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WO2025166124A1 - Inhibiteurs d'ulk et leurs méthodes d'utilisation - Google Patents

Inhibiteurs d'ulk et leurs méthodes d'utilisation

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Publication number
WO2025166124A1
WO2025166124A1 PCT/US2025/013975 US2025013975W WO2025166124A1 WO 2025166124 A1 WO2025166124 A1 WO 2025166124A1 US 2025013975 W US2025013975 W US 2025013975W WO 2025166124 A1 WO2025166124 A1 WO 2025166124A1
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WO
WIPO (PCT)
Prior art keywords
group
heterocyclyl
alkyl
cycloalkyl
atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/013975
Other languages
English (en)
Inventor
Kristen L. STUEVEN
Yu Mi Ahn
Daniel L. Flynn
Andrew M. Harned
Saqib FAISAL
Hunter PICARD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Deciphera Pharmaceuticals LLC
Original Assignee
Deciphera Pharmaceuticals LLC
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Filing date
Publication date
Application filed by Deciphera Pharmaceuticals LLC filed Critical Deciphera Pharmaceuticals LLC
Publication of WO2025166124A1 publication Critical patent/WO2025166124A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Autophagy is a process that enables cells to recycle cellular organelles, proteins, stored lipids, glucagon, and other materials for the purpose of generating nutrients under periods of stress. These cellular contents are recycled by engulfment in vesicles called autophagosomes. Autophagosomes subsequently merge with lysosomes that degrade the autophagosomal contents for recycling of nutrients to the cell. Tumor cells are prone to activate autophagy, as these cells have a high metabolic demand, experience cellular stress, and frequently are in hypoxic environments with limited blood flow and nutrient supply.
  • chemotherapy and targeted anti-cancer therapies have been shown to induce autophagy as a treatment resistance mechanism, and combination of autophagy inhibition (by genetic loss of function mutations in autophagy genes or by pharmacologic means) with chemotherapeutic regimens has been shown to suppress tumor growth and trigger tumor cell apoptosis to a greater extent than single agent chemotherapy.
  • Mutant Ras proteins drive approximately 30 percent of all human cancers - including 95 percent of pancreatic cancers, 45 percent of colorectal cancers, and 30% of lung cancers, and treatment of these mutant Ras cancers is currently an area of high unmet medical need. Mutant Ras cancers are highly proliferative and depend on basal levels of autophagy for survival, suggesting that inhibition of autophagy in these “autophagy addicted” cancers is a viable therapeutic approach.
  • ULK1 kinase is the initiating protein of autophagy and is a serine/threonine kinase.
  • the ULK1 kinase complex is activated in response to cellular stress including nutrient deprivation and energy depletion.
  • Nutrient deprivation activates ULK kinase activity through inhibition of mTORCl
  • energy depletion activates ULK kinase activity through activation by AMP-activated protein kinase AMPK.
  • kinase dead mutants of ULK kinase block initiation of canonical autophagy, suggesting that small molecule inhibitors of ULK kinase activity would be able to block autophagy.
  • ULK1 inhibits autophagy in cancer cells, relieving FOX3 A turn-over and upregulation of the pro-apoptotic protein PUMA.
  • ULK1 kinase activity has been shown to be required for Bcl-2-L-13 mediated mitophagy (autophagy of damaged mitochondria).
  • ULK1 and ULK2 kinases have also been demonstrated to rewire cancer cell glucose metabolism which favors increases in the reducing agent NADPH leading to a reduction in toxic reactive oxygen species (ROS).
  • ROS toxic reactive oxygen species
  • Autophagy is also upregulated in host cells and tissues in cancer.
  • Autophagy in pancreatic tissue stellate cells was demonstrated to support tumor growth.
  • Pancreatic stellate cells were shown to support pancreatic cancer tumor metabolism through autophagic alanine secretion.
  • Inhibition of host tissue autophagy was demonstrated to lead to a depletion in circulating arginine (a required amino acid for tumor metabolism and growth) through liver -mediated increases in arginase secretion.
  • Activation of ULK1 kinase was also shown to inactivate the STING pathway in immune cells through inhibitory phosphorylation of STING, mediating a negative feedback mechanism for limiting an innate immune cell response mediated by interferons.
  • cancer call nonautonomous to support tumor survival and growth.
  • Mutant Ras cancers are addicted to autophagy. In pancreatic cancer, mutant Ras signals predominantly through the MAP kinase pathway. Mutant Ras activates RAF kinases, which in turn activate MEK kinases, which finally activate ERK kinases: mutant Ras ERK. Despite mutant Ras signaling through the MAP kinase pathway, inhibitors of this pathway have provided no or little clinical benefit in clinical trials when used as single agents. It has been recently reported that inhibition of the MAP kinase pathway induces autophagy as a compensatory adaptive stress response resistance mechanism.
  • RTKs tumor driver receptor tyrosine kinases
  • Inhibitors of mutant oncogenic KIT kinase, inhibitors of oncogenic EGFR kinase, and inhibitors of oncogenic FLT3 kinase are known to activate autophagy as an adaptive stress response resistance mechanism; hence there is rationale for combining this class of targeted therapeutics with inhibitors of autophagy.
  • Described herein are compounds that are inhibitors of autophagy, pharmaceutical compositions, and their use as agents in the treatment of disorders such as cancer, processes for their preparation, and pharmaceutical compositions containing them as an active ingredient.
  • Such pharmaceutical compositions may comprise the compound as the sole active agent or in combination with other active agents in the presence of a pharmaceutically acceptable excipient.
  • the described compounds are inhibitors of ULK kinase activity, including ULK1 and ULK2 activity.
  • A is selected from the group consisting of heteroaryl and aryl
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when W is N, R 6 is Cl or CF3, R 7 and U taken together with the
  • A is selected from the group consisting of heteroaryl and aryl;
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and
  • a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein) and a pharmaceutically acceptable carrier or excipient.
  • a compound described herein e.g., a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein
  • a pharmaceutically acceptable carrier or excipient
  • a method of treating a tumor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or of a pharmaceutical composition described herein.
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound described herein or pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof, or of a pharmaceutical composition described herein.
  • the method further comprises administering to the patient one or more additional therapeutic agents.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
  • substituents and substitution patterns on the disclosed compounds can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result.
  • “optionally substituted” refers to the replacement of one to four hydrogen atoms in a given structure with the substituents mentioned above. More preferably, one to three hydrogen atoms are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a hetero
  • substituents can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like.
  • references to chemical moieties herein are understood to include substituted variants.
  • reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • alkyl refers to a straight chained or branched non- aromatic hydrocarbon which is completely saturated.
  • a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10, e.g., may be Ci-Cioalkyl or e.g., Ci-Cealkyl unless otherwise defined.
  • straight chained and branched alkyl groups include, but are not limited to, methyl, ethyl, 1 -propyl (n- propyl), 2-propyl, n-butyl, sec-butyl, tertbutyl, 1 -pentyl, 2-pentyl, 3 -pentyl, neo-pentyl, 1- hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4- octyl and the like.
  • alkyl used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • the “alkyl” group may be optionally substituted.
  • C x -C y when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • C x -C y refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
  • Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • the “hydrocarbyl” group may be optionally substituted.
  • alkoxy refers to a straight or branched, saturated aliphatic (alkyl) hydrocarbon radical bonded to an oxygen atom that is attached to a core structure.
  • alkoxy groups have one to six carbon atoms, z.e., may be C1-C6 alkoxy.
  • alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methyl butoxy and the like.
  • the “alkoxy” group may be optionally substituted.
  • alkoxyalkyl refers to an alkyl group (as defined above) substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkoxyalkyl groups include but are not limited to methyl-O- ethylene-, ethyl-O-ethylene-.
  • the “alkoxyalkyl” group may be optionally substituted.
  • haloalkyl refers to alkyl group (as defined above) is substituted with one or more halogens.
  • a monohaloalkyl radical for example, may have a chlorine, bromine, iodine, or fluorine atom.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms.
  • haloalkyl examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, di chloroethyl, di chloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, and the like.
  • the “haloalkyl” group may be optionally substituted.
  • haloalkoxy refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens.
  • Representative examples of “haloalkoxy” groups include, but not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3).
  • the “haloalkoxy” group may be optionally substituted.
  • aryl includes substituted or unsubstituted singlering aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (fused rings) wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • fused means that the second ring is attached or formed by having two adjacent atoms in common with the first ring.
  • the term “fused” is equivalent to the term “condensed”.
  • aryl groups include but are not limited to phenyl, naphthyl, phenanthryl, phenol, aniline, or indanyl and the like. Unless otherwise specified, all aryl groups described herein may be optionally substituted.
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which one or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • examples of “acyl” include, but are not limited to, instances where R w is Ci-Cioalkyl (Ci-Cioacyl) or Ci-Ce-alkyl (Ci-Ceacyl).
  • each occurrence of the optionally substituted substituent is independently selected from the group consisting of H, OH, alkoxy, cyano, F, and amino.
  • sulfonamide and “sulfonamido” is represented by: wherein R x , R y and R z , at each occurrence, independently represents a hydrogen, optionally substituted hydrocarbyl group, or R z groups taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure which may be optionally substituted.
  • amine and “amino” refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by: or wherein R z independently represent a hydrogen or optionally substituted hydrocarbyl group, or R z groups are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure which may be optionally substituted.
  • amide and “amido” each refer to a group represented by: wherein R x , R y , and R z each independently represents a hydrogen or optionally substituted hydrocarbyl group, or R y and R z are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure which may be optionally substituted.
  • amidine refers to a group represented by wherein R x , R y , and R z each independently represents a hydrogen or optionally substituted hydrocarbyl group, or R y , and R z groups are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure which may be optionally substituted.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • amidoalkyl refers to an alkyl group substituted with an amido group.
  • cyanoalkyl refers to an alkyl group substituted with a cyano group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl-S-.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • hydroxy alkyl refers to an alkyl group substituted with a hydroxy group.
  • cycloalkyl alone or in combination with other term(s) refers to a cyclic hydrocarbon which is completely saturated.
  • “Cycloalkyl” includes monocyclic, bicyclic, and tricyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms (e.g., Cs-Ciocycloalkyl or e.g., Cs-Cecycloalkyl unless otherwise defined.
  • Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • the second ring of a bicyclic cycloalkyl or, the second or third rings of a tricyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • Cycloalkyl includes bicyclic and tricyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused cycloalkyl” refers to a bicyclic or tricyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl or, the second or third rings of a fused tricyclic cycloalkyl may be selected from saturated, unsaturated, and aromatic rings.
  • a “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl -substituted alkyls, -CF3, -CN, and the like.
  • a cycloalkyl may alternatively be polycyclic with more than two rings. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.
  • cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group.
  • the terms “carbocycle,” or “carbocyclic” include bicyclic or tricyclic rings in which one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • carbocyclic Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1, 2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • fused carbocycles include decalin, 4,5- naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene.
  • Carbocycles may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • cyano refers to -CN group.
  • hydroxy or “hydroxyl” refers to -OH group.
  • halo or “halogen” alone or in combination with other term(s) means chloro, fluoro, bromo, and iodo.
  • heteroatom refers an atom of any element other than carbon or hydrogen.
  • exemplary heteroatoms are nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).
  • heterocyclyl refers to a non-aromatic, saturated or partially saturated, including monocyclic, polycyclic (e.g., bicyclic, tricyclic) bridged, or fused, ring system of 3 to 15 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH or C(O) with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • heterocyclyl examples include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyl and N-oxides thereof.
  • heterocycloalkyl refers to 5- to 6-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl and N-oxides thereof.
  • heterocyclyl includes azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl. All heterocyclyl are optionally substituted by one or more aforesaid groups.
  • heteroaryl refers to substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl also refers to substituted or unsubstituted aromatic or partly aromatic ring systems containing at least one heteroatom and having two or more cyclic rings (bicyclic, tricyclic, or polycyclic), containing 8 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be linked covalently, or fused in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • the rings may contain an N or S atom, wherein the N or S atom is optionally oxidized, or the N atom is optionally quatemized. All heteroaryls are optionally substituted. Any suitable ring position of the heteroaryl moiety may be covalently linked to a defined chemical structure.
  • heteroaryl examples include, but are not limited to: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, IH-tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl
  • sulfone or “sulfonyl” refer to the group -S(O)2-R 6d wherein R 6d represents an optionally substituted hydrocarbyl.
  • a ring refers to a single or double bond, as valency permits and which results in the formation of a stable ring moiety.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbol “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. These compounds may also be designated by “(+)” and based on their optical rotation properties. The presently described compounds encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the symbol “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Individual enantiomers and diastereomers of the disclosed compounds can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents.
  • Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
  • the disclosure also embraces isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • a compound of the disclosure may have one or more H atom replaced with deuterium.
  • deuterated mean that at least one hydrogen atom is replaced by deuterium. In any sample of a deuterated compound, some discrete molecules of the compound will likely have hydrogen, rather than deuterium, at the specified position. However, the percent of molecules of the deuterated compound which have deuterium at the specified position will be much greater than would naturally occur. The deuterium at the deuterated position is enriched.
  • a compound described herein can be formulated as a pharmaceutical composition using a pharmaceutically acceptable carrier and administered by a variety of routes.
  • such compositions are for oral administration.
  • compositions formulated for oral administration are provided as tablets.
  • such compositions are for parenteral (by injection) administration.
  • such compositions are for transdermal administration.
  • such compositions are for topical administration.
  • such compositions are for intravenous (IV) administration.
  • such compositions are for intramuscular (IM) administration.
  • Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds., 19 th ed., Mack Publishing Co., 1995).
  • “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • the compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in compounds used in the compositions.
  • compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulf
  • Disease Disease
  • disorder disease
  • condition condition
  • mammals including mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and humans.
  • the compounds described herein can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • veterinary treatment e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • the mammal treated in the methods described herein is desirably a mammal in which treatment of a disorder described herein is desired, such as a human.
  • a “combination therapy” as used herein is a treatment that includes the administration of two or more therapeutic agents, e.g., a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (le- 1 ), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and an additional therapeutic agent described herein, to a patient in need thereof.
  • two or more therapeutic agents e.g., a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (le- 1 ), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and an additional therapeutic agent described herein, to a patient
  • a “RAS/MAPK pathway inhibitor” is an inhibitor of the RAS/MAPK signaling pathway.
  • Inhibitors of this pathway include Ras inhibitors (e.g., AMG-510 (sotorasib), MRTX849 (adagrasib), GDC-6036, MRTX-1133, RMS-9805, RMC-6291, and RMC-6236, and pharmaceutically acceptable salts thereof), RAF inhibitors (e.g., LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, encorafenib, DCC-3084, belvarafenib, KIN-2787, and VS-6766, and pharmaceutically acceptable salts thereof), MEK inhibitors (e.g., trametinib, selumetinib, cobimetinib, and binimetinib, and pharmaceutically acceptable salts thereof), and ERK inhibitors (e.g., ulf
  • a “RTK pathway inhibitor” is an inhibitor of the RTK (Receptor Tyrosine Kinase) signaling pathway.
  • Inhibitors of this pathway include KIT inhibitors (e.g, ripretinib, avapritinib, sunitinib, AZD3229 (NB003), THE-630, imatinib, midostaurin, bezuclastinib, olverembatinib (HQP1351), famitinib, IDRX-42 (M4205), elenestinib, BLU-808, IDRX-73, SLRN-517, THB335, pexidartinib, and regorafenib, and pharmaceutically acceptable salts thereof), EGFR inhibitors (e.g, erlotinib, gefitinib, osimertinib, cetuximab, and pharmaceutically acceptable salts thereof), PDGFRa inhibitors (e.g., ava
  • “Therapeutically effective amount” includes the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • a compound described herein e.g., the compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, is administered in therapeutically effective amounts to treat a condition described herein.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with the condition.
  • treating includes any effect, e.g. , lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
  • compounds of the disclosure comprise compounds of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (Ib-1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.
  • A is selected from the group consisting of heteroaryl and aryl
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when W is N, R 6 is Cl or CF3, R 7 and U taken together with the
  • A is selected from the group consisting of heteroaryl and aryl
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO2R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when R 6 is Cl or CF3, R 7 and U taken together with the nitrogen atom to which they are attached form a piperidine, L is bond, and Z is N(R 8 )SO2
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • X 1 is selected from the group consisting of N and CR 1 ;
  • X 2 is selected from the group consisting of N and CR 2 ;
  • X 3 is selected from the group consisting of N and CR 3 ;
  • X 4 is selected from the group consisting of N and CR 4 ;
  • X 5 is selected from the group consisting of N and CR 5 ; wherein not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N;
  • R 1 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when R 6 is Cl or CF3, R 7 and U taken together with the nitrogen atom to
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • X 1 is selected from the group consisting of N and CR 1 ;
  • X 2 is selected from the group consisting of N and CR 2 ;
  • X 3 is selected from the group consisting of N and CR 3 ;
  • X 4 is selected from the group consisting of N and CR 4 ;
  • X 5 is selected from the group consisting of N and CR 5 ; wherein not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N;
  • R 1 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • X 1 is selected from the group consisting of N and CR 1 ;
  • X 2 is selected from the group consisting of N and CR 2 ; wherein not more than one of X 1 and X 2 are N;
  • R 1 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 2 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when R 6 is Cl or CF3, R 7 and U taken together with the nitrogen atom to
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • X 1 is selected from the group consisting of N and CR 1 ;
  • X 2 is selected from the group consisting of N and CR 2 ; wherein not more than one of X 1 and X 2 are N;
  • R 1 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 2 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, cycloalkyl, and heterocyclyl
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when R 6 is Cl or CF3, R 7 and U taken together with the nitrogen atom to
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl, provided that when
  • Formula (I-I) is a compound represented by Formula (I-I): Formula (I-I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein:
  • A is selected from the group consisting of heteroaryl and aryl
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • A is selected from the group consisting of heteroaryl and aryl
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • N(R 18 )SO 2 NR 19 R 28 , -SO 2 R 29 , -S(O)( NH)-R 10 , X 1 is selected from the group consisting of N and CR 1 ;
  • X 2 is selected from the group consisting of N and CR 2 ;
  • X 3 is selected from the group consisting of N and CR 3 ;
  • X 4 is selected from the group consisting of N and CR 4 ;
  • X 5 is selected from the group consisting of N and CR 5 ; wherein not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N;
  • R 1 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • X 1 is selected from the group consisting of N and CR 1 ;
  • X 2 is selected from the group consisting of N and CR 2 ;
  • X 3 is selected from the group consisting of N and CR 3 ;
  • X 4 is selected from the group consisting of N and CR 4 ;
  • X 5 is selected from the group consisting of N and CR 5 ; wherein not more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N;
  • R 1 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • X 1 is selected from the group consisting of N and CR 1 ;
  • X 2 is selected from the group consisting of N and CR 2 ; wherein not more than one of X 1 and X 2 are N;
  • R 1 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 2 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • X 1 is selected from the group consisting of N and CR 1 ;
  • X 2 is selected from the group consisting of N and CR 2 ; wherein not more than one of X 1 and X 2 are N;
  • R 1 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 2 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • X 1 is N and X 2 is CH. In other embodiments, X 1 is CH and X 2 is N.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and
  • alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , - O
  • R 4 is selected from the group consisting of H, halogen, cyano, amino, amido, alkyl, cycloalkyl, and heterocyclyl, or wherein R 3 and R 4 together with the carbon atoms to which they are attached form a cycloalkyl ring or a heterocyclyl ring, having from 4 to 7 atoms in the ring structure, or a heteroaryl ring having from 4 to 6 atoms in the ring structure;
  • R 5 is selected from the group consisting of H, halogen, cyano, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclyl;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 30 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; and R 31 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbam
  • R 3 is selected from the group consisting of
  • R 3 is selected from the group consisting of
  • R 15 at each occurrence, is independently selected from the group consisting of H, halogen, amino, cyano, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 15 s, taken together with the carbon atom to which they are attached form an optionally substituted ring having from 4 to 6 atoms in the ring structure;
  • R 16 at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 16 s, taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and t, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, or heterocyclyl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulf
  • R 15 is independently selected from the group consisting of wherein R 25 , at each occurrence, is independently selected from the group consisting of H, halogen, amino, cyano, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 25 , taken together with the carbon atom to which they are attached form an optionally substituted ring having from 4 to 6 atoms in the ring structure;
  • R 26 at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 26 , taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and t, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, or heterocyclyl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulf
  • R 15 is selected from the group consisting of
  • R 16 is selected from the group consisting of H, alkyl, alkylamino, cycloalkyl, wherein R 25 , at each occurrence, is independently selected from the group consisting of H, halogen, amino, cyano, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 25 , taken together with the carbon atom to which they are attached form an optionally substituted ring having from 4 to 6 atoms in the ring structure; and R 26 is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, or heterocyclyl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxy
  • R 16 is selected from the group consisting of
  • R 3 and R 4 combine to form a ring selected from the group consisting of wherein R 34 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl. In some embodiments, R 34 is selected from the group consisting of alkyl, and heterocyclyl.
  • R 3 and R 4 combine to form a ring selected from the group consisting of
  • Formula (Id) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: is a single bond or a double bond;
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO2R 9 , -
  • X 11 is selected from the group consisting of N, NR 11 and CR 21 ;
  • X 12 is selected from the group consisting of N, NR 12 and CR 22 ;
  • X 13 is selected from the group consisting of N, NR 13 and CR 23 ;
  • X 14 is selected from the group consisting of N, NR 14 and CR 24 ;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 11 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 12 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl
  • R 13 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, and heterocycloalkyl;
  • R 14 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 21 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 22 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, amidoalkyl, and heterocycloalkyl;
  • R 23 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, amidoalkyl, and heterocycloalkyl;
  • R 24 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • X 11 is selected from the group consisting of N, NR 11 and CR 21 ;
  • X 12 is selected from the group consisting of N, NR 12 and CR 22 ;
  • X 13 is selected from the group consisting of N, NR 13 and CR 23 ;
  • X 14 is selected from the group consisting of N, NR 14 and CR 24 ;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl
  • R 11 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 12 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 13 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, and heterocycloalkyl;
  • R 14 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 21 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 22 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, amidoalkyl, and heterocycloalkyl;
  • R 23 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, amidoalkyl, and heterocycloalkyl;
  • R 24 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO2R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 13 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, and heterocycloalkyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 21 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl
  • R 24 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 13 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, and heterocycloalkyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 21 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 24 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalk
  • Formula (Id-1) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: is a single bond or a double bond;
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO2R 9 , -
  • N(R 18 )SO 2 NR 19 R 28 , -SO2R 29 , -S(O)( NH)-R 10 , vii IS selected from the group consisting of N, NR 11 and CR 21 ;
  • IS selected from the group consisting of N, NR 12 and CR 22 ;
  • IS selected from the group consisting of N, NR 13 and CR 23 ;
  • X is selected from the group consisting of N, NR 14 and CR 24 ;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 IS selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 IS selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 IS selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 11 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 12 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 13 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, and heterocycloalkyl;
  • R 14 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 21 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 22 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, amidoalkyl, and heterocycloalkyl;
  • R 23 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, amidoalkyl, and heterocycloalkyl;
  • R 24 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and
  • alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO2R 9 , -
  • X 11 is selected from the group consisting of N, NR 11 and CR 21 ;
  • X 12 is selected from the group consisting of N, NR 12 and CR 22 ;
  • X 13 is selected from the group consisting of N, NR 13 and CR 23 ;
  • X 14 is selected from the group consisting of N, NR 14 and CR 24 ;
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 11 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 12 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 13 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, and heterocycloalkyl;
  • R 14 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 21 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 22 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, amidoalkyl, and heterocycloalkyl;
  • R 23 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, amidoalkyl, and heterocycloalkyl;
  • R 24 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • Formula (Ie-1) is a pharmaceutically acceptable salt, enantiomer, stereoisomer, or t
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 13 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, and heterocycloalkyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 21 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl
  • R 24 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 32 is selected from the group consisting of H, alkyl, and cycloalkyl; m is 0, 1, or 2; and q, at each occurrence, is independently selected from the group consisting of 1, 2, and wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • W is selected from the group consisting of N and CH;
  • L is selected from the group consisting of a bond, alkyl, cycloalkyl, and heterocyclyl;
  • Z is selected from the group consisting of H, cyano, -N(R 8 )SO 2 R 9 , -
  • R 6 is selected from the group consisting of halogen, cyano, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
  • R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 9 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 10 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl;
  • R 13 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, cyanoalkyl, aminoalkyl, and heterocycloalkyl;
  • R 18 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl;
  • R 19 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl;
  • R 21 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 24 is selected from the group consisting of H, halogen, cyano, alkyl, cycloalkyl, and heterocyclyl;
  • R 28 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and
  • R 29 is selected from the group consisting of amino, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • R 13 is selected from the group consisting of wherein R 35 is selected from the group consisting of H, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, and heterocyclyl, or wherein two occurrences of R 35 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and wherein n is 2, 3, or 4.
  • R 13 is selected from the group consisting of wherein R 35 is selected from the group consisting of H, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, and heterocyclyl, or wherein two occurrences of R 35 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and wherein n is 2, 3, or 4.
  • R 35 is selected from the group consisting of H alkyl, deuterated alkyl, haloalkyl, cycloalkyl, and heterocyclyl, or wherein two occurrences of R 35 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 5 to 6 atoms in the ring structure; and wherein n is 2 or 3.
  • R 13 is selected from the group consisting of
  • R 13 is selected from the group consisting of wherein R 15 , at each occurrence, is independently selected from the group consisting of H, halogen, amino, cyano, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 15 , taken together with the carbon atom to which they are attached form an optionally substituted ring having from 4 to 6 atoms in the ring structure;
  • R 16 at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, or heterocyclyl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulfone, sulfonamide, heterocyclyl, or heteroaryl.
  • R 15 is independently selected from the group consisting of wherein R 25 , at each occurrence, is independently selected from the group consisting of H, halogen, amino, cyano, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 25 , taken together with the carbon atom to which they are attached form an optionally substituted ring having from 4 to 6 atoms in the ring structure;
  • R 26 at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 26 , taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure; and t, at each occurrence, is independently selected from the group consisting of 1, 2, and 3; wherein the alkyl, cycloalkyl, or heterocyclyl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, oxo, amino, alkylamino, amide, acyl, carbamoyl, sulf
  • R 15 is selected from the group consisting of
  • R 16 is selected from the group consisting of H, alkyl, alkylamino, cycloalkyl, wherein R 25 , at each occurrence, is independently selected from the group consisting of H, halogen, amino, cyano, alkyl, cycloalkyl, and heterocyclyl, or wherein two R 25 , taken together with the carbon atom to which they are attached form an optionally substituted ring having from 4 to 6 atoms in the ring structure; and R 26 is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; wherein the alkyl, cycloalkyl, or heterocyclyl, at each occurrence, is optionally substituted with one or more independent occurrences of halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxy
  • R 16 is selected from the group consisting of
  • W is N. In other embodiments, W is CH.
  • R 6 is selected from the group consisting of alkyl, haloalkyl, halogen, cyano, and cycloalkyl. In some embodiments, R 6 is selected from the group consisting of Cl, Br, CN, CF3, and
  • R 7 is H.
  • U is absent.
  • U is selected from the group consisting of
  • U is selected from the group consisting of
  • U and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 8 atoms in the ring structure. In some embodiments, U and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure. In some embodiments, U and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 atoms in the ring structure. In some embodiments, U and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 5 atoms in the ring structure. In some embodiments, U and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 6 atoms in the ring structure.
  • U and R 7 taken together is selected from the group consisting of
  • U and R 7 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 8 atoms in the ring structure and when L is bond, said optionally substituted heterocyclyl ring, together with L and Z may form a spirocyclic heterocyclyl ring having from 8 to 14 atoms in the spirocyclic ring structure.
  • U and R 7 taken together with the nitrogen atom to which they are attached is selected from the group consisting of wherein si is the site attached to the ring containing N and W and s2 is the site attached to L- Z.
  • L is a bond and Z is H.
  • U and R 7 taken together with the nitrogen atom to which they are attached is selected from the group consisting of wherein si is the site attached to the ring containing N and W and s2 is the site attached to L- Z.
  • L is a bond and Z is H.
  • U and R 7 taken together with the nitrogen atom to which they are attached is selected from the group consisting of wherein si is the site attached to the ring containing N and W and s2 is the site attached to L- Z, and wherein each occurrence of R 25 is independently selected from the group consisting of H, and alkyl.
  • L is a bond and Z is H.
  • L is selected from the group consisting of a direct bond, . In some embodiments, L is a direct bond.
  • Z is selected from the group consisting of -N(R 8 )SO2R 9 and -N(R 18 )SO 2 NR 19 R 28 .
  • R 8 is selected from the group consisting of H, and alkyl
  • R 9 is selected from the group consisting of amino, alkyl, and cycloalkyl, or wherein R 8 and R 9 taken together with the nitrogen and sulfur atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure;
  • R 18 is selected from the group consisting of H, and alkyl
  • R 19 is selected from the group consisting of H, and alkyl
  • R 28 is selected from the group consisting of H, and alkyl, or wherein R 18 and R 28 taken together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure, or wherein R 19 and R 28 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl ring having from 4 to 6 atoms in the ring structure [000140]
  • Z is H.
  • Z is selected from the group consisting of cyano, -
  • Z is selected from the group consisting of NHSO2NH2,
  • Z is selected from the group consisting of cyano
  • R 29 is selected from the group consisting of alkyl, cycloalkyl, and amino. In some embodiments, R 29 is selected from the group consisting of CH 3 , CH2CH3, CH(CH 3 ) 2 , CH 2 CH(CH 3 )2, NH 2 , and NHCH 3 .
  • R 10 is CH 3 .
  • L is a bond
  • R 29 is selected from the group consisting of alkyl, cycloalkyl, and amino. In some embodiments, R 29 is selected from the group consisting of CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 )2, NH 2 , and NHCH 3 .
  • R 10 is CH 3 .
  • Compounds described herein can act as inhibitors of autophagy useful in the treatment of a disorder in a patient in need thereof.
  • the disorder for example, can be a tumor, e.g., a solid tumor.
  • the disorder may also be cancer.
  • Exemplary disorders also include gastrointestinal stromal tumors, esophageal cancers, gastric cancers, melanomas, gliomas, glioblastomas, gynecological cancers (e.g., ovarian cancers, cervical cancers, uterine cancers, vaginal cancers, and vulvar cancers), bladder cancers, pancreatic cancers, prostate cancers, lung cancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas, Ewing sarcoma, multiple myelomas, leukemias, cancers that are metastatic to bone, papillary thyroid carcinomas, non-small cell lung cancer, colorectal cancers, acute myeloid leukemia, relapsed acute myeloid leukemia, refractory acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myeloprolif
  • a cancer treated by the methods described herein may be a metastatic cancer.
  • the compounds described herein are useful for the treatment of cancers caused by RAS mutation.
  • the cancer is caused by a KRAS mutation.
  • the cancer has additional mutations in tumor suppressor proteins, including mutations in TP53, PTEN, CDN2A/INK4A, pl6, or STAG2. In some embodiments, these additional mutations occur in one or more of TP53, PTEN, CDN2A/INK4A, pl 6, or STAG2.
  • the cancer is pancreatic ductal adenocarcinoma.
  • the cancer is lung cancer.
  • the cancer is colorectal.
  • the cancer is acute myeloid leukemia.
  • determination of cellular inhibition of autophagy by compounds described herein is determined by monitoring of autophagic flux, for instance by monitoring inhibition of autophagy-mediated clearance of mCherry/GFP-LC3 fusion protein. In some embodiments, determination of cellular inhibition of autophagy by compounds described herein is determined by monitoring of accumulation of autophagic proteins such as p62 or LC-3. In some embodiments, determination of cellular inhibition of autophagy by compounds described herein is determined by decreased clearance of luciferase-tagged LC3 protein. In some embodiments, determination of cellular inhibition of autophagy by compounds described herein is determined by monitoring decreases in cellular autophagosomes, for instance by measurement of fluorescent puncta with the autophagosome marker Cyto-ID.
  • cellular inhibition of ULK kinase by compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates including ATG13, ATG14, Beclin 1, or STING either in tumor cells or in non-tumor host tissues. In some embodiments, cellular inhibition of ULK kinase by compounds described herein is determined in host tissues including immune cells. [000158] In some embodiments, in vivo inhibition of autophagy by compounds described herein is determined by inhibition of phosphorylation of cellular ULK substrates including ATG13, ATG14, Beclin 1, or STING either in tumor cells or in non-tumor host tissues.
  • in vivo inhibition of ULK kinase by compounds described herein is determined in host tissues including immune cells.
  • the in vivo inhibition of autophagic flux by compounds described herein can be used as a pharmacodynamic model for monitoring the kinetics and extent of such ULK inhibition.
  • in vivo inhibition of ULK kinase by compounds described herein is determined in pancreatic cancer-bearing animals.
  • in vivo inhibition of ULK kinase by compounds described herein is determined in lung cancer-bearing animals.
  • in vivo inhibition of ULK kinase is determined in colorectal cancerbearing animals.
  • in vivo inhibition of autophagy by compounds described herein is determined by inhibition of autophagic flux in tumor cells, or in nontumor host tissues by monitoring inhibition of autophagosome formation, or by accumulation of autophagic proteins such as p62 or LC-III. In some embodiments, in vivo inhibition of autophagy is determined in host tissues including immune cells. In some embodiments, the in vivo inhibition of autophagic flux can be used as a pharmacodynamic model for monitoring the kinetics and extent of such ULK inhibition.
  • inhibition of autophagy and anti-tumor activity by compounds described herein are evaluated in xenograft studies utilizing human RAS mutant cell lines in immunocompromised mice, for instance in SCID or nude mice.
  • inhibition of autophagy and anti-tumor activity by compounds described herein are evaluated in xenograft studies utilizing human RAS mutant patient-derived tumor xenografts (PDXs) in immunocompromised mice, for instance in SCID or nude mice.
  • PDXs patient-derived tumor xenografts
  • xenograft studies include evaluation of compounds described herein in pancreatic cancer models.
  • xenograft studies include evaluation of compounds described herein in lung cancer models.
  • xenograft studies include evaluation of compounds described herein in colorectal cancer models. In some embodiments, xenograft studies include evaluation of compounds described herein in acute myeloid leukemia models. In some embodiments, inhibition of autophagy and anti-tumor activity by compounds described herein are evaluated in syngeneic murine genetically engineered models (GEMs) of mutant RAS cancers.
  • GEMs syngeneic murine genetically engineered models
  • inhibition of autophagy and anti-tumor activity by compounds described herein are evaluated in the murine GEM syngeneic orthotopic pancreatic cancer model known as the KPC model (LSL- Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-l-Cre) or variants of the KPC model.
  • KPC model LSL- Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-l-Cre
  • compounds described herein will be evaluated in xenograft or GEM cancer models in combination with a MEK inhibitor. In some embodiments, compounds described herein will be evaluated in xenograft or GEM cancer models in combination with a RAF inhibitor. In some embodiments, compounds described herein will be evaluated in xenograft or GEM cancer models in combination with an ERK inhibitor. In some embodiments, compounds described herein will be evaluated in xenograft or GEM cancer models in combination with a RAS G12C direct inhibitor.
  • inhibition of autophagy and anti-tumor activity by compounds described herein is evaluated in immunocompetent murine cancer models to assess an immunomodulatory component to the mechanism of action of ULK inhibitors.
  • the immunocompetent murine model is the murine GEM syngeneic orthotopic pancreatic cancer model known as the KPC model (LSL-Kras G12D/+ ;LSL- Trp53 R172H/+ ;Pdx-l-Cre) or variants of the KPC model.
  • immunomodulatory properties of compounds described herein are evaluated in combination with a MEK inhibitor.
  • immunomodulatory properties of compounds described herein are evaluated in combination with a RAF inhibitor.
  • immunomodulatory properties of compounds described herein are evaluated in combination with an ERK inhibitor.
  • immunomodulatory properties of compounds described herein are evaluated in combination with a RAS G12C direct inhibitor.
  • the immunomodulatory component of ULK inhibition is an enhanced innate immune response. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced adaptive immune response. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced activity of antigen-presenting cells. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced anti-tumor activity of myeloid cells including macrophages. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced anti-tumor activity of Natural Killer cells. In some embodiments, the immunomodulatory component of ULK inhibition is an enhanced activity of effector T Cells, including cytotoxic T Cells.
  • a method of treating a disorder described herein that includes: administering a therapeutically effective amount of compound described herein in a patient in need thereof, and during or after the course of administration (e.g., at discrete time points, such as one week, two weeks, or on month after initial administration of a contemplated compound) detecting the engagement of the compound with an ULK kinase, wherein detecting comprises contacting a sample obtained from the patient (including but not limited to a tumor, blood, saliva, or tissue) with a phospho- ATG13 antibody ELISA assay to detect inhibition of ULK kinase activity, e.g., based on the level of phospho- ATG13 in the sample.
  • a contemplated method comprises optionally contacting a sample obtained from the patient (including but not limited to a tumor, blood, saliva, or tissue) prior to administration of the compound with a phospho- ATG13 antibody ELISA assay, and comparing the level of phospho- ATG13 in the sample obtained prior to administration with the level of phospho- ATG13 in the sample obtained during or after the course of administration.
  • the phospho-ATG13 is p- S318ATG13.
  • a method of treating a disorder described herein that includes: administering a therapeutically effective amount of compound described herein in a patient in need thereof, and during or after the course of administration (e.g., at discrete time points, such as one week, two weeks, or on month after initial administration of a contemplated compound) detecting the engagement of the compound with an ULK kinase, wherein detecting comprises contacting a sample obtained from the patient (including but not limited to a tumor, blood, saliva, or tissue) with a phospho-ATG14 antibody ELISA assay to detect inhibition of ULK kinase activity, e.g., based on the level of phospho-ATG14 in the sample.
  • a contemplated method comprises optionally contacting a sample obtained from the patient (including but not limited to a tumor, blood, saliva, or tissue) prior to administration of the compound with a phospho- ATG14 antibody ELISA assay, and comparing the level of phospho-ATG14 in the sample obtained prior to administration with the level of phospho-ATG14 in the sample obtained during or after the course of administration.
  • the phospho-ATG14 is p- ATG14 Ser29.
  • a method of treating a disorder described herein that includes: administering a therapeutically effective amount of compound described herein in a patient in need thereof, and during or after the course of administration (e.g., at discrete time points, such as one week, two weeks, or on month after initial administration of a contemplated compound) detecting the engagement of the compound with an ULK kinase, wherein detecting comprises contacting a sample obtained from the patient (including but not limited to a tumor, blood, saliva, or tissue) with a p62 antibody ELISA assay to detect inhibition of ULK kinase activity, e.g., based on the level of p62 in the sample.
  • a contemplated method comprises optionally contacting a sample obtained from the patient (including but not limited to a tumor, blood, saliva, or tissue) prior to administration of the compound with a p62 antibody ELISA assay, and comparing the level of p62 in the sample obtained prior to administration with the level of p62 in the sample obtained during or after the course of administration.
  • a method of treating a disorder described herein that includes: administering a therapeutically effective amount of compound described herein in a patient in need thereof, and during or after the course of administration (e.g., at discrete time points, such as one week, two weeks, or on month after initial administration of a contemplated compound) detecting the engagement of the compound with an ULK kinase, wherein detecting comprises contacting a sample obtained from the patient (including but not limited to a tumor, blood, saliva, or tissue) with a pBeclin antibody ELISA assay to detect inhibition of ULK kinase activity, e.g. based on the level of pBeclin in the sample.
  • a contemplated method comprises optionally contacting a sample obtained from the patient (including but not limited to a tumor, blood, saliva, or tissue) prior to administration of the compound with a pBeclin antibody ELISA assay, and comparing the level of pBeclin in the sample obtained prior to administration with the level of pBeclin in the sample obtained during or after the course of administration.
  • the compounds provided herein may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
  • a compound provided herein may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
  • Treatment can be continued for as long or as short a period as desired.
  • the compositions may be administered on a regimen of, for example, one to four or more times per day.
  • a suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely.
  • a treatment period can terminate when a desired result is achieved.
  • Compounds described herein e.g., a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as defined herein, can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein, such as a cancer described herein.
  • a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient.
  • a compound described herein e.g., a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as defined herein, one or more additional therapeutic agents
  • a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1 ), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as defined herein and two additional therapeutic agents are administered.
  • a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as defined herein and three additional therapeutic agents are administered.
  • Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately.
  • a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1 ), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as defined herein and an additional therapeutic agent can be formulated and administered separately.
  • Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as one therapeutic agent and one or more additional therapeutic agents.
  • a pharmaceutical composition comprising a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as one therapeutic agent and one or more additional therapeutic agents.
  • a compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (I-I), Formula (la-1), Formula (lb- 1), Formula (Ic-1), Formula (Id-1), or Formula (Ie-1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as defined herein and an additional therapeutic agent can be administered in a single formulation.
  • Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y- X-Y, Y-Y-X, X-X-Y- Y, etc.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different routes of administration.
  • Each of the one or more of the agents may be independently administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
  • the one or more additional therapeutic agent that may be administered in combination with a compound described herein can be a RTK pathway inhibitor, a MAP kinase pathway inhibitor, a PI3K inhibitor, an mTOR inhibitor, an immunomodulatory agent, or a chemotherapeutic agent, or any combination thereof.
  • the additional therapeutic agent is a RTK pathway inhibitor.
  • RTK pathway inhibitors include, for example, KIT inhibitors, FLT3 inhibitors, EGFR inhibitors, PDGFRa inhibitors, VEGFR inhibitors, anti-VEGF therapeutics, BCR-Abl inhibitors, and ALK inhibitors.
  • Exemplary KIT inhibitors include, but are not limited, to ripretinib, avapritinib, sunitinib, AZD3229 (NB003), THE-630, imatinib, midostaurin, bezuclastinib, olverembatinib (HQP1351), famitinib, IDRX-42 (M4205), elenestinib, BLU-808, IDRX-73, SLRN-517, THB335, DCC-3009, pexidartinib, and regorafenib, and pharmaceutically acceptable salts thereof.
  • the KIT inhibitor is selected from the group consisting of ripretinib, avapritinib, sunitinib, AZD3229 (NB003), THE-630, imatinib, midostaurin, bezuclastinib, olverembatinib (HQP1351), famitinib, IDRX-42 (M4205), elenestinib, BLU-808, IDRX-73, SLRN-517, THB335, pexidartinib, and regorafenib, and pharmaceutically acceptable salts thereof.
  • Exemplary EGFR inhibitors include, but are not limited to, cetuximab, osimertinib, gefitinib, lapatinib, erlotinib, dacomitinib, neratinib, and afatinib, and pharmaceutically acceptable salts thereof.
  • Exemplary PDGFRa inhibitors include, but are not limited to, ripretinib, JNJ10198409, and avapritinib, and pharmaceutically acceptable salts thereof.
  • VEGFR inhibitors include, but are not limited to, regorafenib, axitinib, lenvatinib, cabozantinib, sorafenib, sunitinib, vandetinib, nintedanib, tivozanib, and pazopanib, and pharmaceutically acceptable salts thereof.
  • Exemplary anti-VEGF therapeutics include bevacizumab.
  • Exemplary BCR-Abl inhibitors include, but are not limited to, imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, and asciminib, and pharmaceutically acceptable salts thereof.
  • Exemplary ALK inhibitors include, but are not limited to, loralatinib, brigatinib, ceritinib, crizotinib, and alectinib, and pharmaceutically acceptable salts thereof.
  • the additional therapeutic agent is a MAP kinase pathway inhibitor.
  • Such MAP kinase pathway inhibitors include, for example, MEK inhibitors, ERK inhibitors, RAF inhibitors, and Ras inhibitors.
  • Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, complicatometinib, mirdametinib, pimasertib, refametinib, and pelitinib, and pharmaceutically acceptable salts thereof.
  • the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, cobimetinib, binimetinib, mirdametinib, and VS-6766, and pharmaceutically acceptable salts thereof.
  • Exemplary ERK inhibitors include, but are not limited to, ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-l le, ERAS-007, and ASTX-029, and pharmaceutically acceptable salts thereof.
  • Exemplary RAF inhibitors include, but are not limited to, LY3009120, LXH254 (naporafenib), RAF709, KIN-2787 (exarafenib), dabrafenib, vemurafenib, encorafenib, tovorafenib, PLX8394, agerafenib, lifirafenib, belvarafenib, uplarafenib, JZP815, BDTX-4933, and DCC-3084, and pharmaceutically acceptable salts thereof.
  • the RAF inhibitor is selected from the group consisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, belvarafenib, KIN-2787, VS-6766, encorafenib, JZP815, and DCC-3084, and pharmaceutically acceptable salts thereof.
  • Exemplary Ras inhibitors include, but are not limited to, sotorasib (AMG- 510), adagrasib (MRTX849), LY3537982, opnurasib, divarasib (GDC-6036), fulzerasib, MRTX-1133, JAB-21822, GFH925, ELI-002, RMC-6236, ASP3082, YL-17231, QTX3034, RMC-9805, HRS-4642, RMC-8839, INCB 161734, and RMC-6291, and pharmaceutically acceptable salts thereof.
  • the Ras inhibitor is selected from the group consisting of AMG-510, MRTX849, GDC-6036, MRTX-1133, RMC-9805, RMC-6291, RMC-6236, LY3537982, opnurasib, divarasib, and pharmaceutically acceptable salts thereof.
  • the Ras inhibitor is a KRAS inhibitor, for example, a KRAS G12C inhibitor, a KRAS G12D inhibitor, or a pan-KRAS inhibitor.
  • the additional therapeutic agent is a PI3K inhibitor an AKT inhibitor, or an mTOR inhibitor.
  • Exemplary PI3K inhibitors include, but are not limited to, alpelisib, LY294002, idelalisib, duvelisib, copanlisib, umbralisib, and omipalisib, and pharmaceutically acceptable salts thereof.
  • Exemplary mTOR inhibitors include, but are not limited to, rapamycin, everolimus, temsirolimus, PF04691502, and PP242, and pharmaceutically acceptable salts thereof.
  • the compounds described herein may be administered in combination with other therapeutic agents known to treat cancers.
  • Such other therapeutic agents include radiation therapy, anti-tubulin agents, DNA alkylating agents, DNA synthesis-inhibiting agents, DNA intercalating agents, anti -estrogen agents, anti-androgens, steroids, anti-EGFR agents, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, AKT inhibitors, cyclin- dependent kinase inhibitors, CD4/CD6 kinase inhibitors, topoisomerase inhibitors, Histone Deacetylase (HD AC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti- angiogenic agents, proteasome inhibitors, PARP inhibitors, cell cycle regulating kinase inhibitors, thalidomide, lenalidomide, antibody-drug-conjugates (ADCs), immunotherapeutic agents including immunomodulating agents, targeted therapeutic agents, cancer vaccines, and CAR-T
  • the additional therapeutic agents can be chemotherapeutic agents including but not limited to an anti-tubulin agents (for example, paclitaxel, paclitaxel protein-bound particles for injectable suspension including nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or maytansinoids), vinorelbine, DNA- alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents or DNA topoisomerase inhibitors (including anthracyclines such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, or epirubicin, camptothecins such as topotecan, irinotecan, or ex
  • the additional therapeutic agent is selected from the group consisting of anti-tubulin agents, vinorelbine, DNA-alkylating agents, DNA intercalating agents, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytadine, gemcitabine, irinotecan, and methotrexate.
  • the additional therapeutic agents can be kinase inhibitors including but not limited to erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, ripretinib, avapritinib, JNJ10198409, nilotinib, idelalisib, ibrutinib, BLU-285, BLU-667, Loxo 292, la
  • the additional therapeutic agents can be immunomodulatory agents including but not limited to anti-PD-1 or anti-PDL-1 therapeutics including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, avelumab, or dostarlimab, anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453, anti-LAG3 therapeutics including but not limited to relatlimab, LAG525, or TSR-033, anti-4-lBB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutics including but not limited to SGN-40, CP-870,893 or R07009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists including but not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazoles,
  • the additional therapeutic agent is an immunomodulatory agent.
  • the immunomodulatory agent is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS- 936559, avelumab, cetuximab, TSR-022, MBG453, relatlimab, LAG525, TSR-033, SGN-40, CP-870,893, R07009789, Hu5F9-G4, ADU-S100, MK-1454, ASA404, doxorubicin, mitoxanthrone, azacytidine, decitabine, statins, metformin, thalidomide, lenalidomide, pomalidomide, prednisone, dexamethasone, and dostarlimab, and pharmaceutically acceptable salts thereof.
  • the additional therapeutic agent is selected from a luteinizing hormone-releasing hormone (LHRH) analog, including goserelin and leuprolide.
  • LHRH luteinizing hormone-releasing hormone
  • the additional therapeutic agent is selected from the group consisting of selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON O91O.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab,
  • compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds described herein, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual nontoxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound provided herein, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, al
  • compositions may also comprise buffering agents.
  • 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 sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include 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, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • 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 a
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams, and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • compositions of the present disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • enteral pharmaceutical formulations including a disclosed compound and an enteric material, and a pharmaceutically acceptable carrier or excipient thereof.
  • Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs.
  • the small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum.
  • the pH of the duodenum is about 5.5
  • the pH of the jejunum is about 6.5
  • the pH of the distal ileum is about 7.5.
  • enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
  • Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such
  • kits for use by a e.g., a consumer in need of treatment of cancer include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . " etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • ADP is adenosine diphosphate
  • Adbrettphos-Pd-G3 is [2-(di-l- adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-l,l'- biphenyl)]palladium(II) methanesulfonate
  • “Boc” is Zc/V-butylcarbonate
  • CAN’ Cerium (IV) ammonium nitrate
  • CbzCl is benzyl chloroformate
  • DCE is di chloroethane
  • DCM dichloromethane
  • DIEA is VN-diisopropylethyl
  • Scheme 1 illustrates an exemplary preparation of intermediates 1-2 and 1-3.
  • Diamines 1-1 (commercially available or synthesized by those skilled in the art) react with sulfonyl chloride followed by deprotection with HC1 to afford 1-2.
  • diamines 1-1 (commercially available or synthesized by those skilled in the art) react with chlorosulfonyl isocyanate followed by deprotection with HC1 to afford 1-3.
  • Scheme 2 illustrates an exemplary preparation of intermediates 1-2 and 1-3.
  • Scheme 2 illustrates an exemplary preparation of intermediate 2-3.
  • ((tert- Butyldiphenylsilyl)imino)dimethyl-X 6 -sulfanone 2-1 reacts with tert-butyl 1,2,3- oxathiazolidine-3 -carboxylate 2,2-dioxide in the presence of base such as //-BuLi to afford tert- butyl (3-(7V-(tert-butyldiphenylsilyl)-S-methylsulfonimidoyl)propyl)carbamate 2-2 which can be treated with ZnBr2 to remove Boc group to afford (3-aminopropyl)((tert- butyldiphenylsilyl)imino)(methyl)- /J’-sulfanone 2-3.
  • Scheme 3 illustrates an exemplary preparation of intermediates 3-4 and 3-6.
  • oxidation of 3-2 with mCPBA affords 3-5 which can be reacted with amines A-NH2 (commercially available or synthesized by those skilled in the art) to afford intermediates 3-6.
  • 2,4-dichloro-5- (trifluoromethyl)pyrimidine 3-1 reacts with amines A-NH2 (commercially available or synthesized by those skilled in the art) in the presence of ZnCh at temperature lower than 10 °C followed by SFC purification to afford intermediates 3-6.
  • Scheme 4 illustrates an exemplary preparation of compounds of Formula I (4- 5).
  • Compounds of Formula I (4-5) can be prepared from five different intermediates, 3-3a, 3- 4, 3-6. 4-3, and 4-4.
  • Chlorides 3-3a react with amines A-NH2 (commercially available or synthesized by those skilled in the art) under Buchwald reaction conditions to afford compounds of Formula I (4-5).
  • Compounds 3-4 react with amines A-NH2 (commercially available or synthesized by those skilled in the art) by a nucleophilic substitution reaction, typically performed in an aprotic solvent at temperatures ranging from ambient temp to 150 °C to afford compounds of Formula I (4-5).
  • intermediates 3-6 (W N) react with amines Z-L-U-NR 7 H (commercially available or synthesized by those skilled in the art) at elevated temperature in aprotic solvent such as 1,4-di oxane affords compounds of Formula I (4-5).
  • Intermediates 4-3 (W CH) react with amines Z-L-U- NR 7 H (commercially available or synthesized by those skilled in the art) under Buchwald reaction conditions to afford compounds of Formula I (4-5).
  • compounds 4-1 react with amines Z-L-U-NR 7 H (commercially available or synthesized by those skilled in the art) under Buchwald reaction conditions to afford 4-4 which can be reacted with amines A-NH2 to afford compounds of Formula I (4-5).
  • Scheme 5 illustrates an exemplary preparation of compounds of Formula I (5- la, 5-lb, 5-2a, and 5-2b).
  • S ⁇ Ar reaction of a mixture of sulfone and sulfoxide 3-4 with nucleophiles 5-1 affords compounds Formula I (5-1).
  • Scheme 6 illustrates an exemplary preparation of compounds of Formula I (6- la, 6-lb, 6-2a, and 6-2b).
  • R 3 or R 4 contains double bonds, compounds of Formula I (6-2a and 6-2b) can be reduced under HVPd-C conditions.
  • Scheme 7a illustrates an exemplary preparation of compounds of Formula I (7- la, 7-2a, 7-3a, 7-4a, and 7-5a).
  • Amidoximes 7-la are directly converted to amidines 7-3a by reaction with ammonium formate and Pd-C.
  • partial solvolysis of nitrile compounds of Formula I (5-1) (Pinner reaction) under HCl/MeOH affords Formula I (7-2a) which can be reacted with nucleophiles, amine CH3NH2 or ethane- 1,2-diamine to afford 7-4a and 7-5a, respectively.
  • Scheme 7b illustrates an exemplary preparation of compounds of Formula I (7- 1b, 7-2b, 7-3b, 7-4b, and 7-5b).
  • Amidoximes 7-lb are directly converted to amidines 7-3b by reaction with ammonium formate and Pd-C.
  • Scheme 8 illustrates an exemplary preparation of compounds of Formula I (8- 3, 8-4, and 8-5).
  • Intermediates 3-6 react with A-Boc-protected amines NR 7 H-U-L-NR 8 Boc, 8- 1 (commercially available or synthesized by those skilled in the art) in the presence of base such as TEA to afford 8-2.
  • Deprotection of 8-2 under acidic conditions such as HC1 affords compounds of Formula I (8-3).
  • Sulfonylation of compounds of Formula I (8-3) with sulfonyl chlorides R 9 SO2C1 (commercially available or synthesized by those skilled in the art) affords compounds of Formula I (8-4) in the presence of organic base.
  • compounds of Formula I (8-3) can be reacted with chlorosulfonyl isocyanate/tert-BuOH in the presence of base such as TEA followed by acid such as HC1 to afford compounds of Formula 1 (8-5).
  • Scheme 9 illustrates an exemplary preparation of compounds of Formula I (9- 3, 9-4, and 9-5).
  • intermediates 3-6 react with A-Boc-protected cyclic amines 9-1 (commercially available or synthesized by those skilled in the art) in the presence of base such as TEA to afford 9-2.
  • Deprotection of 9-2 under acidic conditions such as HC1 affords compounds of Formula I (9-3).
  • Sulfonylation of compounds of Formula I (9-3) with sulfonyl chlorides R 9 SO2C1 (commercially available or synthesized by those skilled in the art) affords compounds of Formula I (9-4) in the presence of organic base.
  • Scheme 11 illustrates an exemplary preparation of compounds of Formula I (Illa, 11-lb, ll-2a, and ll-2b).
  • Deprotection of Boc group of 4-5a and 4-5b in the presence of acid such as HC1 affords compounds of Formula I (11-la and 11-lb, respectively).
  • Treatment of compounds of Formula I (11-la and 11-lb, free base or acid addition salt) with sodium cyanoborohydride or sodium triacetoxyborohydride and either an aldehyde or ketone in the presence of a catalytic amount of acetic acid in polar solvents such as MeOH (reductive amination conditions) affords compounds of Formula I (ll-2a and ll-2b, respectively).
  • Preparation of intermediate Al 2-ethyl-4-(4-methylpiperazin-l-yl)aniline
  • reaction mixture was quenched by water (60 mL) and then extracted with EtOAc 80 mL (3x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% EtOAc/pet-ether) to obtain l -(N-(/c/7-butyl)sulfamoyl)-N-(2- (methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)cyclopropane-l -carboxamide (D13, 10.3 g, 77%) as a white solid.
  • the 2-ethyl-4-(4-methylpiperazin-l-yl)aniline (Al, 18.5 g, 84.4 mmol) was added over 1 h while maintaining the temperature at 20 °C.
  • the solution was stirred for 12 h and then IP Ac (200 mL) was added.
  • the mixture was stirred, and the temperature of the contents was maintained to 20 ⁇ 5 °C.
  • TMEDA (36 mL, 0.24 mol) was added while maintaining the temperature ⁇ 30 °C.
  • the temperature of the contents was adjusted to rt, and the mixture was stirred for 1 h.
  • the slurry was filtered, and the solids were rinsed with IP Ac.
  • the filtrate was adjusted to rt and then NH4CI solution was added.
  • reaction mixture was purified by silica gel column chromatography (0 to 30% DCM/MeOH) to obtain (3-((2-((2-ethyl-4-(4-methylpiperazin-l- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)(methyl)sulfamoyl fluoride (Hl, 0.35 g, 49%) as an off white solid.
  • reaction mixture was diluted with sat’d NaHCCh (aq) and extracted with 20% MeOH/DCM (2x). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% MeOH/DCM) to obtain tert-butyl (3-((4-((3-((A-(tert-butoxycarbonyl)sulfamoyl)amino)propyl)amino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamate (0.34 g, 80%) as a tan foam.
  • the resins were then treated with 10% (30% NH4OH)/MeOH (2 mL) and stirred for 2 h.
  • the suspension was filtered, rinsed with MeOH and the filtrate was concentrated under reduced pressure.
  • the residue was treated with 10% MeOH/DCE (2 mL), MeOH (1 mL), and MP-carbonate (150 mg) and stirred for 1 h. the resins were filtered off and washed with MeOH.
  • Assays were conducted in 384-well plates (100 pL final volume) using 0.1 nM ULK1 (from Beryllium), 0.075 mM peptide substrate (YANWLAASIYLDGKKK), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl 2 , 0.5 mM DTT, 0.004% (w/v) BSA, and 0.004% Triton X-100).
  • Inhibition of ULK1 was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored continuously for 6 h at 30 °C on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 2-3 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC50 values were calculated using software routines in Prism (GraphPad software).
  • ULK1 protein sequence (residues 1-283; SEQ. ID NO: 1)
  • Assays were conducted in 384-well plates (100 mL final volume) using 1 nM ULK2 (Signal Chem U02-11G), 200 mM ULKtide, 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCh, 0.5 mM DTT, 0.1% octyl -glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100).
  • Inhibition of ULK2 was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored continuously for 6 h at 30 °C on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 2-3 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software).
  • ULK2 protein sequence (residues 1-306 with N-terminal GST and His tag; SEQ. ID NO: 2)

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Abstract

L'invention concerne des composés de formule (I) qui sont des inhibiteurs de l'autophagie, en particulier des inhibiteurs de l'activité de la kinase ULK, et leur utilisation dans le traitement de troubles tels que des cancers.
PCT/US2025/013975 2024-02-02 2025-01-31 Inhibiteurs d'ulk et leurs méthodes d'utilisation Pending WO2025166124A1 (fr)

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Citations (8)

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US20050256144A1 (en) * 2004-05-14 2005-11-17 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
WO2008129380A1 (fr) * 2007-04-18 2008-10-30 Pfizer Products Inc. Dérivés de sulfonyle amide pour le traitement d'une croissance cellulaire anormale
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