Classifications

• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
• • 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
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • 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]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to novel compounds that inhibit receptor interacting protein kinases and methods of making and using the same. Specifically, the present invention relates to indazolecarboxamides as receptor interacting protein kinase 1 (RIPK1) inhibitors.
• RIPK1 receptor interacting protein kinase 1
• Apoptosis and necrosis represent two different mechanisms of cell death.
• Apoptosis is a highly regulated process involving the caspase family of cysteine proteases, and characterized by cellular shrinkage, chromatin condensation, and DNA degradation. In contrast, necrosis is associated with cellular and organelle swelling and plasma membrane rupture with ensuing release of intracellular contents and secondary inflammation (Kroemer et al., (2009) Cell Death Differ 16:3-11).
• necrosis has been considered a passive, unregulated form of cell death; however, recent evidence indicates that some necrosis can be induced by regulated signal transduction pathways such as those mediated by receptor interacting protein kinases (RIPKs) especially in conditions where caspases are inhibited or cannot be activated efficiently (Golstein P & Kroemer G (2007) Trends Biochem. Sci. 32:37-43; Festjens et al. (2006) Biochim. Biophys. Acta 1757:1371-1387). Stimulation of the Fas and TNFR family of death domain receptors (DRs) is known to mediate apoptosis in most cell types through the activation of the extrinsic caspase pathway.
• DRs death domain receptors
• DR death domain receptors
• RIPK1 receptor interacting protein kinase 1
• This novel mechanism of cell death is termed “programmed necrosis” or“necroptosis” (Degterev et al., (2005) Nat Chem Biol 1 :112-119).
• Necroptosis can be triggered by a number of mechanisms including of TNF receptor activation, Toll-like receptor engagement, genotoxic stress and viral infection. Downstream of the various stimuli, the signaling pathway that results in necroptosis is dependent on RIPK1 and RIPK3 kinase activity. (He et al., (2009) Cell 137:1100-1111; Cho et. al., (2009) Cell 137: 1112-1123; Zhang et al., (2009) Science 325:332-336).
• inflammatory diseases such as macrophage necrosis in atheroscelerosis development, virus-induced inflammation, systemic inflammatory response syndrome and
• a potent, selective, small molecule inhibitor of RIPK1 activity would block RIPK1 -dependent pro-inflammatory signaling and thereby provide a therapeutic benefit in inflammatory diseases characterized by increased and/or dysregulated RIPK1 kinase activity.
• the present invention provides novel indazolecarboxamides including
• the present invention also provides processes and intermediates for making the compounds of the present invention.
• the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts, or solvates thereof.
• the compounds of the invention may be used in the treatment and/or prophylaxis of conditions associated with aberrant RIPK1 activity.
• the compounds of the present invention may be used in therapy.
• the compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of a condition associated with aberrant RIPK1 activity.
• the present invention is directed to a method of treating diseases mediated at least partially by RIPK1 including inflammatory diseases, ischemia, neurodegeneration, and Gaucher’s disease, which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.
• the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).
• the present invention provides, inter alia , compounds of Formula (I) or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• Ring B is piperidinyl, piperazinyl, or morpholinyl
• R 1 is H, halo, C1-3 alkyl, C1- 3 haloalkyl, C1- 3 deuteroalkyl, C1- 3 alkoxy, C1- 3 haloalkoxy, Ci- 3 alkoxy, C1- 3 haloalkoxy, or C1- 3 deuteroalkoxy;
• R b is H, Ci- 3 alkyl, C1- 3 alkoxy, C1- 3 haloalkyl, C1- 3 haloalkoxy, C1- 3 deuteroalkyl, C1- 3 deuteroalkoxy, halo, NH2, or CN;
• R d is independently H, halo, or C1- 3 alkyl;
• L is C(0)NR a ;
• R a is independently H, Ci-4 alkyl, or Ci-4 deuteroalkyl
• A is A’ or A’-L’
• A’ is C i-4 alkyl substituted with 0-1 OH, Ci-4 deuteroalkyl substituted with 0-1 OH, C3-6 cycloalkyl-Co-3-alkyl-, Co- 3 -alkyl-C 3-6 cycloalkyl-, pyrrolyl-C 1-3-alkyl-,
• L’ is -0-
• R 2 is phenyl, or a 5 to 6 membered heterocycle having 1-4 heteroatoms selected from N and O, wherein any of the phenyl or heterocycle groups are substituted with 0-3
• R 2a is halo, Ci-6 alkyl, Ci-6 alkoxy, hydroxy-Ci e alkoxy, Ci-6 deuteroalkyl, Ci-6
• halocycloalkyl C 3-6 cycloalkoxy, C 3-6 cycloalkyl-Ci-3 alkoxy-, C 3-6 cycloalkyl-Ci-3 deuteroalkoxy-, C 3-6 cycloalkyl-Ci- 3 haloalkoxy-, Ci-6 alkoxy-Ci-3 alkyl-, C 3-6 cycloalkoxy-Ci-3 alkyl-, Ci-4 alkyl-S02-, C 3-6 cycloalkyl-S02-, C 6-10 aryl-S- NR 2c R 2d CO-, heterocycle-, heterocycle-O-, heterocycle-CH2-, wherein each heterocycle is independently a 4-6 membered ring having 1-2 heteroatoms selected from N and O, and wherein each alkyl, cycloalkyl, or heterocycle is substituted with 0-2 R 2b ;
• R 2C and R 2d are independently selected from H, C1- 3 alkyl, C1- 3 deuteroalkyl, C 3 6
• cycloalkyl or taken together with N to which they are attached to form a 4-6 member heterocyclic ring, having 0-1 additional heteroatoms selected from N, O and S, and being substituted with 0-4 substituents chosen from deuterium or halo;
• n 0, 1 or 2.
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• Ring B is , any of which are substituted with 0-1 R b ;
• R 4 is H, or Ci 3 alkyl.
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• R 2 is phenyl, or pyridinyl, or pyrrolyl, any of which are substituted with 0-3 R 2a .
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• A’ is C 1-4 alkyl substituted with 0-1 OH, or Ci 4 deuteroalkyl substituted with 0-1 OH.
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• R 2a is halo, Ci 6 alkyl, Ci 6 alkoxy, Ci 6 haloalkyl, Ci 6 haloalkoxy or C3-6 cycloalkyl-Ci 3 alkoxy-.
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• R b is H, Cl, F, Ci 3 alkyl, or Ci 3 alkoxy
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• A is -CH2-, CD 2 -, -CH2CH2-, -CH(CH 3 )-, -CH(CD 3 )-, -CH2CH 2 CH(CH3)-,
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• A is -CH2-, -CH2CH2-, -CH2CH 2 CH(CH3)-, -CH 2 CH 2 CH(OH)-, -CH 2 CH(0H)CH 2 -0-,
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein
• L is C(0)NH
• R 2 is phenyl substituted with 0-3 R 2a .
• Another embodiment provides a compound of Formula (I), or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the compound is selected from the examples.
• the present invention is also directed to pharmaceutical compositions useful in treating diseases associated with kinase modulation, including the modulation of receptor interacting protein kinases such as RIPK1, comprising compounds of formula (I), or pharmaceutically-acceptable salts thereof, and pharmaceutically-acceptable carriers or diluents.
• the invention further relates to methods of treating diseases associated with kinase modulation, including the modulation of receptor interacting protein kinases such as RIPK1, comprising administering to a patient in need of such treatment a
• the present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides a method for treating proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases and fibrotic diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides a method for treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the disease is inflammatory bowel disease, Crohn’s disease or ulcerative colitis, poriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), transplant rejection, nonalcoholic steatohepatitis (NASH), or ischemia reperfusion.
• a compound of formula (I) wherein the disease is inflammatory bowel disease, Crohn’s disease or ulcerative colitis, poriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), transplant rejection, nonalcoholic steatohepatitis (NASH), or ischemia reperfusion.
• the present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), transplant rejection, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi’s sarcoma, multiple myeloma, solid tumors, ocular neovasculization, and infantile haemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE), psoriatic arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, Type I diabetes, membranous nephritis, autoimmune hemolytic anemia, autoimmune thyroidit
• the present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from macrophage necrosis in atheroscelerosis development, virus-induced inflammation, systemic inflammatory response syndrome and ethanol-induced liver injury, neurodegeneration such as detachment of the retina, retinal degeneration, wet and dry age-related macular degeneration (AMD), ischemia, amyotrophic lateral sclerosis (ALS), and Gaucher’s disease.
• a compound of formula (I) wherein the condition is selected from macrophage necrosis in atheroscelerosis development, virus-induced inflammation, systemic inflammatory response syndrome and ethanol-induced liver injury, neurodegeneration such as detachment of the retina, retinal degeneration, wet and dry age-related macular degeneration (AMD), ischemia, amyotrophic lateral sclerosis (ALS), and Gaucher’s disease.
• the present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, rheumatoid arthritis (RA), heart failure, and nonalcoholic steatohepatitis (NASH).
• a compound of formula (I) wherein the condition is selected from inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, rheumatoid arthritis (RA), heart failure, and nonalcoholic steatohepatitis (NASH).
• the present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and psoriasis.
• the present invention also provides a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from nonalcoholic steatohepatitis (NASH), and ischemia reperfusion.
• NASH nonalcoholic steatohepatitis
• ischemia reperfusion a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), wherein the condition is selected from nonalcoholic steatohepatitis (NASH), and ischemia reperfusion.
• NASH nonalcoholic steatohepatitis
• ischemia reperfusion ischemia reperfusion
• the present invention also provides a method for treating rheumatoid arthritis, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I),
• the present invention also provides a method of treating diseases, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, in combination with other therapeutic agents.
• the present invention also provides the compounds of the present invention or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.
• compounds of formula (I) are selected from exemplified examples or combinations of exemplified examples or other embodiments herein.
• the present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment of cancers, an allergic disease, an autoimmune disease or an inflammatory disease.
• any variable e.g., R 3
• its definition at each occurrence is independent of its definition at every other occurrence.
• R 3 at each occurrence is selected independently from the definition of R 3 .
• combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• nitrogen atoms e.g., amines
• these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
• an oxidizing agent e.g., MCPBA and/or hydrogen peroxides
• a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
• -CONFh is attached through the carbon atom.
• the term“optionally substituted” in reference to a particular moiety of the compound of Formula (I), refers to a moiety having 0, 1, 2, or more substituents.
• “optionally substituted alkyl” encompasses both“alkyl” and“substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.
• alkyl or“alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
• “Ci_io alkyl” (or alkylene), is intended to include Ci, C2, C3, C4, C5, C6, C7, C8, C9, and CK) alkyl groups.
• C1-C6 alkyl denotes alkyl having 1 to 6 carbon atoms.
• Alkyl groups can be
• Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g, n-pentyl, isopentyl, neopentyl), and the like.
• “alkyl” when used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least one of the substituents that the substituted alkyl will contain.
• “arylalkyl” refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl.
• aryl(Co 4 )alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, i.e., aryl(Co)alkyl.
• heteroarylalkyl refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.
• alkenyl or“alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon-carbon bonds that may occur in any stable point along the chain.
• “C2-6 alkenyl” (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups.
• alkenyl include, but are not limited to, ethenyl, l-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
• Alkynyl or“alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain.
• “C2-6 alkynyl” (or alkynylene), is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
• substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group these groups are substituted with one to three substituents as defined above for substituted alkyl groups.
• alkoxy refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein.
• the term“alkoxy” includes the group -O-C , al kyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,
• “Lower alkoxy” refers to alkoxy groups having one to four carbons.
• substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded.
• Keto substituents are not present on aromatic moieties.
• substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
• a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent. It is preferred that the presently recited compounds do not contain a N-halo, S(0)2H, or S(0)H group.
• the term“carbocyclyl” or“carbocyclic” refers to a saturated or unsaturated, or partially unsaturated, monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings.
• Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
• Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
• carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,
• bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).
• Carbocycles can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term “carbocycle” is used, it is intended to include“aryl”.
• a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
• Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
• aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted.
• a preferred aryl group is optionally-substituted phenyl.
• cycloalkyl refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems.
• C3_ 7 cycloalkyl is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups.
• Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, and the like, which optionally may be substituted at any available atoms of the ring(s).
• heterocycloalkyl “heterocyclo”,“heterocycle”,“heterocyclic”, or “heterocyclyl” may be used interchangeably and refer to substituted and unsubstituted aromatic or non-aromatic 3 -to 7-membered monocyclic groups, 7-to 1 l-membered bicyclic groups, and lO-to l5-membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N.
• heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N.
• Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom.
• the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized.
• the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
• the heterocyclo group may be attached at any available nitrogen or carbon atom.
• Exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl,
• thiamorpholinyl sulfone l,3-dioxolane and tetrahydro-l,l-dioxothienyl and the like, including the exemplary groups listed under“heteroaryl”.
• exemplary bicyclic heterocyclo groups include quinuclidinyl.
• heteroaryl refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or lO-membered bicyclic groups, and 11- to l4-membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N.
• Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
• the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
• the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized.
• Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
• Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
• Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,
• benzodioxolyl benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
• Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
• aryl e.g ., phenyl
• cycloalkyl e.g, cyclohexyl
• heterocyclo e.g, pyrrolidinyl, piperidinyl, and morpholinyl
• heteroaryl e.g, tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl
• the reference is intended to include rings having 0 to 3, preferably 0-2, substituents, as appropriate.
• halo or“halogen” refers to chloro, bromo, fluoro and iodo.
• haloalkyl means a substituted alkyl having one or more halo substituents.
• “haloalkyl” includes mono, bi, and trifluorom ethyl.
• haloalkyl means a substituted alkyl having one or more halo substituents.
• “haloalkyl” includes mono, bi, and trifluorom ethyl.
• haloalkoxy means an alkoxy group having one or more halo substituents.
• “haloalkoxy” includes OCF 3.
• deuteroalkyl means a substituted alkyl having one or more deuterium atom.
• the term“deuteroalkyl” includes mono, bi, and trideuterom ethyl.
• heteroatoms shall include oxygen, sulfur and nitrogen.
• the ring or group may be fully unsaturated or partially unsaturated.
• the compounds of formula (I) may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof.
• the term“salt(s)” denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
• the term“salt(s) may include zwitterions (inner salts), e.g ., when a compound of formula (I), contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid.
• Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of the formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides,
• methanesulfonates formed with methanesulfonic acid
• 2-naphthalenesulfonates nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine,
• salts include monohydrochloride, hydrogensulfate, methane
• phrases“pharmaceutically acceptable” is employed herein to refer to those compounds, materials, 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.
• “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic,
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences , 18th ed., Mack
• Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers).
• the definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity.
• the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
• the individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
• the present invention is intended to include all isotopes of atoms occurring in the present compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• an alkyl substituent is intended to cover alkyl groups have either hydrogen, deuterium, and/or some combination thereof.
• Isotopes of carbon include 13 C and 14 C.
• Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate
• prodrugs and solvates of the inventive compounds are also contemplated.
• the term“prodrug” denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula (I), and/or a salt and/or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula (I)) is a prodrug within the scope and spirit of the invention.
• compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula (I) compounds per se.
• prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes.
• Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood.
• physiologically hydrolyzable esters of compounds of formula (I) include C 1 6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,
• alkyl e.g. acetoxy methyl, pivaloyloxymethyl or
• propionyloxy methyl C 1 6 alkoxycarbonyloxy-C 1 6 alkyl, e.g. methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,
• esters (5-methyl-2-oxo-l,3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.
• prodrug derivatives are well known in the art.
• prodrug derivatives see:
• the compounds of the invention modulate kinase activity, including the
• compounds of formula (I) have utility in treating conditions associated with the modulation of kinase activity, and particularly the selective inhibition of RIPK1 activity.
• compounds of formula (I) have advantageous selectivity for RIPK1 activity preferably from at least 20 fold to over 1,000 fold more selective over other kinases.
• the terms“treating” or“treatment” encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it;
• compounds of Formula (I) are useful in treating RIPK1 -associated conditions including, but not limited to, inflammatory diseases such as Crohn’s disease and ulcerative colitis, inflammatory bowel disease, asthma, graft versus host disease, chronic obstructive pulmonary disease;
• autoimmune diseases such as Graves’ disease, rheumatoid arthritis, systemic lupus erythematosis, psoriasis; destructive bone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myelogenous leukemia, chronic myelogenous leukemia;
• angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; infectious diseases such as sepsis, septic shock, and Shigellosis; neurodegenerative diseases such as Alzheimer’s disease,
• Parkinson’s disease ALS, cerebral ischemias or neurodegenerative disease caused by traumatic injury, oncologic and viral diseases such as metastatic melanoma, Kaposi’s sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS; fibrotic conditions such as, nonalcoholic steatohepatitis (NASH); and cardiac conditions such as, ischemia reperfusion; respectively.
• NASH nonalcoholic steatohepatitis
• cardiac conditions such as, ischemia reperfusion
• the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, ALS, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, graft vs.
• Preferred methods of treatment are those wherein the condition is selected from inflammatory bowel disease, Crohn’s disease and ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris, and nonalcoholic steatohepatitis (NASH), and ischemia reperfusion.
• the condition is selected from inflammatory bowel disease, Crohn’s disease and ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris, and nonalcoholic steatohepatitis (NASH), and ischemia reperfusion.
• NASH nonalcoholic steatohepatitis
• ischemia reperfusion injury including cerebral ischemia reperfusions injury arising from stroke and cardiac ischemia reperfusion injury arising from myocardial infarction.
• RIPK1 -associated condition or“RIPK1 -associated disease or disorder” are used herein, each is intended to encompass all of the conditions identified above as if repeated at length, as well as any other condition that is affected by RIPK1 kinase activity.
• the present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically-effective amount of at least one compound of Formula (I) or a salt thereof.
• “Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit RIPK1.
• the methods of treating RIPK1 kinase-associated conditions may comprise administering compounds of Formula (I) alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions. Accordingly, “therapeutically effective amount” is also intended to include an amount of the combination of compounds claimed that is effective to inhibit RIPK1 and/or treat diseases associated with RIPK1.
• Such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), Interleukin- 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; anti-inflammatory anti-bodies such as vedolizumab and ustekinumab, anti-infammatory kinase inhibitors such as TYK2 inhibitors, antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide
• therapeutic agents when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians’ Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
• PDR Physicians’ Desk Reference
• such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the
• the present invention also provides pharmaceutical compositions capable of treating RIPK1 kinase-associated conditions, including IL-l, IL-6, IL-8, ⁇ FNy and TNF-a-mediated conditions, as described above.
• inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g ., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical
• compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier.
• A“pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals.
• Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g ., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art.
• the compounds of Formula (I) may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin-related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated.
• the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrastemal injection or infusion techniques (e.g, as sterile injectable aq.
• Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered.
• the compounds may be administered in a form suitable for immediate release or extended release.
• Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
• compositions for topical administration include a topical carrier such as PLASTIB ASE ® (mineral oil gelled with polyethylene).
• compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
• the inventive compounds may also be orally delivered by sublingual and/or buccal administration, e.g ., with molded, compressed, or freeze-dried tablets.
• compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins.
• fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins.
• high molecular weight excipients such as celluloses (AVICEL ® ) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g, GANTREZ ® ); and agents to control release such as polyacrylic copolymer (e.g, CARBOPOL 934 ® ).
• Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
• compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
• compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, l,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, l,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary
• the therapeutically-effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day.
• the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
• Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like.
• this term“patient” is intended to include all subjects, most preferably mammalian species, that are affected by mediation of RIPK1 enzyme levels.
• HT29-L23 human colorectal adenocarcinoma cells were maintained in RPMI 1640 medium containing 10% heat-inactivated FBS, 1% Penicillin-Streptomycin and 10 mM HEPES. Cells were seeded at 2,000 cells/well in 384 well tissue culture-treated microplates (Greiner # 781090-3B) and incubated at 37 °C (5% CC>2/95% O2) for 2 d. On the day of the assay, the cells were treated with test compounds at final concentrations of 6.25 to 0.106 mM for 30 min at 37 °C (5% C02/95% O2).
• Necroptopsis was induced using a mixture of human TNFa (35 ng/mL) (Peprotech #300-01 A), SMAC mimetic (from US 2015/0322111 Al) (700 nM) and Z-VAD (140 nM) (BD pharmingen #51- 6936). Following 6 h incubation at 37 °C (5% C02/95% O2), the cells were fixed with 4% formaldehyde (ACROS 11969-0010) for 15 min at rt, then permeabilized with phosphate buffered saline (PBS) containing 0.2% Triton-X-lOO for 10 min.
• PBS phosphate buffered saline
• MLKL phosphorylation was detected using anti-MLKL (phospho S358) antibody (Abeam #ab 187091 ) (1 : 1000 dilution in Blocking Buffer [PBS supplemented with 0.1% BSA]) with ON incubation at 4 °C. After washing three times in PBS, goat anti-rabbit Alexa- 488 (1 : 1000 dilution) (Life Technologies, Al 1008) and Hoechst 33342 (Life
• the maximal inhibitory response was defined by the activity induced by Neels (CAS #: 852391-15-2, 6.25 mM).
• the IC50 value was defined as the concentration of compound that produces 50% of the maximal inhibition. The data were fitted using the 4-parameter logistic equation to calculate the IC50 and Ymax values.
• a solution was prepared containing 0.2 nM Anti GST-Tb (Cisbio, 61GSTTLB), 90.6 nM probe and 1 nM His-GST-TVMV-hRIPKl (1-324) in FRET Buffer (20 mM HEPES, 10 mM MgCl2, 0.015% Brij-35, 4mM DTT, 0.05 mg/mL BSA).
• the coding region of human RIPKl(l-324) flanked by Ndel site at 5’ end and stop codon TGA and Xhol site at 3’ end was codon optimized and gene synthesized at GenScript USA Inc. (Piscataway, NJ) and subcloned into a modified pFastBacl vector (Invitrogen, Carlsbad, CA) with N-terminal His-GST-TVMV tag, to generate His-GST- TVMV-hRIPKl (l-324)-pFB.
• GenScript USA Inc. Procataway, NJ
• Baculovirus was generated for the construct using the Bac-to-Bac baculovirus expression system (Invitrogen) according to the manufacturer’s protocol. Briefly, recombinant bacmid was isolated from transformed DHlOBac E.coli competent cells (Invitrogen) and used to transfect Spodoptera frugiperda (Sf9) insect cells (Invitrogen). Baculovirus was harvested 72 hours post transfection and a virus stock was prepared by infecting fresh Sf9 cells at a 1/1000 (v/v) ratio for 66 hours.
• Sf9 cells (Expression System, Davis, CA) grown in ESF921 insect medium (Expression System) at 2 x 106 cells/ml were infected with virus stock at a 1/100
• (v/v) ratio for 66 hours.
• the production was carried out either at a 10 L scale in a 22 L cellbag (GE Healthcare Bioscience, Pittsburgh, PA) or at a 20 L scale in a 50 L cellbag using WAVE-Bioreactor System 20/50 (GE Healthcare Bioscience).
• the infected cells were harvested by centrifugation at 2000 rpm for 20 min at 4 °C in a SORVALL® RC12BP centrifuge.
• the cell pellets was stored at -70 °C before protein was purified.
• RIPK1 containing cell paste was resuspended in 50 mM Tris pH 7.5, 150 mM NaCl, 10 mM imidazole, 5% glycerol, 5 mM MgS0 4 , 1 mM TCEP, 25 U/ml Benzonase, and Complete Protease Inhibitor tablets (1/50 ml, Roche Diagnostics, Indianapolis, IN).
• the cells were lysed by nitrogen cavitation using an unstirred pressure vessel @ 525 PSI (Parr Instrument Company, Moline, IL). The suspension was clarified by centrifugation at 136,000 x g for 40 min, at 4 °C.
• the lysate was decanted from the pellet and passed through a 5 ml NiNTA Superflow cartridge (Qiagen, Valencia, CA) using an AKTA Pure (GE Healthcare). Column was eluted with 10 CV linear gradient into 50 mM Tris 7.5,
• the yield was ⁇ 8 mg/L with a purity >95% as determined by Coomassie stain SDS-PAGE gel analysis.
• LCMS analysis of the protein showed that the protein had lost the N-terminal methionine, had one phosphorylated site, and was partially acetylated. Protein was aliquoted and stored at -80 °C. Using these assays, the IC50 values of the following compounds were determined. See Table A.
• DIEA/DIPEA/Hunig Base dii sopropyl ethyl amine
• the compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic chemistry (Maffrand, J. P. et al.,
• homochiral compounds may be prepared by separation of racemic products by chiral phase preparative HPLC.
• the example compounds may be prepared by methods known to give enantiomerically enriched products. These include, but are not limited to, the incorporation of chiral auxiliary functionalities into racemic intermediates which serve to control the diastereoselectivity of transformations, providing enantio-enriched products upon cleavage of the chiral auxiliary.
• Scheme 1 describes a synthetic route for compound 7. Hydrolysis and amide coupling can yield 3. Protection of the lH-indazole group in 3 with a para- methoxybenzyl group preceded a Buchwald reaction to yield compound 5. Deprotection under acidic conditions at elevated temperatures and hydrolysis provided compounds similar to 6. Compounds exemplified by 7 can be formed by an amide coupling mediated by BOP reagent as shown in the scheme or an alternative amide coupling reagent. ETse of an anhydride or carboxylic acid chloride may also effect this transformation.
• Scheme 2 illustrates access to compounds containing a 3 -piperidine linker (12, 13).
• Compound 3 can undergo Suzuki coupling reaction with 8 to yield compounds like 9. Reduction and deprotection of 9 can yield piperidines similar to 11.
• the analogs exemplified by compound 12 can be accessed via a single pot coupling reaction with diphosgene, followed by the addition of amines.
• Compounds exemplified by 13 can be formed by an amide coupling mediated by BOP reagent as shown in the scheme or an alternative amide coupling reagent. Use of an anhydride or carboxylic acid chloride may also effect this transformation.
• Reverse phase preparative HPLC or LCMS was carried out using Cl 8 columns eluting with gradients of Solvent A (90% water, 10% methanol, 0.1% TFA) and Solvent B (10% water, 90% methanol, 0.1% TFA, UV 220 nm), or with gradients of Solvent A (95% water, 5% acetonitrile, 0.1% TFA) and Solvent B (5% water, 95% acetonitrile, 0.1% TFA, UV 220 nm), or with gradients of Solvent A (98% water, 2% acetonitrile, 0.05% TFA) and Solvent B (98% acetonitrile, 2% water, 0.05% TFA, UV 254 nm), or with gradients of Solvent A (95% water, 5% acetonitrile with 10 mM ammonium acetate) and Solvent B (95% acetonitrile, 5% water with 10 mM ammonium acetate).
• Method A Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 mM particles; Mobile phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate;
• Mobile phase B 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75 minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
• Method B Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 mih particles; Mobile phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature: 50 °C; Gradient: 0-100% B over 3 min, then a 0.75 min hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220nm.
• Method A Column: Sunfire C18, 3.0 x 150 mm, 3.5 mM particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 0-100% B over 10 minutes; Flow: 1 mL/min; Detection: UV at 220 and 254 nm
• Method B Column: Xbridge Phenyl, 3.0 x 150 mm, 3.5 mM particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile: water with 0.1% TFA; Gradient: 0-100% B over 10 minutes; Flow: 1 mL/min; Detection: UV at 220 and 254 nm
• Method C Column: XBridge C18, 3.0 x 150 mm, 3.5 mM particles; Mobile phase A: 5:95 methanol: water with 10 mM ammonium bicarbonate; Mobile phase B: 95:5 methanol: water with 10 mM ammonium bicarbonate; Gradient: 0-100% B over 15 minutes; Flow: 1 mL/min; Detection: UV at 220 and 254 nm.
• Method D Column: XBridge Phenyl, 3.0 x 150 mm, 3.5 mM particles; Mobile phase A: 5:95 methanol: water with 10 mM ammonium bicarbonate; Mobile phase B: 95:5 methanol: water with 10 mM ammonium bicarbonate; Gradient: 0-100% B over 15 minutes; Flow: 1 mL/min; Detection: UV at 220 and 254 nm.
• 6-bromo-lH-indazole-3-carboxylic acid A solution of methyl 6-bromo-lH- indazole-3-carboxylate (5 g, 19.60 mmol) and 1 N NaOH (49.0 mL, 49.0 mmol) in MeOH (70 mL) was heated to 80 °C for 2 h. The reaction mixture was concentrated to yield a crude product which was dissolved in water (100 mL). The aqueous solution was acidified at 0 °C with 1 N HC1 solution until the pH reached about 4-5. The solid was collected as 6-bromo-lH-indazole-3-carboxylic acid (4.60 g, 19.08 mmol, 97 %).
• the reaction mixture was diluted with EtOAc (150 mL). The solution was washed with 10% LiCl solution (30 mL x 2) and brine (30 mL) and dried over Na2S0 4. Filtration and concentration yielded a crude product which was purified on a silica gel column with CFhCh/EtOAc (1/0 - 5/1) to yield methyl l-(l-(4-methoxybenzyl)-3-(methylcarbamoyl)-lH-indazol-6- yl)piperidine-3 -carboxylate (235 mg, 0.535 mmol, 29 %).
• TFA A solution of methyl l-(l-(4-methoxybenzyl)-3-(methylcarbamoyl)-lH-indazol-6- yl)piperidine-3 -carboxylate (242 mg, 0.554 mmol) in TFA (0.043 mL, 0.554 mmol) was heated to 130 °C for 45 min under microwave. The reaction mixture was concentrated to yield methyl l-(3-(methylcarbamoyl)-lH-indazol-6-yl)piperidine-3-carboxylate, TFA which was immediately used in subsequent chemistry.
• 3A ethyl 4-(l-(4-methoxybenzyl)-3-(methylcarbamoyl)-lH-indazol-6- yl)morpholine-2-carboxylate: A degassed solution of 6-bromo-l-(4-methoxybenzyl)-N- methyl-lH-indazole-3-carboxamide (195.6 mg, 0.523 mmol), ethyl morpholine-2- carboxylate (125 mg, 0.784 mmol), Pd(OAc)2 (7.04 mg, 0.031 mmol), CS2CO3 (255 mg, 0.784 mmol) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl, XPhos (24.92 mg, 0.052 mmol) in toluene (3 mL) was heated to 100 °C for 16 h.
• reaction mixture was filtered and concentrated to yield a crude product which was purified on a silica gel column with CTbCh/EtOAc (2/1) to yield ethyl 4-(l-(4-methoxybenzyl)-3- (methylcarbamoyl)-lH-indazol-6-yl)morpholine-2-carboxylate (99 mg, 0.208 mmol, 40 %).
• TFA ethyl 4-(3-(methyl carbamoyl)- lH-indazol-6-yl)morpholine-2-carboxylate
• TFA A solution of ethyl 4-(l-(4-methoxybenzyl)-3-(methylcarbamoyl)-lH-indazol-6- yl)morpholine-2-carboxylate (100 mg, 0.221 mmol) in TFA (1 mL) was heated to 130 °C for 45 min under microwave. The reaction mixture was concentrtated to yield ethyl 4-(3- (methylcarbamoyl)-lH-indazol-6-yl)morpholine-2-carboxylate, TFA which was used as is in subsequent chemistry.
• the crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: 10-60% B over 18 minutes, then a 3 -minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.
• reaction mixture was stirred at 23 °C for 1 h.
• the reaction mixture was concentrated, water (2 mL) was added and the slurry sonicated for 5 min.
• the solid was collected as tert-butyl 4-(l-(4-methoxybenzyl)-3-(methylcarbamoyl)-lH- indazol-6-yl)-2-((3-phenylbutyl)carbamoyl)piperazine-l-carboxylate (58.2 mg) which was used as is in subsequent chemistry.
• the crude material was purified via preparative LC/MS with the following conditions: Column: XB ridge Cl 8, 19 x 200 mm, 5 -pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: 15-55% B over 19 minutes, then a 5- minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.
• tert-butyl 3 -(3 -(methyl carbamoyl)- 1 H-indazol-6-yl)-5 , 6-dihy dropyridine- l(2H)-carboxylate A degassed solution of 6-bromo-N-methyl-lH-indazole-3- carboxamide (100 mg, 0.394 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-5,6-dihydropyridine-l(2h)-carboxylate (122 mg, 0.394 mmol), PdCl2(dppf)-CH2Cl2 adduct (19.28 mg, 0.024 mmol) and potassium phosphate tribasic 2 M solution (0.590 mL, 1.181 mmol) in DMF (2.0 mL) was stirred at 100 °C for 4 h.
• tert-butyl 3-(3-(methylcarbamoyl)-lH-indazol-6-yl)piperidine-l-carboxylate A suspension solution of tert-butyl 3-(3-(methylcarbamoyl)-lH-indazol-6-yl)-5,6- dihydropyridine-l(2H)-carboxylate (86.5 mg, 0.243 mmol) and Pd/C (15.50 mg, 0.015 mmol) in MeOH (5 mL) was stirred under a H2 balloon (0.489 mg, 0.243 mmol) for 24 h. The reaction mixture was filtered and concentrated to yield (64 mg, 0.179 mmol, 74 %).
• the crude product was purified using a reverse phase Isco chromatography (Combiflash RF200, 30 g Cl 8 Redisep Rf high performance gold column, solvent A: 0.1 % TFA in water/MeOH (90/10), solvent B: 0.1 % TFA in water/MeOH (10/90), flow rate: 35 mL/min, 10 - 70% B) to yield the product.
• the product was treated with 2.5 M HC1 in EtOH (0.5 mL) and concentrated to provide N-methyl-6-(piperidin-3-yl)-lH-indazole-3-carboxamide, HC1 (37 mg, 0.126 mmol, 70 %).
• the crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: 20- 60% B over 22 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.
• Table 1 The compounds in Table 1 were prepared by methods similar to those described in Example 1. All compounds are racemic unless otherwise noted.
• Table 2 The compounds in Table 1 were prepared by methods similar to those described in Example 2. All compounds are diastereomeric mixtures.
• Table 3 The compounds in Table 1 were prepared by methods similar to those described in Example 3. All compounds are racemic unless otherwise noted.

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