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WO2023239892A1 - Compounds for modulation of cd68 and uses thereof - Google Patents

Compounds for modulation of cd68 and uses thereof Download PDF

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Publication number
WO2023239892A1
WO2023239892A1 PCT/US2023/024906 US2023024906W WO2023239892A1 WO 2023239892 A1 WO2023239892 A1 WO 2023239892A1 US 2023024906 W US2023024906 W US 2023024906W WO 2023239892 A1 WO2023239892 A1 WO 2023239892A1
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Prior art keywords
alkylene
alkyl
compound
ring
cases
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PCT/US2023/024906
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French (fr)
Inventor
Jean-François Blain
Duane A. Burnett
Christopher J. HOLLER
Gerhard Koenig
James C. Lanter
Ricardo L. SANZ
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Arkuda Therapeutics
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Publication of WO2023239892A1 publication Critical patent/WO2023239892A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • CD68 (SEQ ID NO: 1 or SEQ ID NO: 2); also known as GP110; LAMP4; SCARD1 ) is a heavily glycosylated transmembrane glycoprotein that is highly expressed by human monocytes and tissue macrophages [Holness et al., Blood 81 (6): 1607-13 (1993)]. It is a member of the lysosomal/endosomal-associated membrane protein (LAMP) family of glycoproteins. CD68 primarily localizes to the lysosome/endosome compartment but can also circulate to the cell surface. CD68 is also a member of the family of scavenger receptors.
  • LAMP lysosomal/endosomal-associated membrane protein
  • methods of modulating CD68 comprising contacting CD68 with a compound as disclosed herein, or pharmaceutically acceptable salt thereof, in an amount sufficient to modulate CD68.
  • Figure 1 shows that photoaffinity cross-linking of the target CD68 was competed with Compound 1 .
  • the target was immunoprecipitated via a biotin handle on the photoaffinity ligand, separated on gel and identified with either a fluorescent streptavidin (Strept-700) or an anti-CD68 antibody.
  • the third image shows the overlap between the two signals.
  • Figure 2 shows results of experiments in which the target CD68 was glycosylated, immunoprecipitated via a biotin handle on the photoaffinity ligand, deglycosylated using either EndoH or PNGaseF, separated on gel and identified with either a fluorescent streptavidin (Strept-700) or an anti-CD68 antibody.
  • the third image shows the overlap between the two signals.
  • Figure 3 shows amino acid sequences of CD68.
  • CD68 Provided herein are methods of modulating CD68 by using a compound as disclosed herein. Modulation of CD68 can be assessed using typical biological assays, including those as described in the examples section below. In some cases, the level of CD68 is increased. In some cases, the level of intracellular CD68 is decreased.
  • expression or function of CD68 is increased, compared to a control, by at least 5%, at least 10%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 90%, at least 100%, at least 125%, at least 150%, or at least 200%.
  • expression or function of CD68 is decreased, compared to a control, by at least 5%, at least 10%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 90%, at least 100%, at least 125%, at least 150%, or at least 200%.
  • Amount and/or function of CD68 can be assessed using typical biological assays understood in the art (e.g., immunoblot, quantitative RT-PCR).
  • the disclosure further provides methods of treating a CD68-associated disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound as disclosed herein to a subject in need thereof.
  • the CD68-associated disorder is osteoporosis, cancer, rheumatoid arthritis, lupus, inflammatory bowel disease, chronic liver injury, a wound, malaria, septic shock, or atherosclerosis.
  • the cancer is melanoma, glioma, breast cancer, ovarian cancer, bladder cancer, colorectal cancer and non-small cell lung cancer.
  • the disclosure additionally provides methods of treating additional disorders comprising administering a therapeutically effective amount of a compound as disclosed herein to a subject in need thereof.
  • the additional disorders contemplated by the disclosure include, without limitation, progranulin-associated disorders.
  • the progranulin-associated disorder in various embodiments, is Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), Frontotemporal dementia -Granulin subtype (FTD-GRN), Lewy body dementia (LBD), Prion disease, Motor neuron diseases (MND), Huntington’s disease (HD), Spinocerebellar ataxia (SCA), Spinal muscular atrophy (SMA), a lysosomal storage disease, nephropathy, a disease associated with inclusions and/or misfunction of C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP2B, and/or MAPT, an acute neurological disorder, glioblastoma, or neuroblastoma.
  • AD Alzheimer’s disease
  • PD Parkinson’s disease
  • ALS Amyotrophic lateral
  • the lysosomal storage disease is Paget’s disease, Gaucher’s disease, Nieman’s Pick disease, Tay-Sachs Disease, Fabry Disease, Pompe disease, or Naso-Hakula disease.
  • the acute neurological disorder is stroke, cerebral hemorrhage, traumatic brain injury or head trauma.
  • the disorder is Frontotemporal dementia (FTD).
  • the term "subject” refers to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Preferably, the subject is a human.
  • the terms "effective amount” or “therapeutically effective amount” refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as described herein. In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer. In some embodiments, the amount is that effective for alleviating, reducing or eliminating an inflammatory condition.
  • the therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells.
  • the specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • treatment refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred.
  • Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology.
  • Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder.
  • the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • the treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease.
  • reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • the term "therapeutic effect” refers to a therapeutic benefit and/or a prophylactic benefit as described herein.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the articles “a” and “an” refer to one or to more than one (for example, to at least one) of the grammatical object of the article.
  • “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20-25 percent (%), for example, within 20 percent, 10 percent, 5 percent, 4 percent, 3 percent, 2 percent, or 1 percent of the stated value or range of values.
  • alkyl refers to straight chained and branched saturated hydrocarbon groups containing one to six carbon atoms.
  • C n means the alkyl group has “n” carbon atoms.
  • C 6 alkyl refers to an alkyl group that has 6 carbon atoms.
  • Ci-C 6 alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (e.g., 1 to 6 carbon atoms), as well as all subgroups (e.g., 1 -6, 2-6, 1-5, 3-6, 1 , 2, 3, 4, 5, and 6 carbon atoms).
  • alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), t-butyl (1 ,1 -dimethylethyl), and 3-methylpentyl.
  • an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.
  • alkylene refers to an alkyl group having a substituent.
  • an alkylene group can be -CH 2 CH 2 - or -CH 2 -.
  • C r means the alkylene group has “n” carbon atoms.
  • Ci- 6 alkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for “alkyl” groups.
  • a Co alkylene indicates a direct bond.
  • an alkylene group can be an unsubstituted alkylene group or a substituted alkylene group. Particular substitutions on the alkylene group can be specified, e.g., alkylene-CN, or the like.
  • alkyne or “alkynyl” used herein refers to an unsaturated aliphatic group analogous in length and possible substitution to an alkyl group described above, but that contains at least one triple bond.
  • alkynyl includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group can have six or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 3 includes chains having a number of carbon atoms encompassing the entire range (e.g., 2 to 6 carbon atoms), as well as all subgroups (e.g., 2-6, 2-5, 2-4, 3-6, 2, 3, 4, 5, and 6 carbon atoms).
  • C 3 -C 6 includes chains having a number of carbon atoms encompassing the entire range (e.g., 3 to 6 carbon atoms), as well as all subgroups (e.g., 3- 6, 3-5, 3-4, 3, 4, 5, and 6 carbon atoms).
  • an alkynyl group can be an unsubstituted alkynyl group or a substituted alkynyl group.
  • haloalkyl refers to an alkyl group substituted with one or more halogen substituents.
  • Ci-C 6 haloalkyl refers to a Ci-C 6 alkyl group substituted with one or more halogen atoms, e.g., 1 , 2, 3, 4, 5, or 6 halogen atoms.
  • a Cohaloalkyl refers simply to a halo substituent.
  • Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl groups.
  • halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl substituents.
  • Ci-C 3 hydroxyalkyl refers to a Ci-C 6 alkyl group substituted with one or more hydroxyl groups, e.g., 1 , 2, 3, 4, 5, or 6 hydroxyl groups.
  • a Cohydroxyalkyl refers to a hydroxyl group.
  • Non-limiting examples of hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl groups.
  • alkoxy refers to a straight or branched hydrocarbon group which has an oxygen atom as the point of attachment.
  • the alkoxy group can further comprise additional oxygen atoms in the hydrocarbon backbone, e.g., 1 , 2, 3, or 4 additional oxygen atoms.
  • carbocycle or “carbocyclyl” or “cycloalkyl” refers to a cyclic hydrocarbon group containing three to eight carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 carbon atoms).
  • n-membered carbocycle means the carbocycle group has “n” carbon atoms.
  • 5-membered carbocycle refers to a carbocycle group that has 5 carbon atoms in the ring.
  • 6- to 8-membered carbocycle refers to carbocycle groups having a number of carbon atoms encompassing the entire range (e.g., 6 to 8 carbon atoms), as well as all subgroups (e.g., 6-7, 6-8, 7-8, 6, 7, and 8 carbon atoms).
  • carbocycle groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a carbocycle group can be an unsubstituted carbocycle group or a substituted carbocycle group.
  • the carbocycle groups described herein can be isolated or fused to another carbocycle group.
  • the carbocycles described herein can have a fused, bridged, or spiro structure.
  • each of the carbocycle groups can contain three to eight carbon atoms unless specified otherwise.
  • heterocycle or “heterocycloalkyl” is defined similarly as carbocycle, except the ring contains one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • heterocycle refers to a ring containing a total of three to eight atoms (e.g., three to five, or five to eight), of which 1 , 2, 3 or 4 of those atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, and the remaining atoms in the ring are carbon atoms.
  • heterocycle groups include azetidine, piperdine, piperazine, pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, quinuclidine, and the like.
  • Heterocycle groups can be saturated or partially unsaturated ring systems optionally substituted with, for example, one to three groups, such as halo, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci- 6 haloalkoxy, CN, and SO 2 Ci- 3 alkyl.
  • Other substituents are also contemplated, including C 0-3 alkylene-halo, C 0.3 alkylene-CN, C 0.3 alkylene-NH 2 , C 0-3 alkyleneOH, and C 0-3 alkylene-O-Ci. 3 alkyl.
  • Heterocycloalkyl groups optionally can be further N- substituted with alkyl, alkylene-OH, alkylenearyl, and alkyleneheteroaryl.
  • the heterocycle groups described herein can be isolated or fused to another heterocycle group and/or a carbocycle group. When a heterocycle group is fused to another heterocycle group, then each of the heterocycle groups can contain three to ten total ring atoms, and one to four heteroatoms.
  • aryl refers to a monocyclic aromatic group, such as phenyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four groups independently selected from, for example, halo, alkyl, alkenyl, OCF 3 , N0 2 , CN, NC, OH, alkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl.
  • Aryl groups can be isolated (e.g., phenyl) or fused to another aryl group (e.g., naphthyl, anthracenyl), a cycloalkyl group (e.g., tetraydronaphthyl), a heterocycloalkyl group, and/or a heteroaryl group.
  • aryl groups include, but are not limited to, phenyl, chlorophenyl, fluorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4- methoxychlorophenyl, and the like.
  • heteroaryl refers to a monocyclic aromatic ring having 5 to 6 total ring atoms, and containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur atom in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to four, substituents selected from, for example, halo, alkyl, alkenyl, OCF 3 , NO 2 , CN, NC, OH, alkoxy, amino, CO 2 H, CO 2 alkyl, aryl, and heteroaryl.
  • substituents are also contemplated, including C 0 3 alkylene-halo, C 0 3 alkylene-CN, C 0 3 alkylene-NH 2 , C 0 3 alkylene-OH, and C 0 3 alkylene-O- Ci- 3 alkyl.
  • the heteroaryl group is substituted with one or more of alkyl and alkoxy groups.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
  • substituents when used to modify a chemical functional group, refers to the replacement of at least one hydrogen radical on the functional group with a substituent.
  • substituents can include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, oxy, alkoxy, heteroalkoxy, ester, thioester, carboxy, cyano, nitro, amino, amido, acetamide, and halo (e.g., fluoro, chloro, bromo, or iodo).
  • the substituents can be bound to the same carbon atom or to two or more different carbon atoms.
  • Compounds of the present disclosure can exist in particular geometric or stereoisomeric forms having one or more asymmetric carbon atoms.
  • the present disclosure contemplates such forms, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosed compounds.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended for inclusion herein.
  • the term “pharmaceutically acceptable” means that the referenced substance, such as a compound of the present disclosure, or a formulation containing the compound, or a particular excipient, are safe and suitable for administration to a patient or subject.
  • pharmaceutically acceptable excipient refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.
  • the compounds disclosed herein can be as a pharmaceutically acceptable salt.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benef it/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1 -19, which is incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutamate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, peroxine sodium
  • Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • suitable base include, but are not limited to, alkali metal, alkaline earth metal, aluminum salts, ammonium, N + (Ci- 4 alkyl) 4 salts, and salts of organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N’- dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2- hydroxyethyljamine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N’- bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Formula (I) Compounds: [0036] Provided herein are compounds, or salts thereof, for use in the disclosed methods having a structure of Formula (I): wherein ring B is a 5-12 membered monocyclic, bicyclic, or bridged nitrogen-containing heterocycle comprising 0-1 additional ring heteroatoms selected from N, O, and S,
  • R 1 is either a part of a bicyclic or bridged heterocycle or is H, Ci- 6 alkyl, SO 2 R 6 , or C(O)R 3 ;
  • ring A is a C 6 aryl or 5-7 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S, and is optionally substituted with 1 -3 R 3 groups;
  • X is Ci- 5 alkylene, Co- 5 alkylene-Y or Y-Ci- 5 alkylene-Y; each Y is independently C(O), OC(O), C(O)NR 4 , NR 4 C(O), or SO 2 ;
  • R 2 is C 6 -ioaryl, 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S, or 5-12 membered monocyclic or bicyclic carbocycle or heterocycle, wherein the heterocycle comprises 1-4 ring heteroatoms selected from N, O, and S, and R 2 is optionally substituted with 1-3 R 3 groups; each R 3 , when present, is independently selected from Ci.
  • Ar is 3-8-membered carbocycle or heterocycle, wherein the heterocycle comprises 1 - 4 ring heteroatoms selected from N, O, and S; C 6 -ioaryl; or 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S and Ar is optionally substituted with 1 -3 groups independently selected from halo, Ci-ealkyl, Ci-shaloalkyl, Ci-salkoxy, Ci- ehaloalkoxy, CN, and SO 2 Ci- 3 alkyl; each R 4 and R 5 is independently H, Ci-salkyl, or C(O)Ci-6alkyl; each R 6 is independently Ci-ealkyl, Ci-ehaloalkyl, or Ar; each R 7 is independently H or Ci- 6 alkyl; m is 0-2; and n is 0-2, with the proviso that the compound is not In some cases, the structure of Formula (I) has a structure
  • R 1 is H or Me.
  • ring A comprises phenyl or pyridyl and is optionally substituted with 1 -2 groups selected from fluoro and chloro.
  • ring A is phenyl substituted with 1 fluoro.
  • ring A is phenyl substituted with 1 chloro.
  • ring A is pyridyl substituted with 1 fluoro.
  • ring A is pyridyl substituted with 1 chloro.
  • ring A is unsubstituted phenyl.
  • ring A is unsubstituted pyridyl.
  • X can be Ci-salkylene, Co-salkylene-Y or Y-Ci-salkylene-Y; and each Y is independently C(O), OC(O), C(O)NR 4 , NR 4 C(O), or SO 2 .
  • X is Y (i.e., no alkylene linker is present).
  • X comprises an alkylene linker to ring A (i.e., comprises a Ci- 5 alkylene moiety, with or without a Y group present).
  • X is Co- 5 alkylene-Y or Y-C 0-5 alkylene-Y.
  • Y is NR 4 C(O) or C(O)NR 4 and R 4 is H or Me.
  • X is CH 2 C(O), OC(O), or NR 4 C(O) (e.g., R 4 is H).
  • X is OC(O).
  • X is NHC(O).
  • X is CH 2 C(O).
  • R 2 can be Ce-ioaryl, 5-10 membered heteroaryl comprising 1 -4 ring heteroatoms selected from N, O, and S, or 5-12 membered monocyclic or bicyclic carbocycle or heterocycle, wherein the heterocycle comprises 1 -4 ring heteroatoms selected from N, O, and S, and R 2 is optionally substituted with 1-3 R 3 groups.
  • R 2 is phenyl, e.g., phenyl substituted with 1 -2 fluoro and/or chloro groups.
  • R 2 is pyridyl, pyrazine, pyrimidine, thiophene, benzothiophene, benzofuranyl, piperidinone, indole, indazole, benzodiazole, benzoimidazole, benzoxazole, benzothiazole, indolizine, imidazo- [1 ,2-a]pyridine, imidazo-[1 ,5-a]pyridine, or imidazo-[1 ,2-a]pyrimidine.
  • R 2 is unsubstituted.
  • R 2 is substituted with 1 R 3 .
  • R 2 is substituted with 2 R 3 .
  • R 2 is substituted with 3 R 3 .
  • R 2 is selected from the group consisting of
  • the structure of Formula (I) is a structure of Formula (IA) wherein Y’ is CH 2 , NR 4 or O, and each R 8 is independently H or Me, or both R 8 taken together with the carbon to which they are attached form a cyclopropyl ring.
  • the structure of Formula (IA) can be structure can alternatively various cases, the structure of
  • Formula (IA) can be wherein one R 8 is H and the other Me. In some cases, each R 8 is Me.
  • both R 8 together with the carbon to which they are attached form a cyclopropyl ring.
  • Some specifically contemplated compounds of Formula (I) include those as shown in Table A below, or a pharmaceutically acceptable salt thereof.
  • a compound of the disclosure is one as listed in Table B, or a pharmaceutically acceptable salt thereof.
  • the compound of the disclosure is a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of
  • A is a 4-10 membered heterocycle comprising 1 to 3 ring heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 3 ;
  • Y is Co-salkylene, Co. 6 alkylene-0-Co-6alkylene, C 0.6 alkylene-NR N , Co-salkylene-S0 2 , CO, CO2, or CONH, wherein Co- 6 alkylene is optionally substituted with 1 or 2 R 4 ; each R 1 is independently halo, -O-CH 2 -Csaryl-(OCH2CH2)p-OR 5 , or -O-CH 2 -Het-
  • OCH 3 wherein Het is a 6-membered heteroaryl comprising 2 ring N atoms; one R 2 is H and the other is H, CN, COOCi-salkyl, CONHCi-ealkyl, SO2CH3, or O- propargyl;
  • R 3 is Cvsalkyl, halo, Coealkylene-OH, Co- 6 alkylene-0-propargyl, propargyl, or Co- 6 alkylene-NR N R N ; each R 4 is independently F, OH, or OCi- 6 alkyl, or two R 4 together with the carbon atom to which they are attached form cyclopropyl;
  • R 5 is Ci- 6 alkyl or propargyl; each R N is independently H or Ci- 6 alkyl; n is 1 -3; and p is 0-2; with the proviso that
  • Y is CH 2 , O, or NR N , then one R 2 is H and the other R 2 is not H; or membered heterocycle comprising 1 to 3 ring heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 R 3 ;
  • Y is Co-salkylene, Co. 6 alkylene-0-Co-6alkylene, C 0.6 alkylene-NR N , Co-salkylene-S0 2 , CO 2 -, or CONH-, wherein Co- 6 alkylene is optionally substituted with 1 or 2 R 4 ; each R 1 is independently halo, -O-CH 2 -C6aryl-(OCH 2 CH2) P -OR 5 , or -O-CH 2 -Het-
  • OCH 3 wherein Het is a 6-membered heteroaryl comprising 2 ring N atoms; one R 2 is H and the other is H, CN, COOCi-salkyl, CONHCi-ealkyl, SO 2 CH 3 , or O- propargyl;
  • R 3 is Ci- 6 alkyl; each R 4 is independently F or OR 3 ;
  • R 5 is Ci- 6 alkyl or propargyl
  • R N is H or Ci- 6 alkyl; n is 1 -3; and p is 0-2; with the proviso that
  • Y is CH 2 , O, or NR N , then one R 2 is H and the other R 2 is not H; or hen A does not comprise
  • A is a 4-10 membered heterocycle comprising 1 to 3 ring heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 R 3 ;
  • Y is C 0-6 alkylene, C 0-6 alkylene-O, Co- 6 alkylene-0-Co- s alkylene, C 0-6 alkylene-NR 3 , C o - 6 alkylene-SO 2 , CO 2 -, or CONH-, wherein Co ealkylene is optionally substituted with 1 or 2 R 4 ; each R 1 is independently halo, -O-CH 2 -C 6 aryl-(OCH 2 CH 2 ) P -OR 5 , or -O-CH 2 -Het- (OCH 3 ), wherein Het is a 6-membered heteroaryl comprising 2 ring N atoms; one R 2 is H and the other is H, CN, COOCi. 6 alkyl, CONHCi. 6 alkyl, SO 2 CH 3 , or O- propargyl;
  • R 3 is H or Ci- 6 alkyl; each R 4 is independently F or OR 3 ;
  • R 5 is Ci-salkyl or propargyl; n is 1 -3; and p is 0-2; with the proviso that
  • the compound of Formula (1-1 ) has the structure of Formula (la-1 ) or (lb-1 ): compound of Formula (1-1 ) has the structure of Formula (la-1 ). In some cases, the compound of Formula (1-1 ) has the structure of Formula (lb-1 ).
  • the compound of Formula (l)-1 has the structure of Formula (lc-1 ) or (Id-1): compound of Formula (1-1 ) has the structure of Formula (lc-1 ). In some cases, the compound of Formula (1-1 ) has the structure of Formula (Id-1 ).
  • A comprises a 4 membered heterocycle. In some cases, A comprises a 5 membered heterocycle. In some cases, A comprises a 6 membered heterocycle. In some cases, A comprises a 7 membered heterocycle. In some cases, A comprises an 8 membered heterocycle. In some cases, A comprises a 9 membered heterocycle. In some cases, A comprises a 10 membered heterocycle. In some cases, A comprises a 4-, 6-, 8-, or 10-membered heterocycle comprising 1 or 2 ring heteroatoms selected from N and O. In some cases, A comprises an 8-membered heterocycle comprising 1 or 2 ring heteroatoms selected from N and O. In some cases, A is substituted with 1 to 3 R 3 . In some cases, A is substituted with 1 or 2 R 3 . In some cases, A is unsubstituted.
  • A comprises In some cases, A comprises In some cases, A comprises In some cases, A In some cases, A comprises some cases, A
  • Y is C 0.6 alkylene, Co-6alkylene-0-Co. 6 alkylene (e.g., Co-salkylene-O), C 0 -6alkylene-NR N , C 0 -6alkylene-SO 2 , CO, CO 2 -, or CONH-.
  • Y is Co. 6 alkylene, Co-6alkylene-0-Co-6alkylene (e.g., Co-6alkylene-0), C 0 -salkylene-NR N , C 0 -6alkylene-SO 2 , CO 2 -, or CONH-.
  • Y is C o alkylene (i.e., a bond).
  • Y is Ci. 6 alkylene, Ci-ealkylene-O, or Ci-6alkylene-NR N .
  • Y is C 0.6 alkylene-O or C 0.6 alkylene-NR N . In some cases, Y is C 0 - 6 alkylene-O. In some cases, Y is Ci 6 alkylene-O. In some cases, Y is Ci 6 alkylene-NR N . In some cases, Y is NH or O. In some cases, Y is NH. In some cases, Y is O.
  • the Ci- 6 alkylene of a Y moiety is unsubstituted. In some cases, Ci- 6 alkylene is substituted with 1 or 2 R 4 . In some cases, Ci- 6 alkylene is substituted with 1 R 4 .
  • each R 1 is independently halo. In some cases, each R 1 is independently -O-CH 2 -C 6 aryl-(OCH2CH2)p-OR 5 or -O-CH 2 -Het-(OCH 3 ), wherein Het is a 6- membered heteroaryl comprising 2 ring N atoms. In some cases, each R 1 is independently - O-CH 2 -C 6 aryl-(OCH2CH2)p-OR 5 . In some cases, each R 1 is independently -O-CH 2 -Het- (OCH 3 ).
  • At least one R 1 is halo. In some cases, at least one R 1 is F. In some cases, each R 1 is F. In some cases, at least one R 1 is -O-CH2-C 6 aryl-(OCH 2 CH2)p- OR 5 . In some cases, at least one R 1 is -O-CH 2 -Het. In some cases, Het comprises 2- pyrimidyl or 5-pyrimidyl optionally substituted with OMe. In some cases, Het comprises 2- pyrimidyl. In some cases, Het comprises 5-pyrimidyl. In some cases, Het is unsubstituted. In some cases, Het is substituted with OMe.
  • both R 2 are H.
  • one R 2 is H and the other is CN, COOCi- 6 alkyl, CONHCi- 6 alkyl, SO 2 CH 3 , or O-propargyL
  • one R 2 is H and the other is CN.
  • one R 2 is H and the other is COOCH 3 or CONHCH3.
  • one R 2 is H and the other is COOCH3.
  • one R 2 is H and the other is CONHCH3.
  • one R 2 is H and the other is SO2CH3.
  • one R 2 is H and the other is O-propargyL
  • R 3 is Ci- 6 alkyl, halo, Co- 6 alkylene-OH, C 0-6 alkylene-O-propargyl, propargyl, or Co- 6 alkylene-NR N R N .
  • R 3 is Ci- 6 alkyl.
  • R 3 is C1- 6 alkyl .
  • R 3 is halo.
  • R 3 is fluoro.
  • R 3 is C o - 6 alkylene-OH.
  • R 3 is Cialkylene-OH.
  • R 3 is C 0 alkylene-OH, i.e., R 3 is OH.
  • R 3 is C o 6 alkylene-O-propargyl. In some cases, R 3 is C 2 alkylene-O-propargyl. In some cases, R 3 is propargyl. In some cases, R 3 is Co-6alkylene- NR N R N . In some cases, R 3 is Cialkylene-NR N R N . In some cases, R 3 is Coalkylene-NR N R N , i.e., R 3 is NR N R N .
  • each R 4 is independently F, OH, or OCi- 6 alkyl, or two R 4 together with the carbon atom to which they are attached form cyclopropyl.
  • R 4 is F, OH, or OCH3.
  • R 4 is F.
  • R 4 is OH or OCH 3 .
  • R 4 is OH.
  • R 4 is OCH 3 .
  • two R 4 together with the carbon atom to which they are attached form cyclopropyl.
  • R 5 is methyl. In some cases, R 5 is propargyl.
  • each R N is independently H or Ci- 6 alkyl. In some cases, R N is H. In some cases, R N is Ci- 6 alkyl. In some cases, R N is methyl.
  • p is 0. In some cases, p is 1 . In some cases, p is 2.
  • n is 1 . In some cases, n is 2. In some cases, n is 3.
  • ring A comprises a 4- to 8-membered monocyclic or bicyclic carbocycle or heterocycle optionally substituted with 1 -3 R 2 groups, wherein the heterocycle comprises a ring nitrogen or oxygen, or both; each R 1 is independently Ci- 6 alkyl, O-Ci- 6 alkyl, C 0-3 alkylene-halo, O-Ci- 3 alkylene- halo,C 0-3 alkylene-CN, C 0-3 alkylene-NR 4 2 ,
  • each R 2 is independently halo, OH, Ci- 6 alkyl, Ci. 6 haloalkyl, Ci.
  • each R N is independently H or Ci- 6 alkyl
  • each R 4 is independently H, Ci. 6 alkyl, or C(O)Ci- 6 alkyl
  • each R 5 is independently Ci ealkyl, Ci-ehaloalkyl, or Ar
  • each R 6 is independently H or C-i 6 alkyl ;
  • Ar is 3-8-membered carbocycle or heterocycle, wherein the heterocycle comprises 1 - 4 ring heteroatoms selected from N, O, and S; C 6 -ioaryl; or 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S and Ar is optionally substituted with 1 -3 groups independently selected from halo, Ci. 6 alkyl, Ci. 6 haloalkyl, Ci. 6 alkoxy, Cv 6 haloalkoxy, CN, and SO 2 Ci. 3 alkyl; m is 0-2; n is 0-3; and p is 0-2.
  • one of X and Y is O and the other is CH 2 or CH 2 CH 2 , or X is null or CH 2 and Y is CH 2 O, and each R 2 is independently halo, Ci-ealkyl, or Co- 6 alkylene- N(R N ) 2 .
  • the compound has a structure of Formula (I I-2) : structure of Formula
  • one of X and Y is O and the other is CH 2 or CH 2 CH 2 , or X is null or CH 2 and Y is CH 2 O.
  • each R 2 is independently halo, Ci. 6 alkyl, or -N(R N ) 2 .
  • one of X and Y is O and the other is CH 2 or CH 2 CH 2 , or X is null or CH 2 and Y is CH 2 O and each R 2 is independently halo, Ci. 6 alkyl, or -N(R N ) 2 .
  • Y is O. In some cases, Y is CH 2 or CH 2 CH 2 . In some cases, Y is CH 2 . In some cases, Y is CH 2 CH 2 . In some cases, Y is CH 2 O. [0074] In some cases, X is CH 2 . In some cases, X is CH 2 CH 2 . In some cases, X is O.
  • R 2 is halo. In some cases, R 2 is F. In some cases, R 2 is Ci- 6 alkyl. In some cases, R 2 is methyl. In some cases, R 2 is Co- 6 alkylene-N(R N ) 2 . In some cases, R 2 is C 0 alkylene-N(R N ) 2 , i.e. , N(R N ) 2 . In some cases, R 2 is NH 2 . In some cases, R 2 is OH. In some cases, R 2 is Ci- e haloalkyl. In some cases, R 2 is Ci- S hydroxyalkyl.
  • R 3 is halo. In some cases, R 3 is F.
  • m is 0 or 1 . In some cases, m is 0. In some cases, m is 1 . In some cases, m is 2.
  • n is 0. In some cases, n is 1 , 2, or 3. In some cases, n is 1 . In some cases, n is 2. In some cases, n is 3.
  • the compound has a structure of Formula (111-2):
  • Q 1 is C 0-3 alkylene-NR 6 2 . In some cases, Q 1 is Ci- 3 alkylene-NR 6 2 .
  • Q 1 is CH 2 NH 2 .
  • Q 1 is a 4- to 8-membered monocyclic or bicyclic carbocycle or heterocycle optionally substituted with 1 -3 R 2 groups, wherein the heterocycle comprises a ring nitrogen or oxygen.
  • Q 1 comprises a quinuclidine, piperidine, pyrrolidine, azetidine, or cyclobutane moiety.
  • Q 1 is substituted with 1 -3 R 2 groups.
  • ring A comprises a quinuclidine, piperidine, pyrrolidine, 8- azabicyclo[3.2.1]octane, 6-azabicyclo[3.1 .1]heptane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, furan, pyran, oxepin, morpholine, or thiomorpholine moiety.
  • ring A is substituted with 1 -3 R 2 groups.
  • ring A is i , , is . in some cases, ring A is / In some cases, ring A is . In some cases, ring
  • R 1 is F, Cl, OH, OMe, OiPr, OBn, O-cyclopropyl, CF 3 , OCF 3 , CN, SO 2 Me, S0 2 -cyclopropyl, SO 2 iPr, oxo, imidazolyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, thiadiazolyl, methyl-thiadiazolyl, trifluoromethyl- thiadiazolyl, oxadiazolyl, methyl-oxadiazolyl, trifluoromethyl- oxadiazolyl, or phenyl.
  • R 1 is F or Cl.
  • R 1 is F.
  • R 1 is Cl.
  • p is 0. In some cases, p is 1 . In some cases, p is 2.
  • X is O, NR 2 , or CR A R B ;
  • R A is hydrogen, OH, or O-Ci-3alkyl
  • R B is hydrogen
  • R A and R B together are oxo
  • R 1 is hydrogen, Ci- 6 alkyl, C 0-3 haloalkyl, O-Ci- 3 haloalkyl,C 0-3 alkylene-CN, C 0-3 alkylene-NR N 2 , C 0 6 alkylene-OR N , Co 6 alkylene- C(O)OR N , C 0 6 alkylene-C(O)N(R N ) 2 , or Co 6 alkylene-SO p R N ; each R N is independently hydrogen or Ci. 6 alkyl, and p is 0-2;
  • R 2 is hydrogen, Ci. 6 alkyl, C 3 -6alkynyl, or Ci- 6 alkylene-SO2-Ci- 3 alkyl; each R 3 is independently halo;
  • R 4 is hydrogen, OH, halo, or Co-ealkylene-NR 6 R 7 ; each R 5 is independently hydrogen, C-i- 3 alkyl, C 0-3 hydroxyalkyl, or halo;
  • R 6 is hydrogen
  • R 7 is hydrogen, C ⁇ alkynyl, Co- 3 alkylen C(O)Ci-6haloalkyl; or
  • R 6 and R 7 together with the nitrogen to which they are attached form a 4- to 6- membered heterocycle having 0-1 additional ring heteroatoms selected from N, O, and S and optionally substituted with 1 , 2, or 3 groups independently selected from halo and oxo; m is 1 or 2; n is 0-3; and r is 1 or 2.
  • X is O, NR 2 , or CR A R B ;
  • R A is hydrogen, OH, or O-Ci- 3 alkyl
  • R B is hydrogen
  • R A and R B together are oxo
  • R 1 is hydrogen, Ci- 6 alkyl, C 0-3 haloalkyl, O-Ci- 3 haloalkyl,C 0-3 alkylene-CN, C 0-3 alkylene-NR N 2 , C 0-6 alkylene-OR N , C 0-6 alkylene- C(O)OR N , Co- 6 alkylene-C(0)N(R N ) 2 , or C 0-6 alkylene-SO p R N ; each R N is independently hydrogen or Ci- 6 alkyl, and p is 0-2;
  • R 2 is hydrogen, Ci- 6 alkyl, C 3.6 alkynyl, or Ci- 6 alkylene-SO 2 -Ci- 3 alkyl; each R 3 is independently halo;
  • R 4 is hydrogen, OH, halo, or C 0-6 alkylene-NR 6 R 7 ; each R 5 is independently hydrogen, Ci- 3 alkyl, or halo;
  • R 6 is hydrogen or Ci- 3 alkyl
  • R 7 is hydrogen, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2-6 alkynyl, Ci- 3 alkylene-O-C 2-6 alkynyl, C o - 3 alkylene-SO 2 -Ci- 3 alkyl, Co- 3 alkylene-S0 2 -Ci- 3 haloalkyl, C(O)Ci- 6 alkyl, or C(0)Ci- 6 haloalkyl; or
  • R 6 and R 7 together with the nitrogen to which they are attached form a 4- to 6- membered heterocycle having 0-1 additional ring heteroatoms selected from N, O, and S and optionally substituted with 1 , 2, or 3 groups independently selected from halo and oxo; m is 1 or 2; n is 0-3; and r is 1 or 2.
  • X is O. In some cases, X is CR A R B . In some cases, X is CH 2 . In some cases, X is NR 2 .
  • R A is OH. In some cases, R A and R B together are oxo.
  • Y is Coalkylene. In some cases, Y is Ci-ealkylene. In some cases,
  • Y is Cialkylene. In some cases, Y is C 2 alkylene. In some cases, Y is C 3 alkylene.
  • ring A is a 3- to 5-membered carbocycle. In some cases, ring A is a 6- to 8-membered carbocycle. In some cases, ring A is a 3-membered carbocycle. In some cases, ring A is a 4-membered carbocycle. In some cases, ring A is a 5-membered carbocycle. In some cases, ring A is a 6-membered carbocycle. In some cases, ring A is a 7-membered carbocycle. In some cases, ring A is a 8-membered carbocycle. In some
  • R 1 is hydrogen. In some cases, R 1 is Ci- 6 alkyl, C 0-3 haloalkyl, O-Ci- 3 haloalkyl,C 0-3 alkylene-CN, C 0-3 alkylene-NR N 2 , C 0-6 alkylene-OR N , C 0-6 alkylene- C(O)OR N , Co- 6 alkylene-C(0)N(R N ) 2 , or Co- 6 alkylene-SO p R N .
  • R 1 is F, Cl, OH, OMe, OiPr, OBn, O-cyclopropyl, CF 3 , OCF 3 , CN, SO 2 Me, S0 2 -cyclopropyl, SO 2 iPr, oxo, imidazolyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, thiadiazolyl, methyl-thiadiazolyl, trifluoromethyl- thiadiazolyl, oxadiazolyl, methyl-oxadiazolyl, trifluoromethyl- oxadiazolyl, or phenyl.
  • R 1 is F or Cl. In some cases, R 1 is F.
  • R 1 is hydrogen, Ci- 6 alkyl, C 0-3 haloalkyl, 0-Ci- 3 haloalkyl,C 0-3 alkylene-CN, C 0-3 alkylene-NR N 2 , C 0-6 alkylene-OR N , C 0-6 alkylene- C(O)OR N , C 06 alkylene-C(O)N(R N ) 2 , or Co 6 alkylene-SO p R N ; each R N is independently hydrogen or Ci. 6 alkyl, and p is 0-2.
  • At least one R N is hydrogen. In some cases, each R N is hydrogen. In some cases, at least one R N is Ci- 6 alkyl. In some cases, each R N is Ci- 6 alkyl.
  • R 2 is hydrogen. In some cases, R 2 is Ci- 6 alkyl, C 3.6 alkynyl, or Ci- 6 alkylene-SO 2 -Ci- 3 alkyl. In some cases, R 2 is CH 3 .
  • R 3 is fluoro
  • R 4 is hydrogen. In some cases, R 4 is OH. In some cases, R 4 is halo. In some cases, R 4 is F. In some cases, R 4 is Co-6alkylene-NR 6 R 7 . In some cases, R 4 is -CH 2 NH 2 , -CH 2 NHCH 3 , -CH 2 CH 2 NH 2 , -CH 2 CH(CH 3 )NH 2 , -CH 2 C(CH 3 ) 2 NH 2 , or -CH 2 CH 2 N(CH 3 ) 2 . In some cases, R 4 is NR 6 R 7 . In some cases, R 4 is Cialkylene-NR 6 R 7 .
  • R 4 is -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -NHCH 2 CF 3 , -NH-propargyl, -NHC(O)CH 3 , -NHC(O)CF 3 , -NHSO 2 CH 3 , -NHSO 2 CF 3 , or -NHCH 2 CH 2 SO 2 CH 3 .
  • R 4 is -NH 2 .
  • R 5 is hydrogen, Ci- 3 alkyl, or halo.
  • R 6 is hydrogen. In some cases, R 6 is Ci- 3 alkyl. In some cases, R 6 is methyl.
  • R 7 is hydrogen. In some cases, R 7 is Ci- 3 alkyl. In some cases, R 7 is methyl. In some cases, R 7 is ethyl. In some cases, R 7 is Ci- 3 haloalkyl. In some cases, R 7 is trifluoroethyl. In some cases, R 7 is C 2.6 alkynyl. In some cases, R 7 is propargyl. In some cases, R 7 is C 0-3 alkylene-SO 2 -Ci- 3 alkyl or C 0-3 alkylene-SO 2 -Ci- 3 haloalkyl. In some cases, R 7 is SO 2 -methyl or SO 2 CF 3 .
  • R 7 is C 2 alkylene-SO 2 -methyl. In some cases, wherein R 7 is C(O)Ci- 6 alkyl or C(0)Ci- 6 haloalkyl. In some cases, R 7 is C(O)CH 3 or C(O)CF 3 . In some cases, R 7 is hydrogen, Ci- 3 alkyl, Ci- 3 haloalkyl, C 2.6 alkynyl, Ci- 3 alkylene-O-C 2 .
  • R 6 and R 7 together with the nitrogen to which they are attached form a 4- to 6-membered heterocycle. In some cases, R 6 and R 7 together with the nitrogen to which they are attached form a heterocycle selected from , wherein N* indicates the nitrogen to which R 6 and R 7 are attached.
  • At least one R 5 is H. In some cases, each R 5 is hydrogen. In some cases, at least one R 5 is Ci- 3 alkyl. In some cases, at least one R 5 is methyl. In some cases, each R 5 is methyl. In some cases, at least one R 5 is halo. In some cases, at least one R 5 is fluoro. In some cases, each R 5 is fluoro.
  • R N is hydrogen. In some cases, R N is Ci. 6 alkyl. In some cases, R N is methyl.
  • n is 1 . In some cases, m is 2.
  • n is 0. In some cases, n is 1 . In some cases, n is 2. In some cases, n is 3.
  • p is 0. In some cases, p is 1 . In some cases, p is 2.
  • r is 1 . In some cases, r is 2. [0112] Specific compounds contemplated include those listed in Table A-3, or a pharmaceutically acceptable salt thereof:
  • the compounds described herein can be administered to a subject in a therapeutically effective amount, alone or as part of a pharmaceutically acceptable composition or formulation.
  • the compounds can be administered all at once, multiple times, or delivered substantially uniformly over a period of time. It is also noted that the dose of the compound can be varied over time.
  • a particular administration regimen for a particular subject will depend, in part, upon the compound, the amount of compound administered, the route of administration, and the cause and extent of any side effects.
  • the amount of compound administered to a subject e.g., a mammal, such as a human
  • Dosage typically depends upon the route, timing, and frequency of administration. Accordingly, the clinician titers the dosage and modifies the route of administration to obtain the optimal therapeutic effect, and conventional range-finding techniques are known to those of ordinary skill in the art.
  • the method comprises administering, for example, from about 0.1 mg/kg up to about 100 mg/kg of compound or more, depending on the factors mentioned above.
  • the dosage ranges from 1 mg/kg up to about 100 mg/kg; or 5 mg/kg up to about 100 mg/kg; or 10 mg/kg up to about 100 mg/kg.
  • Some conditions require prolonged treatment, which may or may not entail administering lower doses of compound over multiple administrations.
  • a dose of the compound is administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the treatment period will depend on the particular condition and type of pain, and may last one day to several months.
  • Suitable methods of administering a physiologically acceptable composition such as a pharmaceutical composition comprising the compounds disclosed herein are well known in the art. Although more than one route can be used to administer a compound, a particular route can provide a more immediate and more effective reaction than another route. Depending on the circumstances, a pharmaceutical composition comprising the compound is applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and/or introduced into circulation.
  • a pharmaceutical composition comprising the agent orally, through injection by intravenous, intraperitoneal, intracerebral (intra- parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means, by sustained release systems, or by implantation devices.
  • intracerebral intra- parenchymal
  • intracerebroventricular intramuscular
  • intra-ocular intraarterial
  • intraportal intralesional, intramedullary
  • intrathecal intraventricular
  • transdermal subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means, by sustained release systems, or by implantation devices.
  • the compound is administered regionally via intrathecal administration, intracerebral (intra-parenchymal) administration, intracerebroventricular administration, or intraarterial or intravenous administration feeding the region of interest.
  • the composition is administered locally via implantation of a membrane, sponge, or another appropriate material onto which the desired compound has been absorbed or encapsulated.
  • the device is, in one aspect, implanted into any suitable tissue or organ, and delivery of the desired compound is, for example, via diffusion, timed-release bolus, or continuous administration.
  • the compound is, in various aspects, formulated into a physiologically acceptable composition
  • a carrier e.g., vehicle, adjuvant, or diluent.
  • the particular carrier employed is limited only by physico-chemical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration.
  • Physiologically acceptable carriers are well known in the art.
  • Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Patent No. 5,466,468).
  • a pharmaceutical composition comprising the compound is, in one aspect, placed within containers, along with packaging material that provides instructions regarding the use of such pharmaceutical compositions.
  • such instructions include a tangible expression describing the reagent concentration, as well as, in certain embodiments, relative amounts of excipient ingredients or diluents (e.g., water, saline or PBS) that may be necessary to reconstitute the pharmaceutical composition.
  • excipient ingredients or diluents e.g., water, saline or PBS
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, mannitol, and silicic acid;
  • binders as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
  • humectants as for example, glycerol;
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • solution retarders as for example, paraffin;
  • absorption accelerators as for example, quaternary ammonium compounds;
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art.
  • the solid dosage forms may also contain opacifying agents.
  • the solid dosage forms may be embedding compositions, such that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes.
  • the active compound can also be in micro-encapsulated form, optionally with one or more excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solub
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
  • compositions used in the methods of the invention may be formulated in micelles or liposomes.
  • Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes.
  • Such formulations can facilitate intracellular delivery, since lipid bilayers of liposomes and micelles are known to fuse with the plasma membrane of cells and deliver entrapped contents into the intracellular compartment.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the frequency of dosing will depend on the pharmacokinetic parameters of the agents and the routes of administration.
  • the optimal pharmaceutical formulation will be determined by one of skill in the art depending on the route of administration and the desired dosage. See, for example, Remington’s Pharmaceutical Sciences, 18th Ed. (1990) Mack Publishing Co., Easton, PA, pages 1435-1712, incorporated herein by reference. Such formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents.
  • a suitable dose may be calculated according to body weight, body surface areas or organ size.
  • the precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition, e.g., disease or disorder, being treated, the mode of administration and the particular active substance employed.
  • the compounds may be administered by any conventional route, in particular enterally, and, in one aspect, orally in the form of tablets or capsules.
  • Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of a disease of interest. These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.
  • compositions and treatment methods of the invention are useful in fields of human medicine and veterinary medicine.
  • the subject to be treated is in one aspect a mammal.
  • the mammal is a human.
  • PAL photoaffinity labeling
  • BV2 cells were pre-treated with vehicle or Compound 1 (competitor, 10 pM) for 30 minutes and then photoaffinity labeling compound (PAL, 100 nM) was added for another 30 minutes. Cells were then washed, plates transferred to ice and irradiated with UV light for 10 minutes. After the crosslinking reaction, the cells were washed once with cold PBS and a cell scraper was used to collect cells. Pellets were washed three times with cold PBS and stored at -80 °C.
  • Proteins were precipitated using a mixture of methanol:chloroform:water (2:0.5:1 .3) and the resulting pellet resuspended in 800 pL of resuspension buffer (50 mM Tris-HCI, pH 8.0 and 1% SDS).
  • resuspended proteins were incubated with enzyme mix and incubated following the manufacturer’s (NEB) protocol. Biotinylated proteins were immunoprecipitated using streptavidin beads for 1 hour at room temperature. Bound proteins were eluted by incubating beads with 2x sample buffer containing TCEP at 100°C for 10minutes.
  • Figure 1 shows that a band running around 100 kDa could be competed by Compound 1 .
  • This band was in-gel digested with trypsin and mass spectrometry analysis identified CD68 as the potential enriched protein in the PAL sample.
  • samples were blotted with both a fluorescent streptavidin and an anti-CD68 antibody showing the overlap of the two signals ( Figure 1 ).
  • CD68 is known to be highly glycosylated.
  • a deglycosylation experiment was performed using EndoH and PNGaseF treatment of the cross-linked sample to determine whether the biotinylated protein (streptavidin signal) and CD68 signal still overlapped.
  • streptavidin and CD68 still overlapped perfectly, confirming the identity of the immunoprecipitated protein as CD68.

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Abstract

Provided herein are methods of modulating CD68, or treating CD68-associated disorders, by using a compound as disclosed herein.

Description

COMPOUNDS FOR MODULATION OF CD68 AND USES THEREOF
BACKGROUND
[0001] CD68 (SEQ ID NO: 1 or SEQ ID NO: 2); also known as GP110; LAMP4; SCARD1 ) is a heavily glycosylated transmembrane glycoprotein that is highly expressed by human monocytes and tissue macrophages [Holness et al., Blood 81 (6): 1607-13 (1993)]. It is a member of the lysosomal/endosomal-associated membrane protein (LAMP) family of glycoproteins. CD68 primarily localizes to the lysosome/endosome compartment but can also circulate to the cell surface. CD68 is also a member of the family of scavenger receptors.
INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY
[0002] The Sequence Listing, which is a part of the present disclosure, is submitted concurrently with the specification as a text file. The name of the text file containing the Sequence Listing is “ 5001 1 P2_Seqlisting.txt", which was created on June 8, 2022 and is 6,216 bytes in size. The subject matter of the Sequence Listing is incorporated herein in its entirety by reference.
SUMMARY
[0003] In any aspects or embodiments of the disclosure, methods of modulating CD68 are provided comprising contacting CD68 with a compound as disclosed herein, or pharmaceutically acceptable salt thereof, in an amount sufficient to modulate CD68.
BRIEF DESCRIPTION OF THE FIGURES
[0004] Figure 1 shows that photoaffinity cross-linking of the target CD68 was competed with Compound 1 . The target was immunoprecipitated via a biotin handle on the photoaffinity ligand, separated on gel and identified with either a fluorescent streptavidin (Strept-700) or an anti-CD68 antibody. The third image shows the overlap between the two signals.
[0005] Figure 2 shows results of experiments in which the target CD68 was glycosylated, immunoprecipitated via a biotin handle on the photoaffinity ligand, deglycosylated using either EndoH or PNGaseF, separated on gel and identified with either a fluorescent streptavidin (Strept-700) or an anti-CD68 antibody. The third image shows the overlap between the two signals.
[0006] Figure 3 shows amino acid sequences of CD68.
DETAILED DESCRIPTION
[0007] Provided herein are methods of modulating CD68 by using a compound as disclosed herein. Modulation of CD68 can be assessed using typical biological assays, including those as described in the examples section below. In some cases, the level of CD68 is increased. In some cases, the level of intracellular CD68 is decreased.
[0008] In some embodiments, with the methods disclosed herein, expression or function of CD68 is increased, compared to a control, by at least 5%, at least 10%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 90%, at least 100%, at least 125%, at least 150%, or at least 200%. In some embodiments, with the methods disclosed herein, expression or function of CD68 is decreased, compared to a control, by at least 5%, at least 10%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 90%, at least 100%, at least 125%, at least 150%, or at least 200%. Amount and/or function of CD68 can be assessed using typical biological assays understood in the art (e.g., immunoblot, quantitative RT-PCR).
[0009] The disclosure further provides methods of treating a CD68-associated disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound as disclosed herein to a subject in need thereof. In various embodiments, the CD68-associated disorder is osteoporosis, cancer, rheumatoid arthritis, lupus, inflammatory bowel disease, chronic liver injury, a wound, malaria, septic shock, or atherosclerosis. In further embodiments, the cancer is melanoma, glioma, breast cancer, ovarian cancer, bladder cancer, colorectal cancer and non-small cell lung cancer. The disclosure additionally provides methods of treating additional disorders comprising administering a therapeutically effective amount of a compound as disclosed herein to a subject in need thereof. The additional disorders contemplated by the disclosure include, without limitation, progranulin-associated disorders. The progranulin-associated disorder, in various embodiments, is Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), Frontotemporal dementia -Granulin subtype (FTD-GRN), Lewy body dementia (LBD), Prion disease, Motor neuron diseases (MND), Huntington’s disease (HD), Spinocerebellar ataxia (SCA), Spinal muscular atrophy (SMA), a lysosomal storage disease, nephropathy, a disease associated with inclusions and/or misfunction of C9orf72, TDP-43, FUS, UBQLN2, VCP, CHMP2B, and/or MAPT, an acute neurological disorder, glioblastoma, or neuroblastoma. In further embodiments, the lysosomal storage disease is Paget’s disease, Gaucher’s disease, Nieman’s Pick disease, Tay-Sachs Disease, Fabry Disease, Pompe disease, or Naso-Hakula disease. In still further embodiments, the acute neurological disorder is stroke, cerebral hemorrhage, traumatic brain injury or head trauma. In some embodiments, the disorder is Frontotemporal dementia (FTD).
[0010] As used herein, the term "subject" refers to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Preferably, the subject is a human. [0011 ] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as described herein. In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer. In some embodiments, the amount is that effective for alleviating, reducing or eliminating an inflammatory condition.
[0012] The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
[0013] As used herein, the terms "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.
[0014] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and/or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
[0015] All language such as "from," "to," "up to," "at least," "greater than," "less than," and the like include the number recited and refer to ranges which can subsequently be broken down into sub-ranges.
[0016] As used in this specification and the appended claims, the articles "a" and "an" refer to one or to more than one (for example, to at least one) of the grammatical object of the article.
[0017] "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20-25 percent (%), for example, within 20 percent, 10 percent, 5 percent, 4 percent, 3 percent, 2 percent, or 1 percent of the stated value or range of values.
Compounds for Use
[0018] Compounds for use in the disclosed methods are described below. Synthesis of these compounds can be performed via any suitable means, e.g., as described in WO 2019/118528, WO 2020/252222, or WO 2021/081272.
[0019] As used herein, the term “alkyl” refers to straight chained and branched saturated hydrocarbon groups containing one to six carbon atoms. The term Cn means the alkyl group has “n” carbon atoms. For example, C6 alkyl refers to an alkyl group that has 6 carbon atoms. Ci-C6 alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (e.g., 1 to 6 carbon atoms), as well as all subgroups (e.g., 1 -6, 2-6, 1-5, 3-6, 1 , 2, 3, 4, 5, and 6 carbon atoms). Nonlimiting examples of alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), t-butyl (1 ,1 -dimethylethyl), and 3-methylpentyl. Unless otherwise indicated, an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.
[0020] The term “alkylene” used herein refers to an alkyl group having a substituent. For example, an alkylene group can be -CH2CH2- or -CH2-. The term Cr means the alkylene group has “n” carbon atoms. For example, Ci-6 alkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for “alkyl” groups. A Co alkylene indicates a direct bond. Unless otherwise indicated, an alkylene group can be an unsubstituted alkylene group or a substituted alkylene group. Particular substitutions on the alkylene group can be specified, e.g., alkylene-CN, or the like.
[0021] The term “alkyne” or “alkynyl” used herein refers to an unsaturated aliphatic group analogous in length and possible substitution to an alkyl group described above, but that contains at least one triple bond. For example, the term “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl), and branched alkynyl groups. For example, a straight chain or branched alkynyl group can have six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C3” includes chains having a number of carbon atoms encompassing the entire range (e.g., 2 to 6 carbon atoms), as well as all subgroups (e.g., 2-6, 2-5, 2-4, 3-6, 2, 3, 4, 5, and 6 carbon atoms). The term “C3-C6” includes chains having a number of carbon atoms encompassing the entire range (e.g., 3 to 6 carbon atoms), as well as all subgroups (e.g., 3- 6, 3-5, 3-4, 3, 4, 5, and 6 carbon atoms). Unless otherwise indicated, an alkynyl group can be an unsubstituted alkynyl group or a substituted alkynyl group.
[0022] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more halogen substituents. For example, Ci-C6haloalkyl refers to a Ci-C6 alkyl group substituted with one or more halogen atoms, e.g., 1 , 2, 3, 4, 5, or 6 halogen atoms. A Cohaloalkyl refers simply to a halo substituent. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl groups.
[0023] As used herein, the term “halo” or “halogen” refers to fluorine, chlorine, bromine, or iodine.
[0024] As used herein, the term “hydroxyalkyl” refers to an alkyl group substituted with one or more hydroxyl substituents. For example, Ci-C3hydroxyalkyl refers to a Ci-C6 alkyl group substituted with one or more hydroxyl groups, e.g., 1 , 2, 3, 4, 5, or 6 hydroxyl groups. A Cohydroxyalkyl refers to a hydroxyl group. Non-limiting examples of hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl groups.
[0025] As used herein, the term “alkoxy” refers to a straight or branched hydrocarbon group which has an oxygen atom as the point of attachment. The alkoxy group can further comprise additional oxygen atoms in the hydrocarbon backbone, e.g., 1 , 2, 3, or 4 additional oxygen atoms.
[0026] As used herein, the term “oxo” refers to =0 substituent, e.g., a carbon can be substituted with an oxo to form a carbonyl (C=O) group.
[0027] As used herein, the term “carbocycle” or “carbocyclyl” or “cycloalkyl” refers to a cyclic hydrocarbon group containing three to eight carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 carbon atoms). The term “n-membered carbocycle” means the carbocycle group has “n” carbon atoms. For example, 5-membered carbocycle refers to a carbocycle group that has 5 carbon atoms in the ring. 6- to 8-membered carbocycle refers to carbocycle groups having a number of carbon atoms encompassing the entire range (e.g., 6 to 8 carbon atoms), as well as all subgroups (e.g., 6-7, 6-8, 7-8, 6, 7, and 8 carbon atoms). Nonlimiting examples of carbocycle groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise indicated, a carbocycle group can be an unsubstituted carbocycle group or a substituted carbocycle group. The carbocycle groups described herein can be isolated or fused to another carbocycle group. In particular, the carbocycles described herein can have a fused, bridged, or spiro structure. When a carbocycle group is fused to another carbocycle group, then each of the carbocycle groups can contain three to eight carbon atoms unless specified otherwise.
[0028] As used herein, the term “heterocycle” or “heterocycloalkyl” is defined similarly as carbocycle, except the ring contains one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur. In particular, the term “heterocycle” refers to a ring containing a total of three to eight atoms (e.g., three to five, or five to eight), of which 1 , 2, 3 or 4 of those atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, and the remaining atoms in the ring are carbon atoms. Nonlimiting examples of heterocycle groups include azetidine, piperdine, piperazine, pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, quinuclidine, and the like. Heterocycle groups can be saturated or partially unsaturated ring systems optionally substituted with, for example, one to three groups, such as halo, Ci-6alkyl, Ci-6haloalkyl, Ci- 6alkoxy, Ci-6haloalkoxy, CN, and SO2Ci-3alkyl. In various cases, cycloalkyl and heterocycloalkyl groups can be saturated or partially unsaturated ring systems optionally substituted with, for example, one to three groups, independently selected alkyl, alkyleneOH, C(O)NH2, NH2, OXO (=0), aryl, alkylenehalo, halo, and OH. Other substituents are also contemplated, including C0-3 alkylene-halo, C0.3 alkylene-CN, C0.3 alkylene-NH2, C0-3 alkyleneOH, and C0-3alkylene-O-Ci.3alkyl. Heterocycloalkyl groups optionally can be further N- substituted with alkyl, alkylene-OH, alkylenearyl, and alkyleneheteroaryl. The heterocycle groups described herein can be isolated or fused to another heterocycle group and/or a carbocycle group. When a heterocycle group is fused to another heterocycle group, then each of the heterocycle groups can contain three to ten total ring atoms, and one to four heteroatoms.
[0029] As used herein, the term “aryl" refers to a monocyclic aromatic group, such as phenyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four groups independently selected from, for example, halo, alkyl, alkenyl, OCF3, N02, CN, NC, OH, alkoxy, amino, CO2H, CO2alkyl, aryl, and heteroaryl. Other substituents are also contemplated, including Co-3alkylene-halo, Co-3 alkylene-CN, Co-3alkylene-NH2, Co-3 alkylene-OH, and Co-3alkylene-0-Ci-3alkyl. Aryl groups can be isolated (e.g., phenyl) or fused to another aryl group (e.g., naphthyl, anthracenyl), a cycloalkyl group (e.g., tetraydronaphthyl), a heterocycloalkyl group, and/or a heteroaryl group. Exemplary aryl groups include, but are not limited to, phenyl, chlorophenyl, fluorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4- methoxychlorophenyl, and the like.
[0030] As used herein, the term “heteroaryl” refers to a monocyclic aromatic ring having 5 to 6 total ring atoms, and containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur atom in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to four, substituents selected from, for example, halo, alkyl, alkenyl, OCF3, NO2, CN, NC, OH, alkoxy, amino, CO2H, CO2alkyl, aryl, and heteroaryl. Other substituents are also contemplated, including C0 3alkylene-halo, C0 3 alkylene-CN, C0 3alkylene-NH2, C0 3 alkylene-OH, and C0 3alkylene-O- Ci-3alkyl. In some cases, the heteroaryl group is substituted with one or more of alkyl and alkoxy groups. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
[0031] As used herein, the term “substituted,” when used to modify a chemical functional group, refers to the replacement of at least one hydrogen radical on the functional group with a substituent. Unless otherwise specified for a particular moiety, substituents can include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, oxy, alkoxy, heteroalkoxy, ester, thioester, carboxy, cyano, nitro, amino, amido, acetamide, and halo (e.g., fluoro, chloro, bromo, or iodo). When a chemical functional group includes more than one substituent, the substituents can be bound to the same carbon atom or to two or more different carbon atoms.
[0032] Compounds of the present disclosure can exist in particular geometric or stereoisomeric forms having one or more asymmetric carbon atoms. The present disclosure contemplates such forms, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosed compounds. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended for inclusion herein.
[0033] As used herein, the term “pharmaceutically acceptable” means that the referenced substance, such as a compound of the present disclosure, or a formulation containing the compound, or a particular excipient, are safe and suitable for administration to a patient or subject. The term “pharmaceutically acceptable excipient” refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.
[0034] The compounds disclosed herein can be as a pharmaceutically acceptable salt.
As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benef it/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1 -19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutamate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such salts include, but are not limited to, alkali metal, alkaline earth metal, aluminum salts, ammonium, N+(Ci-4alkyl)4 salts, and salts of organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N’- dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2- hydroxyethyljamine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N’- bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
[0035] Formula (I) Compounds: [0036] Provided herein are compounds, or salts thereof, for use in the disclosed methods having a structure of Formula (I):
Figure imgf000011_0001
wherein ring B is a 5-12 membered monocyclic, bicyclic, or bridged nitrogen-containing heterocycle comprising 0-1 additional ring heteroatoms selected from N, O, and S,
R1 is either a part of a bicyclic or bridged heterocycle or is H, Ci-6alkyl, SO2R6, or C(O)R3; ring A is a C6aryl or 5-7 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S, and is optionally substituted with 1 -3 R3 groups;
X is Ci-5alkylene, Co-5alkylene-Y or Y-Ci-5alkylene-Y; each Y is independently C(O), OC(O), C(O)NR4, NR4C(O), or SO2;
R2 is C6-ioaryl, 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S, or 5-12 membered monocyclic or bicyclic carbocycle or heterocycle, wherein the heterocycle comprises 1-4 ring heteroatoms selected from N, O, and S, and R2 is optionally substituted with 1-3 R3 groups; each R3, when present, is independently selected from Ci.6alkyl, Co-3alkylene-halo, 0-Ci-3 alkylene-halo,Co-3alkylene-CN, C0-3alkylene-NR5 2, C0-6 alkylene- OR5, Co-salkylene- C(O)OR7, C(O)N(R7)2, SO2R6, O-Co-ealkylene-Ar, oxo, and Co.6alkylene-Ar;
Ar is 3-8-membered carbocycle or heterocycle, wherein the heterocycle comprises 1 - 4 ring heteroatoms selected from N, O, and S; C6-ioaryl; or 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S and Ar is optionally substituted with 1 -3 groups independently selected from halo, Ci-ealkyl, Ci-shaloalkyl, Ci-salkoxy, Ci- ehaloalkoxy, CN, and SO2Ci-3alkyl; each R4 and R5 is independently H, Ci-salkyl, or C(O)Ci-6alkyl; each R6 is independently Ci-ealkyl, Ci-ehaloalkyl, or Ar; each R7 is independently H or Ci-6alkyl; m is 0-2; and n is 0-2, with the proviso that the compound is not
Figure imgf000012_0001
In some cases, the structure of Formula (I) has a structure
Figure imgf000012_0002
Figure imgf000012_0003
SO2Me, or C(O)Me. In some cases, R1 is H or Me.
[0038] In various cases, ring A comprises phenyl or pyridyl and is optionally substituted with 1 -2 groups selected from fluoro and chloro. In some cases, ring A is phenyl substituted with 1 fluoro. In some cases, ring A is phenyl substituted with 1 chloro. In some cases, ring A is pyridyl substituted with 1 fluoro. In some cases, ring A is pyridyl substituted with 1 chloro. In some cases, ring A is unsubstituted phenyl. In some cases, ring A is unsubstituted pyridyl.
[0039] X can be Ci-salkylene, Co-salkylene-Y or Y-Ci-salkylene-Y; and each Y is independently C(O), OC(O), C(O)NR4, NR4C(O), or SO2. In some cases, X is Y (i.e., no alkylene linker is present). In some cases, X comprises an alkylene linker to ring A (i.e., comprises a Ci-5alkylene moiety, with or without a Y group present). In various cases, X is Co-5alkylene-Y or Y-C0-5alkylene-Y. In some cases, Y is NR4C(O) or C(O)NR4 and R4 is H or Me. In some specific cases, X is CH2C(O), OC(O), or NR4C(O) (e.g., R4 is H). In various cases, X is OC(O). In some cases, X is NHC(O). In some cases, X is CH2C(O).
[0040] R2 can be Ce-ioaryl, 5-10 membered heteroaryl comprising 1 -4 ring heteroatoms selected from N, O, and S, or 5-12 membered monocyclic or bicyclic carbocycle or heterocycle, wherein the heterocycle comprises 1 -4 ring heteroatoms selected from N, O, and S, and R2 is optionally substituted with 1-3 R3 groups. In various cases, R2 is phenyl, e.g., phenyl substituted with 1 -2 fluoro and/or chloro groups. In some cases, R2 is pyridyl, pyrazine, pyrimidine, thiophene, benzothiophene, benzofuranyl, piperidinone, indole, indazole, benzodiazole, benzoimidazole, benzoxazole, benzothiazole, indolizine, imidazo- [1 ,2-a]pyridine, imidazo-[1 ,5-a]pyridine, or imidazo-[1 ,2-a]pyrimidine. In various cases, R2 is unsubstituted. In some cases, R2 is substituted with 1 R3. In some cases, R2 is substituted with 2 R3. In some cases, R2 is substituted with 3 R3.
[0041] In some specific cases, R2 is selected from the group consisting
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000014_0001
[0042] In various cases, the structure of Formula (I) is a structure of Formula (IA)
Figure imgf000014_0002
wherein Y’ is CH2, NR4 or O, and each R8 is independently H or Me, or both R8 taken together with the carbon to which they are attached form a cyclopropyl ring. In some cases, the structure of Formula (IA) can be
Figure imgf000014_0003
structure can alternatively
Figure imgf000015_0001
various cases, the structure of
Formula (IA) can be wherein one R8 is H and the other Me. In some cases, each R8 is Me.
In various cases, both R8 together with the carbon to which they are attached form a cyclopropyl ring.
[0043] Some specifically contemplated compounds of Formula (I) include those as shown in Table A below, or a pharmaceutically acceptable salt thereof.
Table A
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000021_0002
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000027_0002
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000029_0003
Figure imgf000029_0002
[0044] In various cases, a compound of the disclosure is one as listed in Table B, or a pharmaceutically acceptable salt thereof.
Table B
Figure imgf000029_0001
Figure imgf000030_0001
[0045] In various cases, the compound of the disclosure is a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure imgf000031_0001
Figure imgf000032_0001
[0046] Formula (1-1) Compounds:
[0047] Provided herein are compounds, or salts thereof, for use in the disclosed methods having a structure of Formula (1-1):
Figure imgf000032_0002
wherein A is a 4-10 membered heterocycle comprising 1 to 3 ring heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R3;
Y is Co-salkylene, Co.6alkylene-0-Co-6alkylene, C0.6alkylene-NRN, Co-salkylene-S02, CO, CO2, or CONH, wherein Co-6alkylene is optionally substituted with 1 or 2 R4; each R1 is independently halo, -O-CH2-Csaryl-(OCH2CH2)p-OR5, or -O-CH2-Het-
(OCH3), wherein Het is a 6-membered heteroaryl comprising 2 ring N atoms; one R2 is H and the other is H, CN, COOCi-salkyl, CONHCi-ealkyl, SO2CH3, or O- propargyl;
R3 is Cvsalkyl, halo, Coealkylene-OH, Co-6alkylene-0-propargyl, propargyl, or Co- 6alkylene-NRNRN; each R4 is independently F, OH, or OCi-6alkyl, or two R4 together with the carbon atom to which they are attached form cyclopropyl;
R5 is Ci-6alkyl or propargyl; each RN is independently H or Ci-6alkyl; n is 1 -3; and p is 0-2; with the proviso that
Figure imgf000033_0001
Y is CH2, O, or NRN, then one R2 is H and the other R2 is not H; or
Figure imgf000033_0002
membered heterocycle comprising 1 to 3 ring heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 R3;
Y is Co-salkylene, Co.6alkylene-0-Co-6alkylene, C0.6alkylene-NRN, Co-salkylene-S02, CO2-, or CONH-, wherein Co-6alkylene is optionally substituted with 1 or 2 R4; each R1 is independently halo, -O-CH2-C6aryl-(OCH2CH2)P-OR5, or -O-CH2-Het-
(OCH3), wherein Het is a 6-membered heteroaryl comprising 2 ring N atoms; one R2 is H and the other is H, CN, COOCi-salkyl, CONHCi-ealkyl, SO2CH3, or O- propargyl;
R3 is Ci-6alkyl; each R4 is independently F or OR3;
R5 is Ci-6alkyl or propargyl;
RN is H or Ci-6alkyl; n is 1 -3; and p is 0-2; with the proviso that
(a) if A comprises
Figure imgf000033_0003
Y is CH2, O, or NRN, then one R2 is H and the other R2 is not H; or hen A does not comprise
Figure imgf000033_0004
Figure imgf000033_0005
[0048] In some embodiments, A is a 4-10 membered heterocycle comprising 1 to 3 ring heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 R3;
Y is C0-6alkylene, C0-6alkylene-O, Co-6alkylene-0-Co-salkylene, C0-6alkylene-NR3, Co- 6alkylene-SO2, CO2-, or CONH-, wherein Co ealkylene is optionally substituted with 1 or 2 R4; each R1 is independently halo, -O-CH2-C6aryl-(OCH2CH2)P-OR5, or -O-CH2-Het- (OCH3), wherein Het is a 6-membered heteroaryl comprising 2 ring N atoms; one R2 is H and the other is H, CN, COOCi.6alkyl, CONHCi.6alkyl, SO2CH3, or O- propargyl;
R3 is H or Ci-6alkyl; each R4 is independently F or OR3;
R5 is Ci-salkyl or propargyl; n is 1 -3; and p is 0-2; with the proviso that
Figure imgf000034_0001
Figure imgf000034_0002
[0049] In some embodiments, the compound of Formula (1-1 ) has the structure of Formula (la-1 ) or (lb-1 ):
Figure imgf000034_0003
compound of Formula (1-1 ) has the structure of Formula (la-1 ). In some cases, the compound of Formula (1-1 ) has the structure of Formula (lb-1 ).
[0050] In some embodiments, the compound of Formula (l)-1 has the structure of Formula (lc-1 ) or (Id-1):
Figure imgf000035_0001
compound of Formula (1-1 ) has the structure of Formula (lc-1 ). In some cases, the compound of Formula (1-1 ) has the structure of Formula (Id-1 ).
[0051] In some cases, A comprises a 4 membered heterocycle. In some cases, A comprises a 5 membered heterocycle. In some cases, A comprises a 6 membered heterocycle. In some cases, A comprises a 7 membered heterocycle. In some cases, A comprises an 8 membered heterocycle. In some cases, A comprises a 9 membered heterocycle. In some cases, A comprises a 10 membered heterocycle. In some cases, A comprises a 4-, 6-, 8-, or 10-membered heterocycle comprising 1 or 2 ring heteroatoms selected from N and O. In some cases, A comprises an 8-membered heterocycle comprising 1 or 2 ring heteroatoms selected from N and O. In some cases, A is substituted with 1 to 3 R3. In some cases, A is substituted with 1 or 2 R3. In some cases, A is unsubstituted.
Figure imgf000035_0002
Figure imgf000036_0001
[0053] In some cases, A comprises
Figure imgf000036_0002
In some cases, A comprises
Figure imgf000036_0003
In some cases, A comprises
Figure imgf000036_0004
In some cases, A
Figure imgf000036_0005
In some cases, A comprises
Figure imgf000037_0001
some cases, A
Figure imgf000037_0002
[0055] In some cases, Y is C0.6alkylene, Co-6alkylene-0-Co.6alkylene (e.g., Co-salkylene-O), C0-6alkylene-NRN, C0-6alkylene-SO2, CO, CO2-, or CONH-. In some cases, Y is Co.6alkylene, Co-6alkylene-0-Co-6alkylene (e.g., Co-6alkylene-0), C0-salkylene-NRN, C0-6alkylene-SO2, CO2-, or CONH-. In some cases, Y is Co alkylene (i.e., a bond). In some cases, Y is Ci.6alkylene, Ci-ealkylene-O, or Ci-6alkylene-NRN.
[0056] In some cases, Y is C0.6alkylene-O or C0.6alkylene-NRN. In some cases, Y is C0- 6alkylene-O. In some cases, Y is Ci 6alkylene-O. In some cases, Y is Ci 6alkylene-NRN. In some cases, Y is NH or O. In some cases, Y is NH. In some cases, Y is O.
[0057] In some cases, the Ci-6alkylene of a Y moiety is unsubstituted. In some cases, Ci- 6alkylene is substituted with 1 or 2 R4. In some cases, Ci-6alkylene is substituted with 1 R4.
[0058] In some cases, each R1 is independently halo. In some cases, each R1 is independently -O-CH2-C6aryl-(OCH2CH2)p-OR5 or -O-CH2-Het-(OCH3), wherein Het is a 6- membered heteroaryl comprising 2 ring N atoms. In some cases, each R1 is independently - O-CH2-C6aryl-(OCH2CH2)p-OR5. In some cases, each R1 is independently -O-CH2-Het- (OCH3).
[0059] In some cases, at least one R1 is halo. In some cases, at least one R1 is F. In some cases, each R1 is F. In some cases, at least one R1 is -O-CH2-C6aryl-(OCH2CH2)p- OR5. In some cases, at least one R1 is -O-CH2-Het. In some cases, Het comprises 2- pyrimidyl or 5-pyrimidyl optionally substituted with OMe. In some cases, Het comprises 2- pyrimidyl. In some cases, Het comprises 5-pyrimidyl. In some cases, Het is unsubstituted. In some cases, Het is substituted with OMe.
[0060] In some cases, both R2 are H. In some cases, one R2 is H and the other is CN, COOCi-6alkyl, CONHCi-6alkyl, SO2CH3, or O-propargyL In some cases, In some cases, one R2 is H and the other is CN. In some cases, one R2 is H and the other is COOCH3 or CONHCH3. In some cases, one R2 is H and the other is COOCH3. In some cases, one R2 is H and the other is CONHCH3. In some cases, In some cases, one R2 is H and the other is SO2CH3. In some cases, In some cases, one R2 is H and the other is O-propargyL
[0061] In some cases, R3 is Ci-6alkyl, halo, Co-6alkylene-OH, C0-6alkylene-O-propargyl, propargyl, or Co-6alkylene-NRNRN. In some cases, R3 is Ci-6alkyl. In some cases, R3 is C1- 6alkyl . In some cases, R3 is halo. In some cases, R3 is fluoro. In some cases, R3 is Co- 6alkylene-OH. In some cases, R3 is Cialkylene-OH. In some cases, R3 is C0alkylene-OH, i.e., R3 is OH. In some cases, R3 is Co 6alkylene-O-propargyl. In some cases, R3 is C2alkylene-O-propargyl. In some cases, R3 is propargyl. In some cases, R3 is Co-6alkylene- NRNRN. In some cases, R3 is Cialkylene-NRNRN. In some cases, R3 is Coalkylene-NRNRN, i.e., R3 is NRNRN.
[0062] In some cases, each R4 is independently F, OH, or OCi-6alkyl, or two R4 together with the carbon atom to which they are attached form cyclopropyl. In some cases, R4 is F, OH, or OCH3. In some cases, R4 is F. In some cases, R4 is OH or OCH3. In some cases, R4 is OH. In some cases, R4 is OCH3. In some cases, two R4 together with the carbon atom to which they are attached form cyclopropyl.
[0063] In some cases, R5 is methyl. In some cases, R5 is propargyl.
[0064] In some cases, each RN is independently H or Ci-6alkyl. In some cases, RN is H. In some cases, RN is Ci-6alkyl. In some cases, RN is methyl.
[0065] In some cases, p is 0. In some cases, p is 1 . In some cases, p is 2.
[0066] In some cases, n is 1 . In some cases, n is 2. In some cases, n is 3.
[0067] Specific compounds contemplated include those listed in Table A-1 , or a pharmaceutically acceptable salt thereof:
Figure imgf000038_0001
Figure imgf000038_0003
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000041_0002
Figure imgf000041_0001
Figure imgf000042_0002
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000046_0002
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000049_0002
Figure imgf000049_0001
Figure imgf000050_0002
Figure imgf000050_0001
Figure imgf000051_0002
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000054_0001
[0068] Some other compounds for use contemplated include those listed in Table B-1 , or a pharmaceutically acceptable salt thereof.
Table B-1
Figure imgf000054_0002
Figure imgf000054_0003
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000058_0002
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000062_0002
Figure imgf000062_0001
Figure imgf000063_0002
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000066_0002
Figure imgf000066_0001
Figure imgf000067_0002
[0069] Compounds of Formula (1-2):
[0070] Provided herein are compounds, or salts thereof, for use in the disclosed methods having a structure of Formula (1-2):
Figure imgf000067_0001
wherein one of X and Y is O and the other is CH2 or CH2CH2, or X is null or CH2 and Y is CH2O or (C=O)NH; one of Q1 and Q2 is H and the other is C0-3alkylene-NR6 2 or ring A, or Q1 and Q2 together with the atom to which they are attached form ring A; ring A comprises a 4- to 8-membered monocyclic or bicyclic carbocycle or heterocycle optionally substituted with 1 -3 R2 groups, wherein the heterocycle comprises a ring nitrogen or oxygen, or both; each R1 is independently Ci-6alkyl, O-Ci-6alkyl, C0-3alkylene-halo, O-Ci-3alkylene- halo,C0-3alkylene-CN, C0-3alkylene-NR4 2, C0-6alkylene-OR4, C0-6alkylene-C(O)OR6, C(O)N(R6)2, SOpR5, O-C0 6alkylene-Ar, oxo, and C06alkylene-Ar; each R3 is independently halo, Ci.6alkyl, C0-3alkylene-halo, 0-Ci-3aikylene-halo,Co- 3alkylene-CN, C0.3alkylene-NR4 2, C0.6alkylene-OR4, C0-6alkylene-C(O)OR6, C(O)N(R6)2, SO2R5, O-C0-6alkylene-Ar, and C0.6alkylene-Ar; each R2 is independently halo, OH, Ci-6alkyl, Ci.6haloalkyl, Ci.6hydroxyalkyl, or Co- 6alkylene-N(RN)2; each RN is independently H or Ci-6alkyl; each R4 is independently H, Ci.6alkyl, or C(O)Ci-6alkyl; each R5 is independently Ci ealkyl, Ci-ehaloalkyl, or Ar; each R6 is independently H or C-i 6alkyl ;
Ar is 3-8-membered carbocycle or heterocycle, wherein the heterocycle comprises 1 - 4 ring heteroatoms selected from N, O, and S; C6-ioaryl; or 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S and Ar is optionally substituted with 1 -3 groups independently selected from halo, Ci.6alkyl, Ci.6haloalkyl, Ci.6alkoxy, Cv 6haloalkoxy, CN, and SO2Ci.3alkyl; m is 0-2; n is 0-3; and p is 0-2. In some cases, one of X and Y is O and the other is CH2 or CH2CH2, or X is null or CH2 and Y is CH2O, and each R2 is independently halo, Ci-ealkyl, or Co-6alkylene- N(RN)2.
[0071] In some cases, the compound has a structure of Formula (I I-2) : structure of Formula
Figure imgf000068_0001
Figure imgf000068_0002
[0072] In some cases, one of X and Y is O and the other is CH2 or CH2CH2, or X is null or CH2 and Y is CH2O. In some cases, each R2 is independently halo, Ci.6alkyl, or -N(RN)2. In some cases, one of X and Y is O and the other is CH2 or CH2CH2, or X is null or CH2 and Y is CH2O and each R2 is independently halo, Ci.6alkyl, or -N(RN)2.
[0073] In some cases, Y is O. In some cases, Y is CH2 or CH2CH2. In some cases, Y is CH2. In some cases, Y is CH2CH2. In some cases, Y is CH2O. [0074] In some cases, X is CH2. In some cases, X is CH2CH2. In some cases, X is O.
[0075] In some cases, X is CH2 and Y is O. In some cases, X is CH2CH2 and Y is O. In some cases, X is CH2 and Y is CH2O. In some cases, X is null and Y is CH2O. In some cases, X is null and Y is (C=O)NH.
[0076] In some cases, R2 is halo. In some cases, R2 is F. In some cases, R2 is Ci-6alkyl. In some cases, R2 is methyl. In some cases, R2 is Co-6alkylene-N(RN)2. In some cases, R2 is C0alkylene-N(RN)2, i.e. , N(RN)2. In some cases, R2 is NH2. In some cases, R2 is OH. In some cases, R2 is Ci-ehaloalkyl. In some cases, R2 is Ci-Shydroxyalkyl.
[0077] In some cases, R3 is halo. In some cases, R3 is F.
[0078] In some cases, m is 0 or 1 . In some cases, m is 0. In some cases, m is 1 . In some cases, m is 2.
[0079] In some cases, n is 0. In some cases, n is 1 , 2, or 3. In some cases, n is 1 . In some cases, n is 2. In some cases, n is 3.
[0080] In some cases, the compound has a structure of Formula (111-2):
Figure imgf000069_0001
[0081] In some cases, Q1 is C0-3alkylene-NR6 2. In some cases, Q1 is Ci-3alkylene-NR6 2.
In some cases, Q1 is CH2NH2.
[0082] In some cases, Q1 is a 4- to 8-membered monocyclic or bicyclic carbocycle or heterocycle optionally substituted with 1 -3 R2 groups, wherein the heterocycle comprises a ring nitrogen or oxygen. In some cases, Q1 comprises a quinuclidine, piperidine, pyrrolidine, azetidine, or cyclobutane moiety. In some cases, Q1 is substituted with 1 -3 R2 groups. In
Figure imgf000069_0002
[0083] In some cases, ring A comprises a quinuclidine, piperidine, pyrrolidine, 8- azabicyclo[3.2.1]octane, 6-azabicyclo[3.1 .1]heptane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, furan, pyran, oxepin, morpholine, or thiomorpholine moiety.
[0084] In some cases, ring A is substituted with 1 -3 R2 groups. In some cases, ring A is i
Figure imgf000070_0001
, ,
Figure imgf000070_0002
is
Figure imgf000070_0004
. in some cases, ring A is / In some cases, ring A is
Figure imgf000070_0003
. In some cases, ring
Figure imgf000070_0005
[0085] In some cases, R1 is F, Cl, OH, OMe, OiPr, OBn, O-cyclopropyl, CF3, OCF3, CN, SO2Me, S02-cyclopropyl, SO2iPr, oxo, imidazolyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, thiadiazolyl, methyl-thiadiazolyl, trifluoromethyl- thiadiazolyl, oxadiazolyl, methyl-oxadiazolyl, trifluoromethyl- oxadiazolyl, or phenyl. In some cases, R1 is F or Cl. In some cases, R1 is F. In some cases, R1 is Cl.
[0086] In some cases, p is 0. In some cases, p is 1 . In some cases, p is 2.
[0087] Specific compounds contemplated include those listed in Table A-2, or a pharmaceutically acceptable salt thereof:
Table A-2
Figure imgf000070_0006
Figure imgf000070_0007
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000075_0002
Figure imgf000075_0001
[0088] Also contemplated for use in the disclosed methods are compounds, or pharmaceutically acceptable salts thereof, as listed in Table B-2:
Table B-2
Figure imgf000075_0004
Figure imgf000075_0003
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000077_0002
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0002
Figure imgf000080_0001
Figure imgf000081_0002
Figure imgf000081_0001
[0089] Additional compounds contemplated for use in the disclosed methods include those listed in Table C-2, or a pharmaceutically acceptable salt thereof:
Table C-2
Figure imgf000081_0004
Figure imgf000081_0003
Figure imgf000082_0002
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000084_0002
Figure imgf000084_0003
[0090] Compounds of Formula (1-3):
[0091 ] The disclosure provides compounds of Formula (I-3):
Figure imgf000084_0001
wherein
X is O, NR2, or CRARB;
Y is Co salkylene; ring A is a 3- to 8-membered carbocycle;
RA is hydrogen, OH, or O-Ci-3alkyl;
RB is hydrogen; or
RA and RB together are oxo;
R1 is hydrogen, Ci-6alkyl, C0-3 haloalkyl, O-Ci-3 haloalkyl,C0-3alkylene-CN, C0-3 alkylene-NRN 2, C0 6 alkylene-ORN, Co 6 alkylene- C(O)ORN, C06 alkylene-C(O)N(RN)2, or Co 6 alkylene-SOpRN; each RN is independently hydrogen or Ci.6alkyl, and p is 0-2;
R2 is hydrogen, Ci.6alkyl, C3-6alkynyl, or Ci-6alkylene-SO2-Ci-3alkyl; each R3 is independently halo;
R4 is hydrogen, OH, halo, or Co-ealkylene-NR6R7; each R5 is independently hydrogen, C-i-3alkyl, C0-3hydroxyalkyl, or halo;
R6 is hydrogen
R7 is hydrogen, C^alkynyl, Co-3alkylen
Figure imgf000085_0001
C(O)Ci-6haloalkyl; or
R6 and R7 together with the nitrogen to which they are attached form a 4- to 6- membered heterocycle having 0-1 additional ring heteroatoms selected from N, O, and S and optionally substituted with 1 , 2, or 3 groups independently selected from halo and oxo; m is 1 or 2; n is 0-3; and r is 1 or 2.
[0092] In some cases, X is O, NR2, or CRARB;
Y is Co salkylene; ring A is a 3- to 8-membered carbocycle;
RA is hydrogen, OH, or O-Ci-3alkyl;
RB is hydrogen; or
RA and RB together are oxo;
R1 is hydrogen, Ci-6alkyl, C0-3 haloalkyl, O-Ci-3 haloalkyl,C0-3 alkylene-CN, C0-3 alkylene-NRN 2, C0-6 alkylene-ORN, C0-6 alkylene- C(O)ORN, Co-6 alkylene-C(0)N(RN)2, or C0-6 alkylene-SOpRN; each RN is independently hydrogen or Ci-6alkyl, and p is 0-2;
R2 is hydrogen, Ci-6alkyl, C3.6alkynyl, or Ci-6alkylene-SO2-Ci-3alkyl; each R3 is independently halo;
R4 is hydrogen, OH, halo, or C0-6alkylene-NR6R7; each R5 is independently hydrogen, Ci-3alkyl, or halo;
R6 is hydrogen or Ci-3alkyl;
R7 is hydrogen, Ci-3alkyl, Ci-3haloalkyl, C2-6alkynyl, Ci-3alkylene-O-C2-6alkynyl, Co- 3alkylene-SO2-Ci-3alkyl, Co-3alkylene-S02-Ci-3haloalkyl, C(O)Ci-6alkyl, or C(0)Ci-6haloalkyl; or
R6 and R7 together with the nitrogen to which they are attached form a 4- to 6- membered heterocycle having 0-1 additional ring heteroatoms selected from N, O, and S and optionally substituted with 1 , 2, or 3 groups independently selected from halo and oxo; m is 1 or 2; n is 0-3; and r is 1 or 2.
[0093] In some cases, X is O. In some cases, X is CRARB. In some cases, X is CH2. In some cases, X is NR2.
[0094] In some cases, RA is OH. In some cases, RA and RB together are oxo.
[0095] In some cases, Y is Coalkylene. In some cases, Y is Ci-ealkylene. In some cases,
Y is Cialkylene. In some cases, Y is C2alkylene. In some cases, Y is C3alkylene.
[0096] In some cases, ring A is a 3- to 5-membered carbocycle. In some cases, ring A is a 6- to 8-membered carbocycle. In some cases, ring A is a 3-membered carbocycle. In some cases, ring A is a 4-membered carbocycle. In some cases, ring A is a 5-membered carbocycle. In some cases, ring A is a 6-membered carbocycle. In some cases, ring A is a 7-membered carbocycle. In some cases, ring A is a 8-membered carbocycle. In some
Figure imgf000086_0001
[0097] In some cases, R1 is hydrogen. In some cases, R1 is Ci-6alkyl, C0-3 haloalkyl, O-Ci- 3 haloalkyl,C0-3 alkylene-CN, C0-3 alkylene-NRN 2, C0-6 alkylene-ORN, C0-6 alkylene- C(O)ORN, Co-6alkylene-C(0)N(RN)2, or Co-6alkylene-SOpRN. In some cases, R1 is F, Cl, OH, OMe, OiPr, OBn, O-cyclopropyl, CF3, OCF3, CN, SO2Me, S02-cyclopropyl, SO2iPr, oxo, imidazolyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, thiadiazolyl, methyl-thiadiazolyl, trifluoromethyl- thiadiazolyl, oxadiazolyl, methyl-oxadiazolyl, trifluoromethyl- oxadiazolyl, or phenyl. In some cases, R1 is F or Cl. In some cases, R1 is F. In some cases, R1 is hydrogen, Ci-6alkyl, C0-3 haloalkyl, 0-Ci-3 haloalkyl,C0-3 alkylene-CN, C0-3 alkylene-NRN 2, C0-6alkylene-ORN, C0-6 alkylene- C(O)ORN, C06 alkylene-C(O)N(RN)2, or Co 6 alkylene-SOpRN; each RN is independently hydrogen or Ci.6alkyl, and p is 0-2.
[0098] In some cases, at least one RN is hydrogen. In some cases, each RN is hydrogen. In some cases, at least one RN is Ci-6alkyl. In some cases, each RN is Ci-6alkyl.
[0099] In some cases, R2 is hydrogen. In some cases, R2 is Ci-6alkyl, C3.6alkynyl, or Ci- 6alkylene-SO2-Ci-3alkyl. In some cases, R2 is CH3.
[0100] In some cases, R3 is fluoro.
[0101] In some cases, R4 is hydrogen. In some cases, R4 is OH. In some cases, R4 is halo. In some cases, R4 is F. In some cases, R4 is Co-6alkylene-NR6R7. In some cases, R4 is -CH2NH2, -CH2NHCH3, -CH2CH2NH2, -CH2CH(CH3)NH2, -CH2C(CH3)2NH2, or -CH2CH2N(CH3)2. In some cases, R4 is NR6R7. In some cases, R4 is Cialkylene-NR6R7. In some cases, R4 is -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH2CF3, -NH-propargyl, -NHC(O)CH3, -NHC(O)CF3, -NHSO2CH3, -NHSO2CF3, or -NHCH2CH2SO2CH3. In some cases, R4 is -NH2.
[0102] In some cases, R5 is hydrogen, Ci-3alkyl, or halo.
[0103] In some cases, R6 is hydrogen. In some cases, R6 is Ci-3alkyl. In some cases, R6 is methyl.
[0104] In some cases, R7 is hydrogen. In some cases, R7 is Ci-3alkyl. In some cases, R7 is methyl. In some cases, R7 is ethyl. In some cases, R7 is Ci-3haloalkyl. In some cases, R7 is trifluoroethyl. In some cases, R7 is C2.6alkynyl. In some cases, R7 is propargyl. In some cases, R7 is C0-3alkylene-SO2-Ci-3alkyl or C0-3alkylene-SO2-Ci-3haloalkyl. In some cases, R7 is SO2-methyl or SO2CF3. In some cases, R7 is C2alkylene-SO2-methyl. In some cases, wherein R7 is C(O)Ci-6alkyl or C(0)Ci-6haloalkyl. In some cases, R7 is C(O)CH3 or C(O)CF3. In some cases, R7 is hydrogen, Ci-3alkyl, Ci-3haloalkyl, C2.6alkynyl, Ci-3alkylene-O-C2.
6alkynyl, C0-3alkylene-SO2-Ci-3alkyl, C0-3alkylene-S02-Ci-3haloalkyl, C(O)Ci-6alkyl, or C(O)Ci- 6haloalkyl.
[0105] In some cases, R6 and R7 together with the nitrogen to which they are attached form a 4- to 6-membered heterocycle. In some cases, R6 and R7 together with the nitrogen to which they are attached form a heterocycle selected from
Figure imgf000087_0001
Figure imgf000087_0002
, wherein N* indicates the nitrogen to which R6 and R7 are attached.
[0106] In some cases, at least one R5 is H. In some cases, each R5 is hydrogen. In some cases, at least one R5 is Ci-3alkyl. In some cases, at least one R5 is methyl. In some cases, each R5 is methyl. In some cases, at least one R5 is halo. In some cases, at least one R5 is fluoro. In some cases, each R5 is fluoro.
[0107] In some cases, RN is hydrogen. In some cases, RN is Ci.6alkyl. In some cases, RN is methyl.
[0108] In some cases, m is 1 . In some cases, m is 2.
[0109] In some cases, n is 0. In some cases, n is 1 . In some cases, n is 2. In some cases, n is 3.
[0110] In some cases, p is 0. In some cases, p is 1 . In some cases, p is 2.
[0111] In some cases, r is 1 . In some cases, r is 2. [0112] Specific compounds contemplated include those listed in Table A-3, or a pharmaceutically acceptable salt thereof:
Table A-3
Figure imgf000088_0002
Figure imgf000088_0001
Figure imgf000089_0002
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000091_0002
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000093_0002
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000096_0002
Figure imgf000096_0001
Pharmaceutical Formulations, Dosing, and Routes of Administration
[0113] The compounds described herein can be administered to a subject in a therapeutically effective amount, alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds can be administered all at once, multiple times, or delivered substantially uniformly over a period of time. It is also noted that the dose of the compound can be varied over time.
[0114] A particular administration regimen for a particular subject will depend, in part, upon the compound, the amount of compound administered, the route of administration, and the cause and extent of any side effects. The amount of compound administered to a subject (e.g., a mammal, such as a human) in accordance with the disclosure should be sufficient to effect the desired response over a reasonable time frame. Dosage typically depends upon the route, timing, and frequency of administration. Accordingly, the clinician titers the dosage and modifies the route of administration to obtain the optimal therapeutic effect, and conventional range-finding techniques are known to those of ordinary skill in the art.
[0115] Purely by way of illustration, the method comprises administering, for example, from about 0.1 mg/kg up to about 100 mg/kg of compound or more, depending on the factors mentioned above. In other embodiments, the dosage ranges from 1 mg/kg up to about 100 mg/kg; or 5 mg/kg up to about 100 mg/kg; or 10 mg/kg up to about 100 mg/kg. Some conditions require prolonged treatment, which may or may not entail administering lower doses of compound over multiple administrations. If desired, a dose of the compound is administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. The treatment period will depend on the particular condition and type of pain, and may last one day to several months.
[0116] Suitable methods of administering a physiologically acceptable composition, such as a pharmaceutical composition comprising the compounds disclosed herein are well known in the art. Although more than one route can be used to administer a compound, a particular route can provide a more immediate and more effective reaction than another route. Depending on the circumstances, a pharmaceutical composition comprising the compound is applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and/or introduced into circulation. For example, in certain circumstances, it will be desirable to deliver a pharmaceutical composition comprising the agent orally, through injection by intravenous, intraperitoneal, intracerebral (intra- parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means, by sustained release systems, or by implantation devices. If desired, the compound is administered regionally via intrathecal administration, intracerebral (intra-parenchymal) administration, intracerebroventricular administration, or intraarterial or intravenous administration feeding the region of interest. Alternatively, the composition is administered locally via implantation of a membrane, sponge, or another appropriate material onto which the desired compound has been absorbed or encapsulated. Where an implantation device is used, the device is, in one aspect, implanted into any suitable tissue or organ, and delivery of the desired compound is, for example, via diffusion, timed-release bolus, or continuous administration.
[0117] To facilitate administration, the compound is, in various aspects, formulated into a physiologically acceptable composition comprising a carrier (e.g., vehicle, adjuvant, or diluent). The particular carrier employed is limited only by physico-chemical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. Physiologically acceptable carriers are well known in the art. Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Patent No. 5,466,468). Injectable formulations are further described in, e.g., Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia. Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)). A pharmaceutical composition comprising the compound is, in one aspect, placed within containers, along with packaging material that provides instructions regarding the use of such pharmaceutical compositions. Generally, such instructions include a tangible expression describing the reagent concentration, as well as, in certain embodiments, relative amounts of excipient ingredients or diluents (e.g., water, saline or PBS) that may be necessary to reconstitute the pharmaceutical composition.
[0118] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0119] These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[0120] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, as for example, paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
[0121] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. The solid dosage forms may also contain opacifying agents. Further, the solid dosage forms may be embedding compositions, such that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound can also be in micro-encapsulated form, optionally with one or more excipients.
[0122] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like. [0123] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
[0124] Compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
[0125] The compositions used in the methods of the invention may be formulated in micelles or liposomes. Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes. Such formulations can facilitate intracellular delivery, since lipid bilayers of liposomes and micelles are known to fuse with the plasma membrane of cells and deliver entrapped contents into the intracellular compartment.
[0126] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
[0127] The frequency of dosing will depend on the pharmacokinetic parameters of the agents and the routes of administration. The optimal pharmaceutical formulation will be determined by one of skill in the art depending on the route of administration and the desired dosage. See, for example, Remington’s Pharmaceutical Sciences, 18th Ed. (1990) Mack Publishing Co., Easton, PA, pages 1435-1712, incorporated herein by reference. Such formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface areas or organ size. Further refinement of the calculations necessary to determine the appropriate treatment dose is routinely made by those of ordinary skill in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein, as well as the pharmacokinetic data observed in animals or human clinical trials. [0128] The precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition, e.g., disease or disorder, being treated, the mode of administration and the particular active substance employed. The compounds may be administered by any conventional route, in particular enterally, and, in one aspect, orally in the form of tablets or capsules. Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of a disease of interest. These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.
[0129] It will be appreciated that the pharmaceutical compositions and treatment methods of the invention are useful in fields of human medicine and veterinary medicine. Thus, the subject to be treated is in one aspect a mammal. In another aspect, the mammal is a human.
[0130] In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will self-administer by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.
EXAMPLES
[0131] In this example, experiments are described that aimed to identify the protein target of the compounds as disclosed herein. In order to achieve this, a photoaffinity labeling (PAL) molecule (shown below) was synthesized using Compound 1 (shown below) to perform cross-linking experiments. Briefly, BV2 cells were pre-treated with vehicle or Compound 1 (competitor, 10 pM) for 30 minutes and then photoaffinity labeling compound (PAL, 100 nM) was added for another 30 minutes. Cells were then washed, plates transferred to ice and irradiated with UV light for 10 minutes. After the crosslinking reaction, the cells were washed once with cold PBS and a cell scraper was used to collect cells. Pellets were washed three times with cold PBS and stored at -80 °C.
Photoaffinity labeling (PAL) molecule:
Figure imgf000102_0001
[0132] Next, pellets were lysed with Cyto lysis buffer (50 mM Tris, pH 8.0, 150 mM NaCI, 0.5% Triton X-100) containing protease/phosphatase inhibitors for 10 minutes. Samples were centrifuged, supernatants were collected, and a protein assay was performed. A click chemistry reaction was performed to add a biotin by following the manufacturer’s protocol (Click Chemistry Tools). A maximum of 250 pg of protein lysate was used per click reaction. Proteins were precipitated using a mixture of methanol:chloroform:water (2:0.5:1 .3) and the resulting pellet resuspended in 800 pL of resuspension buffer (50 mM Tris-HCI, pH 8.0 and 1% SDS). For deglycosylation experiments, resuspended proteins were incubated with enzyme mix and incubated following the manufacturer’s (NEB) protocol. Biotinylated proteins were immunoprecipitated using streptavidin beads for 1 hour at room temperature. Bound proteins were eluted by incubating beads with 2x sample buffer containing TCEP at 100°C for 10minutes.
[0133] Figure 1 shows that a band running around 100 kDa could be competed by Compound 1 . This band was in-gel digested with trypsin and mass spectrometry analysis identified CD68 as the potential enriched protein in the PAL sample. To confirm the identity of the protein, samples were blotted with both a fluorescent streptavidin and an anti-CD68 antibody showing the overlap of the two signals (Figure 1 ). CD68 is known to be highly glycosylated. To add confidence to the competition result, a deglycosylation experiment was performed using EndoH and PNGaseF treatment of the cross-linked sample to determine whether the biotinylated protein (streptavidin signal) and CD68 signal still overlapped. As shown in Figure 2, streptavidin and CD68 still overlapped perfectly, confirming the identity of the immunoprecipitated protein as CD68.

Claims

WHAT IS CLAIMED:
1 . A method of modulating CD68 comprising contacting CD68 with a compound, or pharmaceutically acceptable salt thereof, in an amount sufficient to modulate CD68, wherein the compound has a structure of Formula (I):
Figure imgf000103_0001
wherein ring B is a 5-12 membered monocyclic, bicyclic, or bridged nitrogen-containing heterocycle comprising 0-1 additional ring heteroatoms selected from N, O, and S,
R1 is either a part of a bicyclic or bridged heterocycle or is H, Ci-6alkyl, SO2R6, or C(O)R3; ring A is a C6aryl or 5-7 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S, and is optionally substituted with 1 -3 R3 groups;
X is Ci-5alkylene, Co 5alkylene-Y or Y-Ci-5alkylene-Y; each Y is independently C(O), OC(O), C(O)NR4, NR4C(O), or SO2;
R2 is C6-ioaryl, 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S, or 5-12 membered monocyclic or bicyclic carbocycle or heterocycle, wherein the heterocycle comprises 1-4 ring heteroatoms selected from N, O, and S, and R2 is optionally substituted with 1-3 R3 groups; each R3, when present, is independently selected from C-i-6alkyl, C0-3alkylene-halo, 0-Ci-3 alkylene-halo,Co-3alkylene-CN, Co-3alkylene-NR5 2, Co-6 alkylene- OR5, Co ealkylene- C(O)OR7, C(O)N(R7)2, SO2R6, O-Co ealkylene-Ar, oxo, and Co ealkylene-Ar;
Ar is 3-8-membered carbocycle or heterocycle, wherein the heterocycle comprises 1 - 4 ring heteroatoms selected from N, O, and S; Ce-ioaryl; or 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S and Ar is optionally substituted with 1 -3 groups independently selected from halo, Ci ealkyl, Ci-shaloalkyl, C--3alkoxy, Ci- 6haloalkoxy, CN, and SO2Ci-3alkyl; each R4 and R5 is independently H, Ci-6alkyl, or C(O)Ci-6alkyl; each R6 is independently Ci-6alkyl, Ci-6haloalkyl, or Ar; each R7 is independently H or Ci-6alkyl; m is 0-2; and n is 0-2, with the proviso that the compound is not
Figure imgf000104_0001
2. The method of claim 1 , wherein ring B comprises
Figure imgf000104_0002
Figure imgf000104_0003
3. The method of claim 2, wherein ring B comprises
Figure imgf000104_0004
4. The method of claim 1 or 2, wherein R1, when present, is H, Me, SO2Me, or
C(O)Me.
5. The method of claim 4, wherein R1 is H or Me.
6. The method of any one of claims 1 to 5, wherein ring A comprises phenyl or pyridyl and is optionally substituted with 1 -2 groups selected from fluoro and chloro.
7. The method of any one of claims 1 to 6, wherein X is Co-salkylene-Y or Y-Co- salkylene-Y.
8. The method of any one of claims 1 to 6, wherein X is CH2C(O), OC(O), or NR4C(O).
9. The method of any one of claims 1 to 8, wherein R2 is substituted with 1 -3 R3, and each R3 is independently selected from F, Cl, OH, OMe, OiPr, OBn, O-cyclopropyl, CF3, OCF3, CN, SO2Me, SO2-cyclopropyl, SO2iPr, oxo, imidazolyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, thiadiazolyl, methyl-thiadiazolyl, trifluoromethyl- thiadiazolyl, oxadiazolyl, methyl-oxadiazolyl, trifluoromethyl- oxadiazolyl, and phenyl.
10. The method of claim 9, wherein R2 is substituted with 1 R3.
11 . The method of claim 9, wherein R2 is substituted with 2 R3.
12. The method of claim 9, wherein R2 is substituted with 3 R3.
13. The method of any one of claims 1 to 1 1 , wherein R2 comprises phenyl and is optionally substituted with 1 -2 groups selected from fluoro and chloro.
14. The method of any one of claims 1 to 13, wherein R2 is selected from the
Figure imgf000105_0001
Figure imgf000106_0001
15. The method of claim 14, wherein R2 is:
Figure imgf000106_0002
16. The method of any one of claims 1 to 15, having a structure of:
Figure imgf000106_0003
17. The method of any one of claims 1 to 16, having a structure of Formula (IA):
Figure imgf000106_0004
wherein Y’ is CH2, NR4 or O, and each R8 is independently H or Me, or both R8 taken together with the carbon to which they are attached form a cyclopropyl ring.
18. The method of claim 17, having a structure of:
Figure imgf000107_0001
19. The method of claim 17, having a structure of:
Figure imgf000107_0002
20. The method of claim 17, having a structure of:
Figure imgf000107_0003
21 . The method of any one of claims 17 to 20, wherein one R8 is H and the other Me.
22. The method of any one of claims 17 to 20, wherein each R8 is Me.
23. The method of any one of claims 17 to 20, wherein both R8 together with the carbon to which they are attached form a cyclopropyl ring.
24. The method of any one of claims 1 to 23, wherein each R4 is H or Me.
25. The method of claim 24, wherein each R4 is H.
26. The method of any one of claims 1 to 25, wherein n is 0.
27. The method of any one of claims 1 to 25, wherein n is 1 and R3 is F or Cl.
28. The method of any one of claims 1 to 27, wherein m is 0.
29. The method of any one of claims 1 to 27, wherein m is 1 .
30. The method of any one of claims 1 to 27, wherein m is 2.
31 . The method of claim 1 , wherein the compound, or salt thereof, has a structure as shown in Table A.
32. The method of claim 1 , wherein the compound, or salt thereof, has a structure as shown in Table B.
33. A method of modulating CD68 comprising contacting CD68 with a compound, or pharmaceutically acceptable salt thereof, in an amount sufficient to modulate CD68, wherein the compound has a structure of Formula (1-1 ):
Figure imgf000108_0001
wherein
A is a 4-10 membered heterocycle comprising 1 to 3 ring heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R3;
Y is Co-6alkylene, Co-6alkylene-0-Co-6alkylene, C0-6alkylene-NRN, Co-6alkylene-S02, CO, CO2, or CONH, wherein Co ealkylene is optionally substituted with 1 or 2 R4; each R1 is independently halo, -O-CH2-C6aryl-(OCH2CH2)P-OR5, or -O-CH2-Het- (OCH3), wherein Het is a 6-membered heteroaryl comprising 2 ring N atoms; one R2 is H and the other is H, CN, COOCi.6alkyl, CONHCi.6alkyl, SO2CH3, or O- propargyl;
R3 is Ci.6alkyl, halo, Co-6alkylene-OH, Co-6alkylene-0-propargyl, propargyl, or Co- 6alkylene-NRNRN; each R4 is independently F, OH, or OCi.6alkyl, or two R4 together with the carbon atom to which they are attached form cyclopropyl;
R5 is Ci-salkyl or propargyl; each RN is independently H or C-i-ealkyl; n is 1 -3; and p is 0-2; with the proviso that
Figure imgf000108_0002
Y is CH2, O, or NRN, then one R2 is H and the other R2 is not H; or hen A does not comprise
Figure imgf000108_0003
Figure imgf000108_0004
34. The method of claim 33, having a structure of Formula (la) or (lb):
Figure imgf000109_0001
35. The method of claim 33, having a structure of Formula (Ic) or (Id):
Figure imgf000109_0002
36. The method of any one of claims 33 to 35, wherein A comprises a 4-, 6-, 8-, or 10-membered heterocycle comprising 1 or 2 ring heteroatoms selected from N and O.
37. The method of claim 36, wherein A comprises an 8-membered heterocycle comprising 1 or 2 ring heteroatoms selected from N and O.
Figure imgf000109_0003
Figure imgf000110_0001
The method of any one of claims 33 to 38, wherein A comprises
Figure imgf000110_0002
Figure imgf000110_0003
The method of any one of claims 33 to 38, wherein A comprises
Figure imgf000110_0004
Figure imgf000110_0005
The method of any one of claims 33 to 38, wherein A comprises
Figure imgf000110_0006
Figure imgf000110_0007
The method of claim 41 , wherein A comprises
Figure imgf000110_0008
43. The method of any one of claims 33 to 38, wherein A comprises
Figure imgf000111_0002
45. The method of any one of claims 33 to 38, wherein A comprises
Figure imgf000111_0001
46. The method of any one of claims 33 to 45, wherein Y is NH or O.
47. The method of claim 46, wherein Y is NH.
48. The method of claim 46, wherein Y is O.
49. The method of any one of claims 33 to 45, wherein Y is Co salkylene, Ci- ealkylene-O, Ci-6alkylene-NRN, Ci-6alkylene-SC>2, CO2, or CONH, and Ci-ealkylene is optionally substituted with 1 to 3 R4.
50. The method of claim 49, wherein Y is Co alkylene (i.e., a bond) .
51 . The method of claim 49, wherein Y is Ci-6alkylene, Ci-6alkylene-O, or C-i- oalkylene-NR3.
52. The method of claim 51 , wherein Y is Ci-6alkylene-O.
53. The method of claim 51 , wherein Y is Ci-6alkylene-NRN.
54. The method of any one of claims 49 to 53, wherein Ci-ealkylene is substituted with 1 or 2 R4.
55. The method of claim 54, wherein R4 is OH or OCH3.
56. The method of claim 55, wherein R4 is OH.
57. The method of claim 55, wherein R4 is OCH3.
58. The method of any one of claims 33 to 57, wherein at least one R1 is halo.
59. The method of claim 58, wherein at least one R1 is F.
60. The method of claim 58, wherein each R1 is F.
61 . The method of any one of claims 33 to 57, wherein at least one R1 is -O-CH2-
C6aryl-(OCH2CH2)P-OR5.
62. The method of claim 61 , wherein p is 0.
63. The method of claim 61 , wherein p is 1 .
64. The method of claim 61 , wherein p is 2.
65. The method of any one of claims 61 to 64, wherein R5 is methyl.
66. The method of any one of claims 61 to 64, wherein R5 is propargyl.
67. The method of any one of claims 33 to 57, wherein at least one R1 is -O-CH2-
Het.
68. The method of claim 67, wherein Het comprises 2-pyrimidyl or 5-pyrimidyl optionally substituted with OMe.
69. The method of any one of claims 33 to 68, wherein n is 1 .
70. The method of any one of claims 33 to 68, wherein n is 2.
71 . The method of any one of claims 33 to 68, wherein n is 3.
72. The method of any one of claims 33 to 71 , wherein R2 is H.
73. The method of any one of claims 33 to 71 , wherein R2 is CN.
74. The method of any one of claims 33 to 71 , wherein R2 is COOCH3 or
CONHCH3.
75. The method of claim 74, wherein R2 is COOCH3.
76. The method of claim 74, wherein R2 is CONHCH3.
77. The method of any one of claims 33 to 76, wherein R2 is SO2CH3.
78. The method of any one of claims 33 to 76, wherein R2 is O-propargyL
79. The method of claim 33, wherein the compound, or salt thereof, has a structure as shown in Table A-1 .
80. The method of claim 79, wherein the compound is selected from the group consisting of Compound 2001 , Compound 2171 , Compound 2172, Compound 2176, Compound 2179, Compound 2180, Compound 2181 , Compound 2243, Compound 2552, Compound 2250, Compound 2251 , Compound 2253, and Compound 2254.
81 . The method of claim 33, wherein the compound, or salt thereof, has a structure as shown in Table B-1 .
82. A method of modulating CD68 comprising contacting CD68 with a compound, or pharmaceutically acceptable salt thereof, in an amount sufficient to modulate CD68, wherein the compound has a structure of Formula (I-2):
Figure imgf000113_0001
wherein one of X and Y is O and the other is CH2 or CH2CH2, or X is null or CH2 and Y is CH2O or (C=O)NH; one of Q1 and Q2 is H and the other is C0.3alkylene-NR6 2 or ring A, or Q1 and Q2 together with the atom to which they are attached form ring A; ring A comprises a 4- to 8-membered monocyclic or bicyclic carbocycle or heterocycle optionally substituted with 1 -3 R2 groups, wherein the heterocycle comprises a ring nitrogen or oxygen, or both; each R1 is independently Ci-6alkyl, O-Ci.6alkyl, Co-3alkylene-halo, O-Ci.3alkylene- halo,C0-3alkylene-CN, C0.3alkylene-NR4 2, C0-6alkylene-OR4, C0-6alkylene-C(O)OR6, C(O)N(R6)2, SOpR5, O-Co-ealkylene-Ar, oxo, and Co-ealkylene-Ar; each R3 is independently halo, Ci.6alkyl, C0.3alkylene-halo, 0-Ci-3alkylene-halo,Co- 3alkylene-CN, C0.3alkylene-NR4 2, C0-6alkylene-OR4, C0-6alkylene-C(O)OR6, C(O)N(R6)2, SO2R5, O-Co-ealkylene-Ar, and Co-ealkylene-Ar; each R2 is independently halo, OH, Ci-ealkyl, Ci-ehaloalkyl, Ci-ehydroxyalkyl, or Co- ealkylene-N(RN)2; each RN is independently H or C-i-ealkyl; each R4 is independently H, Ci-6alkyl, or C(O)Ci-6alkyl; each R5 is independently Ci-6alkyl, Ci-6haloalkyl, or Ar; each R6 is independently H or Ci-6alkyl;
Ar is 3-8-membered carbocycle or heterocycle, wherein the heterocycle comprises 1- 4 ring heteroatoms selected from N, O, and S; Ce waryl; or 5-10 membered heteroaryl comprising 1-4 ring heteroatoms selected from N, O, and S and Ar is optionally substituted with 1 -3 groups independently selected from halo, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- 6haloalkoxy, CN, and SO2Ci-3alkyl; m is 0-2; n is 0-3; and p is 0-2.
83. The method of claim 82, wherein one of X and Y is O and the other is CH2 or CH2CH2, or X is null or CH2 and Y is CH2O; and each R2 is independently halo, Ci.6alkyl, or - N(RN)2.
The method of claim 82 or 83, having a structure of Formula (11-2):
Figure imgf000114_0001
od of claim 84, having a structure of Formula (lla-2):
(lla-2). od of claim 84, having a structure of Formula (llb-2):
Figure imgf000114_0002
(llb-2).
87. The method of any one of claims 82 to 86, wherein Y is O.
88. The method of any one of claims 82 to 87, wherein X is CH2.
89. The method of any one of claims 82 to 87, wherein X is CH2CH2.
90. The method of any one of claims 82 to 87, wherein X is O.
91 . The method of claim 90, wherein Y is CH2.
92. The method of any one of claims 82 to 86, wherein X is CH2 and Y is CH2O.
93. The method of any one of claims 82 to 86, wherein X is null and Y is CH2O.
94. The method of any one of claims 82 to 86, wherein X is null and Y is
(C=O)NH.
95. The method of any one of claims 82 to 94, wherein R2 is halo.
96. The method of claim 95, wherein R2 is F.
97. The method of any one of claims 82 to 94, wherein R2 is Ci-6alkyl.
98. The method of claim 97, wherein R2 is methyl.
99. The method of any one of claims 82 to 94, wherein R2 is N(RN)2.
100. The method of claim 99, wherein R2 is NH2.
101. The method of any one of claims 82 to 100, wherein R3 is halo.
102. The method of claim 101 , wherein R3 is F.
103. The method of any one of claims 82 to 102, wherein n is 0.
104. The method of any one of claims 82 to 103, wherein n is 1 , 2, or 3.
105. The method of claim 104, wherein n is 1 .
106. The method of claim 104, wherein n is 2.
107. The method of claim 104, wherein n is 3.
108. The method of any one of claims 82 and 87 to 107, having a structure of
Formula (111-2):
Figure imgf000115_0001
109. The method of claim 108, wherein Q1 is is C0-3alkylene-NR6 2.
110. The method of claim 109, wherein Q1 is Ci-3alkylene-NR6 2.
111. The method of claim 110, wherein Q1 is CH2NH2.
112. The method of claim 108, wherein Q1 is a 4- to 8-membered monocyclic or bicyclic carbocycle or heterocycle optionally substituted with 1 -3 R2 groups, wherein the heterocycle comprises a ring nitrogen or oxygen.
113. The method of claim 1 12, wherein Q1 comprises a quinuclidine, piperidine, pyrrolidine, azetidine, or cyclobutane moiety.
114. The method of claim 1 13, wherein Q1 is substituted with 1 -3 R2 groups.
115. The method of claim 108, wherein Q1
Figure imgf000116_0001
Figure imgf000116_0002
116. The method of claim 115, wherein
Figure imgf000116_0003
117. The method of claim 115, wherein Q2 is
Figure imgf000116_0004
118. The method of claim 115, wherein Q2 is
Figure imgf000116_0005
119. The method of claim 115, wherein Q2 is
Figure imgf000116_0006
120. The method of any one of claims 84 to 107, wherein ring A comprises a quinuclidine, piperidine, pyrrolidine, 8-azabicyclo[3.2.1]octane, 6-azabicyclo[3.1.1]heptane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, furan, pyran, oxepin, morpholine, or thiomorpholine moiety.
121 . The method of claim 120, wherein ring A is substituted with 1 -3 R2 groups.
Figure imgf000116_0007
attachment.
123. The method of claim 122, wherein ring A is
Figure imgf000116_0008
124. The method of claim 122, wherein ring A is
Figure imgf000116_0009
Figure imgf000117_0001
125. The method of claim 122, wherein ring A is /
126. The method of claim 122, wherein ring A is
Figure imgf000117_0002
127. The method of claim 122, wherein ring A is
Figure imgf000117_0003
128. The method of any one of claims 82 to 127, wherein R1 is F, Cl, OH, OMe, OiPr, OBn, O-cyclopropyl, CF3, OCF3, CN, SO2Me, S02-cyclopropyl, SO2iPr, oxo, imidazolyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, thiadiazolyl, methyl-thiadiazolyl, trifluoromethyl- thiadiazolyl, oxadiazolyl, methyl-oxadiazolyl, trifluoromethyl- oxadiazolyl, or phenyl.
129. The method of claim 128, wherein R1 is F or Cl.
130. The method of claim 129, wherein R1 is F.
131. The method of any one of claims 82 to 130, wherein p is 0.
132. The method of any one of claims 82 to 130, wherein p is 1 .
133. The method of any one of claims 82 to 130, wherein p is 2.
134. The method of claim 82, wherein the compound, or salt thereof, has a structure as shown in Table A-2.
135. The method of claim 82, wherein the compound, or salt thereof, has a structure as shown in Table B-2.
136. The method of claim 82, wherein the compound, or salt thereof, has a structure as shown in Table C-2.
137. A method of modulating CD68 comprising contacting CD68 with a compound, or pharmaceutically acceptable salt thereof, in an amount sufficient to modulate CD68, wherein the compound has a structure of Formula (I-3):
Figure imgf000117_0004
wherein
X is O, NR2, or CRARB; Y is Co ^alkylene; ring A is a 3- to 8-membered carbocycle;
RA is hydrogen, OH, or O-Ci.3alkyl;
RB is hydrogen; or
RA and RB together are oxo;
R1 is hydrogen, Ci.6alkyl, C0.3 haloalkyl, O-Ci.3 haloalkyl,C0-3 alkylene-CN, C0-3 alkylene-NRN 2, C0.6 alkyl ene-ORN, C0.6 alkylene- C(O)ORN, C0-6 alkylene-C(O)N(RN)2, or C0.6 alkylene-SOpRN; each RN is independently hydrogen or Cvealkyl, and p is 0-2;
R2 is hydrogen, Ci-ealkyl, C3-6alkynyl, or Ci-6alkylene-SO2-Ci-3alkyl; each R3 is independently halo;
R4 is hydrogen, OH, halo, or Co-6alkylene-NR6R7; each R5 is independently hydrogen, Ci-3alkyl, Co-3hydroxyalkyl, or halo;
R6 is hydrogen or Ci-3alkyl;
R7 is hydrogen, Ci-3alkyl, Ci-3haloalkyl, Ci-3hydroxyalkyl, C2.6alkynyl, Ci-3alkylene-O- C2-6alkynyl, Co-3alkylene-S02-Ci-3alkyi, Co-3alkylene-S02-Ci-3haloaikyl, C(O)Ci-6alkyl, or C(0)Ci-6haloalkyl; or
R6 and R7 together with the nitrogen to which they are attached form a 4- to 6- membered heterocycle having 0-1 additional ring heteroatoms selected from N, O, and S and optionally substituted with 1 , 2, or 3 groups independently selected from halo and oxo; m is 1 or 2; n is 0-3; and r is 1 or 2.
138. The method of claim 137, wherein X is O.
139. The method of claim 137, wherein X is CH2.
140. The method of claim 137, wherein X is NR2.
141 . The method of claim 140, wherein R2 is hydrogen.
142. The method of claim 140, wherein R2 is CH3.
143. The method of any one of claims 137 to 142, wherein Y is Coalkylene.
144. The method of any one of claims 137 to 142, wherein Y is Ci.6alkylene.
145. The method of claim 144, wherein Y is C-ialkylene.
146. The method of claim 144, wherein Y is C2alkylene.
147. The method of claim 144, wherein Y is C3alkylene.
148. The method of any one of claims 137 to 147, wherein ring A is a 3- to 5- membered carbocycle.
149. The method of any one of claims 137 to 147, wherein ring A is a 6- to 8- membered carbocycle.
150. The method of any one of claims 137 to 147, wherein ring A is
Figure imgf000119_0001
O, Q,
Figure imgf000119_0002
151. The method of claim 150, wherein ring A is Q .
152. The method of any one of claims 137 to 151 , wherein R4 is hydrogen.
153. The method of any one of claims 137 to 151 , wherein R4 is OH.
154. The method of any one of claims 137 to 151 , wherein R4 is halo.
155. The method of claim 154, wherein R4 is F.
156. The method of any one of claims 137 to 151 , wherein R4 is Co-6alkylene- NR6R7.
157. The method of claim 156, wherein R4 is -CH2NH2, -CH2NHCH3, -CH2CH2NH2, -CH2CH(CH3)NH2, -CH2C(CH3)2NH2, or -CH2CH2N(CH3)2.
158. The method of claim 156, wherein R4 is NRSR7.
159. The method of claim 156, wherein R4 is Cialkylene-NR6R7.
160. The method of claim 158 or 159, wherein R6 is hydrogen.
161 . The method of claim 158 or 159, wherein R6 is Ci -3al kyl .
162. The method of claim 161 , wherein R6 is methyl.
163. The method of any one of claims 158 to 162, wherein R7 is hydrogen.
164. The method of any one of claims 158 to 162, wherein R7 is Ci-3alkyl.
165. The method of claim 164, wherein R7 is methyl.
166. The method of claim 164, wherein R7 is ethyl.
167. The method of any one of claims 158 to 162, wherein R7 is
Ci.3haloalkyl.
168. The method of claim 167, wherein R7 is trifluoroethyl.
169. The method of any one of claims 158 to 162, wherein R7 is C2.6alkynyl.
170. The method of claim 169 wherein R7 is propargyl.
171. The method of any one of claims 158 to 162, wherein R7 is Co-3alkylene-S02-Ci.3alkyl or Co-3alkylene-S02-Ci-3haloaikyl.
172. The method of claim 171 , wherein R7 is SO2-methyl or SO2CF3.
173. The method of claim 171 , wherein R7 is C2alkylene-SO2-methyl.
174. The method of any one of claims 158 to 162, wherein R7 is
C(O)Ci-6alkyl or C(0)Ci-6haloalkyl.
175. The method of claim 174, wherein R7 is C(O)CH3 or C(O)CF3.
176. The method of claim 159 or 160, wherein R6 and R7 together with the nitrogen to which they are attached form a 4- to 6-membered heterocycle.
1 in. The method of claim 176, wherein R6 and R7 together with the nitrogen to which they are attached form a heterocycle selected from
Figure imgf000120_0001
, , ,
Figure imgf000120_0002
, wherein N* indicates the nitrogen to which R6 and R7 are attached.
178. The method of any one of claims 137 to 151 , wherein R4 is -NH2, -NHCH3, -N(CH3)2J -NHCH2CH3, -NHCH2CF3, -NH-propargyl, -NHC(O)CH3, -NHC(O)CF3, -NHSO2CH3, -NHSO2CF3, or -NHCH2CH2SO2CH3.
179. The method of claim 178, wherein R4 is -NH2.
180. The method of any one of claims 137 to 179, wherein m is 1 .
181 . The method of any one of claims 137 to 179, wherein m is 2.
182. The method of any one of claims 137 to 181 , wherein at least one R5 is H.
183. The method of claim 182, wherein each R5 is hydrogen.
184. The method of any one of claims 137 to 181 , wherein at least one R5 is Cisalkyl.
185. The method of claim 184, wherein at least one R5 is methyl.
186. The method of claim 185, wherein each R5 is methyl.
187. The method of any one of claims 137 to 181 , wherein at least one R5 is halo.
188. The method of claim 187, wherein at least one R5 is fluoro.
189. The method of claim 188, wherein each R5 is fluoro.
190. The method of any one of claims 137 to 189, wherein n is 1 .
191. The method of any one of claims 137 to 190, wherein R3 is fluoro.
192. The method of any one of claims 137 to 191 , wherein RN is hydrogen.
193. The method of any one of claims 137 to 191 , wherein RN is Ci-6alkyl.
194. The method of any one of claims 137 to 193, wherein R1 is F, Cl, OH, OMe,
OiPr, OBn, O-cyclopropyl, CF3, OCF3, CN, SO2Me, S02-cyclopropyl, SO2iPr, oxo, imidazolyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, thiadiazolyl, methyl-thiadiazolyl, trifluoromethyl- thiadiazolyl, oxadiazolyl, methyl-oxadiazolyl, trifluoromethyl- oxadiazolyl, or phenyl.
195. The method of claim 194, wherein R1 is F or Cl.
196. The method of claim 195, wherein R1 is F.
197. The method of claim 82, wherein the compound, or salt thereof, has a structure as shown in Table A-3.
198. The method of any one of claims 1 to 197, wherein the contacting comprising administering the compound, or salt thereof, to a subject in need thereof.
199. The method of claim 198, wherein the subject suffers from a CD68- associated disorder.
200. The method of claim 199, wherein the CD68-associated disorder is osteoporosis, cancer, rheumatoid arthritis, lupus, inflammatory bowel disease, chronic liver injury, a wound, malaria, septic shock, or atherosclerosis.
201 . The method of claim 200, wherein the cancer is melanoma, glioma, breast cancer, ovarian cancer, bladder cancer, colorectal cancer, or non-small cell lung cancer.
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