatory or autoinflammatory disorder).
• the compounds of the present application e.g., a compound of formula I, G, II, IF, III, IIF, IV, and/or IV’
• the present application relates to a method of inhibiting
• RIPK2 in a subject comprising administering to the subject a provided compound, or a composition comprising said compound.
• Inhibition of enzymes in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to biological assays, gene expression studies, and biological target identification.
• the present application relates to a method of treating an inflammatory disorder, an autoimmune disorder, or a disorder associated with NODI, NOD2, and/or RIPK2 in a biological sample comprising the step of contacting said biological sample with a compound or composition reported herein (e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV’) ⁇
• a compound or composition reported herein e.g., a compound of formula I, F, II, IF, III, IIF, IV, and/or IV’
• one or more compounds and/or compositions as described herein are useful, for example, as a method for treating a disorder mediated by RIPK2 comprising administering to a subject a compound or composition described herein.
• the disorder is an inflammatory disorder, an autoimmune disorder, or a disorder associated with NODI, NOD2, and/or RIPK2.
• the disorder is an inflammatory disorder.
• the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• the inflammatory disorder is inflammatory bowel disease. In some embodiments, the inflammatory disorder is sarcoidosis. In some embodiments, the inflammatory disorder is inflammatory arthritis. In some embodiments, the inflammatory disorder is Crohn’s disease. In some embodiments, the inflammatory disorder is peritonitis. In some embodiments, the inflammatory disorder is multiple sclerosis. In some embodiments, the inflammatory disorder is rheumatoid arthritis. In some embodiments, the inflammatory disorder is Wegener’s granulomatosis.
• one or more compounds and/or compositions as described herein are useful in medicine.
• the present application relates to a use of a compound and/or composition described herein for inhibiting RIPK2 in a patient.
• the present application relates to a use of a compound and/or composition described herein for treating a disorder mediated by RIPK2.
• the disorder mediated by RIPK2 is an inflammatory disorder, an autoimmune disorder, or a disorder associated with NODI and/or NOD2 receptors.
• the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament for inhibiting RIPK2.
• the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament for treating a disorder mediated by RIPK2.
• the disorder mediated by RIPK2 is an inflammatory disorder, an autoimmune disorder, or a disorder associated with NODI and/or NOD2 receptors.
• the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• the present application relates to a compound or composition described herein for use in treating a disorder mediated by RIPK2.
• the disorder mediated by RIPK2 is an inflammatory disorder, an autoimmune disorder, or a disorder associated with NODI and/or NOD2 receptors.
• the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• the present application relates to a compound or composition described herein for use in treating an inflammatory disorder, an autoimmune disorder, or a disorder associated with NODI and/or NOD2 receptors.
• the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• R 1 a 4- to 7-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9- to 10-membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 1 is substituted with (R 2 )p; each R 2 is independently halogen, optionally substituted Ci- 6 aliphatic, -OR, -N(R)2, -C(0)R, -C(0)0R, -SO2R, or an optionally substituted 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen, optionally substituted Ci- 6 aliphatic, or an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on a nitrogen atom, together with the atoms to which they are attached, form a 4- to 6-membered heterocyclic ring having 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each R 3 is independently halogen, CN, -N(R)2, -OR, or optionally substituted Ci- 6 aliphatic;
• p 0-4;
• Embodiment 2 The compound of Embodiment 1, wherein R 1 is a 4- to 7- membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 1 is substituted with (R 2 )p.
• Embodiment 3 The compound of Embodiments 1 or 2, wherein R 1 is
• Embodiment 4 The compound of any one of Embodiments 1-3, wherein R 1 is
• Embodiment 5 The compound of any one of Embodiments 1-3, wherein R 1 is
• Embodiment 6 The compound of any one of Embodiments 1-4, wherein R 1 is
• Embodiment 7 The compound of any one of Embodiments 1-4, wherein R 1 is
• Embodiment 8 The compound of any one of Embodiments 1-4, wherein R 1 is
• Embodiment 9 The compound of any one of Embodiments 1-4, wherein R 1 is
• Embodiment 10 The compound of any one of Embodiments 1-4, wherein R 1 is
• Embodiment 11 The compound of any one of Embodiments 1-3 or 5, wherein R 1 is
• Embodiment 12 The compound of any one of Embodiments 1-3 or 5, wherein R 1 is
• Embodiment 13 The compound of any one of Embodiments 1-3 or 5, wherein R 1 is
• Embodiment 14 The compound of any one of Embodiments 1-3 or 5, wherein R 1 is
• Embodiment 15 The compound of any one of Embodiments 1-3 or 5, wherein R 1 is
• Embodiment 16 The compound of Embodiments 1 or 2, wherein R 1 is
• Embodiment 17 The compound of any one of Embodiments 1-2 or 16, wherein
• Embodiment 18 The compound of any one of Embodiments 1-2 or 16-17, wherein R 1 is [0211] Embodiment 19. The compound of any one of Embodiments 1-2 or 16-17, wherein R 1 is
• Embodiment 20 The compound of any one of Embodiments 1-2 or 16-17, wherein R 1 is
• Embodiment 21 The compound of any one of Embodiments 1-2 or 16-17, wherein R 1 is
• Embodiment 22 The compound of any one of Embodiments 1-2 or 16-17, wherein R 1 is
• Embodiment 23 The compound of any one of Embodiments 1-2 or 16, wherein
• Embodiment 24 The compound of any one of Embodiments 1-2, 16, or 23, wherein R 1 is
• Embodiment 25 The compound of any one of Embodiments 1-2, 16, or 23, wherein R 1 is
• Embodiment 26 The compound of any one of Embodiments 1-2, 16, or 23, wherein R 1 is
• Embodiment 27 The compound of any one of Embodiments 1-2, 16, or 23, wherein R 1 is
• Embodiment 28 The compound of any one of Embodiments 1-2, 16, or 23, wherein R 1 is
• Embodiment 29 The compound of any one of Embodiments 1-28, wherein R 2 is optionally substituted Ci- 6 aliphatic.
• Embodiment 30 The compound of any one of Embodiments 1-3, 7, or 29, wherein R 1 is [0223] Embodiment 31. The compound of any one of Embodiments 1-3, 7, 29, or 30, wherein R 1 is
• Embodiment 32 The compound of Embodiment 1, wherein R 1 is selected from
• Embodiment 33 The compound of any of Embodiments 1-32, wherein the compound is of Formula II:
• Embodiment 34 The compound of any of Embodiments 1-32, wherein the compound is of Formula III:
• Embodiment 35 The compound of any of Embodiments 1-32, wherein the compound is of Formula IV:
• Embodiment 36 The compound of Embodiment 1, wherein the compound is selected from:
• Embodiment 37 The compound of Embodiment 1, wherein the compound is:
• Embodiment 38 The compound of Embodiment 1, wherein the compound is
• Embodiment 39 The compound of Embodiment 1, wherein the compound is
• Embodiment 40 The compound of Embodiment 1, wherein the compound is
• Embodiment 4E The compound of Embodiment 1, wherein the compound is
• Embodiment 42 The compound of Embodiment 1, wherein the compound is
• Embodiment 43 A composition comprising a compound of any one of
• Embodiments 1-42 and a pharmaceutically acceptable carrier or excipient are provided.
• Embodiment 44 A method of inhibiting RIPK2 in a biological sample or in a patient, comprising contacting the biological sample or administering to the patient a therapeutically effective amount of any one of Embodiments 1-42, or a composition thereof.
• Embodiment 45 A method of treating a disorder mediated by RIPK2 in a patient, comprising administering to the patient a therapeutically effective amount of any one of Embodiments 1-42, or a composition thereof.
• Embodiment 46 The method of Embodiment 45, wherein the disorder mediated by RIPK2 is an inflammatory disorder, an autoimmune disorder, or a disorder associated with NOD2 receptors.
• Embodiment 47 The method of Embodiment 46, wherein the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• Embodiment 48 The method of Embodiments 46 or 47, wherein the inflammatory disorder is inflammatory bowel disease.
• Embodiment 49 The compound of any one of Embodiments 1-42, or a composition thereof, for use in medicine.
• Embodiment 50 Else of a compound of any one of Embodiments 1-42, or a composition thereof, for inhibiting RIPK2 in a biological sample or in a patient.
• Embodiment 51 Use of a compound of any one of Embodiments 1-42, or a composition thereof, for treating a disorder mediated by RIPK2.
• Embodiment 52 The use of Embodiment 51, wherein the disorder mediated by
• RIPK2 is an inflammatory disorder, an autoimmune disorder, or a disorder associated with NOD2 receptors.
• Embodiment 53 The use of Embodiment 52, wherein the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• Embodiment 54 Use of a compound of any one of Embodiments 1-42, or a composition thereof, in the manufacture of a medicament for inhibiting RIPK2.
• Embodiment 55 Use of a compound of any one of Embodiments 1-42, or a composition thereof, in the manufacture of a medicament for treating a disorder mediated by RIPK2.
• Embodiment 56 The use of Embodiment 55, wherein the disorder mediated by
• RIPK2 is an inflammatory disorder, an autoimmune disorder, or a disorder associated with NOD2 receptors.
• Embodiment 57 The use of Embodiment 56, wherein the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• the inflammatory disorder is selected from inflammatory bowel disease, sarcoidosis, inflammatory arthritis, Crohn’s disease, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener’s granulomatosis.
• Embodiment 58 The compound of any one of Embodiments 1-35, wherein p is
• Embodiment 59 The compound of Embodiment 58, wherein p is 1.
• Embodiment 60 The compound of Embodiment 58, wherein p is 2.
• Embodiment 61 The compound of Embodiment 58, wherein p is 3.
• Embodiment 62 The compound of Embodiment 29, wherein R 2 is Ci- 6 aliphatic.
• Embodiment 63 The compound of Embodiment 62, wherein R 2 is methyl or ethyl.
• Embodiment 64 The compound of Embodiment 63, wherein R 2 is methyl.
• Embodiment 65 A compound of formula G :
• R 1 is a 4- to 7-membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9- to 10- membered bicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered spirocyclic fused heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein R 1 is substituted with (R 2 )p;
• each R 2 is independently halogen, optionally substituted Ci- 6 aliphatic, -OR, -N(R)2, -C(0)R, -C(0)0R, -SO2R, or an optionally substituted 3- to 7-membered saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen, optionally substituted Ci- 6 aliphatic, or an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
• each R 3 is independently halogen, CN, -N(R)2, -OR, or optionally substituted Ci- 6 aliphatic;
• X is hydrogen or halogen
• p 0-4;
• Embodiment 66 The compound of Embodiment 65, wherein R 1 is a 4- to 7- membered monocyclic saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 1 is substituted with (R 2 )p.
• Embodiment 67 The compound of Embodiments 65 or 66, wherein R 1 is
• Embodiment 68 The compound of Embodiment 67, wherein R 1 is
• Embodiment 69 The compound of Embodiment 67, wherein R 1 is
• Embodiment 70 The compound of Embodiment 69, wherein R 1 is
• Embodiment 71 The compound of Embodiment 67, wherein R 1 is
• Embodiment 72 The compound of Embodiment 71, wherein R 1 is
• Embodiment 73 The compound of Embodiment 70, wherein R 1 is
• Embodiment 74 The compound of Embodiment 70, wherein R 1 is
• Embodiment 75 The compound of Embodiment 70, wherein R 1 is
• Embodiment 76 The compound of Embodiment 70, wherein R 1 is
• Embodiment 77 The compound of Embodiment 70, wherein R 1 is
• Embodiment 78 The compound of Embodiment 72, wherein R 1 is
• Embodiment 79 The compound of Embodiment 72, wherein R 1 is
• Embodiment 80 The compound of Embodiment 72, wherein R 1 is
• Embodiment 8 E The compound of Embodiment 72, wherein R 1 is
• Embodiment 82 The compound of Embodiment 72, wherein R 1 is
• Embodiment 83 The compound of Embodiments 65 or 66, wherein R 1 is
• Embodiment 84 The compound of Embodiment 83, wherein R 1 is
• Embodiment 85 The compound of Embodiment 84, wherein R 1 is
• Embodiment 86 The compound of Embodiment 85, wherein R 1 is
• Embodiment 87 The compound of Embodiment 86, wherein R 1 is
• Embodiment 88 The compound of Embodiment 86, wherein R 1 is
• Embodiment 89 The compound of Embodiment 86, wherein R 1 is
• Embodiment 90 The compound of Embodiment 86, wherein R 1 is
• Embodiment 9E The compound of Embodiment 86, wherein R 1 is
• Embodiment 92 The compound of Embodiment 84, wherein R 1 is
• Embodiment 93 The compound of Embodiment 92, wherein R 1 is
• Embodiment 94 The compound of Embodiment 93, wherein R 1 is
• Embodiment 95 The compound of Embodiment 93, wherein R 1 is
• Embodiment 96 The compound of Embodiment 93, wherein R 1 is
• Embodiment 97 The compound of Embodiment 93, wherein R 1 is
• Embodiment 98 The compound of Embodiment 93, wherein R 1 is
• Embodiment 99 The compound of Embodiments 65 or 66, wherein R 1 is
• Embodiment 100 The compound of Embodiment 99, wherein R 1 is
• Embodiment 101 The compound of Embodiment 99, wherein R 1 is
• Embodiment 102 The compound of Embodiment 100, wherein R 1 is
• Embodiment 103 The compound of Embodiment 100, wherein R 1 is
• Embodiment 104 The compound of Embodiment 100, wherein R 1 is
• Embodiment 105 The compound of Embodiment 100, wherein R 1 is
• Embodiment 106 The compound of Embodiment 100, wherein R 1 is
• Embodiment 107 The compound of Embodiment 100, wherein R 1 is
• Embodiment 108 The compound of Embodiment 101, wherein R 1 is
• Embodiment 109 The compound of Embodiment 101, wherein R 1 is
• Embodiment 110 The compound of Embodiment 101, wherein R 1 is
• Embodiment 111 The compound of Embodiment 101, wherein R 1 is

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