WO2025217249A1 - Methods for treating endometriosis and/or other ovary-related diseases and for monitoring treatment - Google Patents

Methods for treating endometriosis and/or other ovary-related diseases and for monitoring treatment

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Publication number
WO2025217249A1
WO2025217249A1 PCT/US2025/023804 US2025023804W WO2025217249A1 WO 2025217249 A1 WO2025217249 A1 WO 2025217249A1 US 2025023804 W US2025023804 W US 2025023804W WO 2025217249 A1 WO2025217249 A1 WO 2025217249A1
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optionally substituted
phenyl
methyl
pyrazolo
group
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French (fr)
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Diana MONSIVAIS
Fei YUAN
Martin M. Matzuk
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Baylor College of Medicine
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Baylor College of Medicine
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • Endometriosis is a debilitating inflammatory disease that is associated with dysmenorrhea, dyspareunia, and menorrhagia, causes infertility, and results in increased incidence of endometrioid and clear-cell ovarian cancer.
  • endometrial tissue enters the peritoneal cavity via retrograde menstruation, leading to the attachment and persistent growth of endometrial tissue outside of the uterine cavity.
  • the disease affects approximately 190 million ( ⁇ 10%) of women ages 15-49 worldwide. Women with endometriosis will typically endure the painful symptoms of the disease for about 10 years before receiving a conclusive diagnosis.
  • a method of identifying a female human subject that has developed or is likely to develop endometriosis comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • a method of identifying a female human subject that has developed or is likely to develop ovarian cancer comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • a method of monitoring NTRK inhibition in a female human subject being administered a NTRK inhibitor comprises determining the pre-treatment expression level of at least one gene in the female human patient.
  • the method comprises determining the expression level of the at least one gene in the female human patient after being administered the NTRK inhibitor.
  • reduction in expression level of the at least one gene after treatment indicates NTRK inhibition in the female human subject
  • the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, - 2 - 55387290.3
  • FIG.1 illustrates interaction between Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2) and Brain Derived Neurotrophic Factor (BDNF), an extracellular ligand for NTRK2.
  • NTRK2 Neurotrophic Receptor Tyrosine Kinase 2
  • BDNF Brain Derived Neurotrophic Factor
  • FIG.2A-2C show Volcano plots displaying differentially expressed genes in eutopic endometrial organoids treated with BDNF and NTRK inhibitors.
  • Organoids were pre-treated with vehicle (DMSO) (FIG.2A), 1 ⁇ M CDD-2737 (FIG.2B), or 1 ⁇ M CDD-3031 (FIG.2C) for 30 minutes prior to stimulation with 50ng/ml BDNF for 3 hours.
  • mRNA was extracted and transcriptomic analysis performed using RNA sequencing with the Illumina platform. DEseq was used to identify up and down-regulated genes using a cutoff of >1.2, FDR ⁇ .05 or ⁇ 0.8, FDR ⁇ .05. Genes are displayed in the volcano plot in red (up), green (down), or unchanged (gray).
  • RNAseq shows that Brain Derived Neurotrophic Factor (BDNF), an extracellular ligand for Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2; TRKB), stimulates expression of pro-inflammatory genes (IL32, CXCL10, CXCL11, etc.) and genes involved in oxidative stress (NOS2, NOS1, and SOD1).
  • BDNF Brain Derived Neurotrophic Factor
  • NTRK2 Neurotrophic Receptor Tyrosine Kinase 2
  • TRKB Neurotrophic Receptor Tyrosine Kinase 2
  • Inhibition of NTRK2 with kinase inhibitors CDD-2737 and CDD-3031 in the presence of BDNF suppresses these pro- inflammatory genes (IL1RN, TNF, CXCL10, CXCL11, etc.) and oxidative stress pathway genes (NOS2, NOS1).
  • FIGs.3A-3B show plots displaying the association between NTRK2 and BDNF gene variants and endometriosis.
  • FIG.3A A total of 182 NTRK2 variants were found to be associated more frequently in women with endometriosis relative to controls.
  • FIGS.4A-4D illustrate differentially expressed genes in eutopic endometrial organoids treated with BDNF and NTRK inhibitors.
  • FIG.4A of 585 genes upregulated by BDNF, and 96 genes downregulated by BDNF+CDD-3031, 84 genes were in both categories. Non-limiting results for 12 genes selected from those 84 are shown.
  • FIG.4B detailed results - 3 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) for the 12 genes.
  • FIG.4C gene ontology analysis for genes that were both upregulated by BDNF,and downregulated by BDNF+CDD-3031 reveals genes involved in interferon alpha response, interferon gamma response, TNF-alpha signaling via NF-kB, inflammatory response, allograft rejection, apoptosis, IL-6/JAK/STAT3 signaling, IL-2/STAT5 signaling, hypoxia, epithelial mesenchymal transition, p53 pathway, and KRAS signaling up.
  • FIG.4D details the genes identified in the pathways listed in FIG.4C.
  • values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range.
  • the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Definitions The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.
  • acyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is bonded to a hydrogen forming a “formyl” group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning herein.
  • a nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • alkenyl refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein.
  • Examples of linear alkoxy groups - 5 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.
  • alkyl refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • alkyl encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • alkylene or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g., -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -, inter alia).
  • alkynyl refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • Examples include, but are not limited to – C ⁇ CH, -C ⁇ C(CH3), -C ⁇ C(CH2CH3), -CH2C ⁇ CH, -CH2C ⁇ C(CH3), and -CH2C ⁇ C(CH2CH3) among others.
  • amine refers to primary, secondary, and tertiary amines - 6 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • amine also includes ammonium ions as used herein.
  • amino group refers to a substituent of the form -NH 2 , - NHR, -NR2, -NR3 + , wherein each R is independently selected, and protonated forms of each, except for -NR 3 + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.
  • alkylamino includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • aralkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
  • aryl refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined herein.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof.
  • the term “atm” as used herein refers to a pressure in atmospheres under standard conditions. Thus, 1 atm is a pressure of 101 kPa, 2 atm is a pressure of 202 kPa, and so on.
  • cycloalkyl refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, - 7 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • a disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.
  • the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the terms “epoxy-functional” or “epoxy-substituted” as used herein refers to a functional group in which an oxygen atom, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system.
  • epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5- epoxypentyl, 2,3-epoxypropoxy, epoxypropoxypropyl, 2-glycidoxyethyl, 3-glycidoxypropyl, 4-glycidoxybutyl, 2-(glycidoxycarbonyl)propyl, 3-(3,4-epoxycylohexyl)propyl, 2-(3,4- epoxycyclohexyl)ethyl, 2-(2,3-epoxycylopentyl)ethyl, 2-(4-methyl-3,4- epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcylohexyl)-2-methylethyl, and 5,6- - 8 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) epoxyhexyl.
  • halo halogen
  • halide halide group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • haloalkyl as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl examples include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.
  • heteroaryl refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C 2 -heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
  • Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydry
  • heteroarylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.
  • heterocyclylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein.
  • heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. - 10 - 55387290.3 Attorney Docket No.046641-7063WO1(00172)
  • heterocyclyl refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • heterocyclyl group includes fused ring species including those that include fused aromatic and non-aromatic groups.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, x
  • substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein.
  • the term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups.
  • hydrocarbyl refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (C a - Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon - 11 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) atoms.
  • (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C 2 ), propyl (C 3 ), or butyl (C 4 ), and (C 0 -C b )hydrocarbyl means in certain embodiments there is no hydrocarbyl group.
  • the term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise.
  • X 1 , X 2 , and X 3 are independently selected from noble gases” would include the scenario where, for example, X 1 , X 2 , and X 3 are all the same, where X 1 , X 2 , and X 3 are all different, where X 1 and X 2 are the same but X 3 is different, and other analogous permutations.
  • the term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.
  • organic group as used herein refers to any carbon-containing functional group.
  • Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups.
  • an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group
  • a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester such as an alkyl and aryl sulfide group
  • sulfur-containing group such as an alkyl and aryl sulfide group
  • Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 , N(R)SO2R, N(R)SO2N(R)2, N(R
  • room temperature refers to a temperature of about 15 °C to 28 °C.
  • patient refers to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject or individual is a human.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual - 12 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic,
  • Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, - 13 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) including the compound(s) described herein, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein.
  • Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • solvent refers to a liquid that can dissolve a solid, liquid, or gas.
  • Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.
  • substantially refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%.
  • substantially free of can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less.
  • substantially free of can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or - 14 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.
  • substituted refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms.
  • functional group or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group.
  • substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups.
  • a halogen e.g., F, Cl, Br, and I
  • an oxygen atom in groups such as hydroxy groups, al
  • Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2 N(R)C(O)R, (CH 2 ) 0-2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.
  • thioalkyl refers to a sulfur atom connected to an alkyl group, as defined herein.
  • the alkyl group in the thioalkyl can be straight chained or branched. Examples of linear thioalkyl groups include but are not limited to thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, and the like.
  • branched alkoxy examples include but are not limited to iso-thiopropyl, sec-thiobutyl, tert-thiobutyl, iso- thiopentyl, iso-thiohexyl, and the like.
  • the sulfur atom can appear at any suitable position in the alkyl chain, such as at the terminus of the alkyl chain or anywhere within the alkyl chain. - 15 - 55387290.3 Attorney Docket No.046641-7063WO1(00172)
  • the terms “treat,” “treating” and “treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject.
  • entrectinib refers to N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4- methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide.
  • LOXO-101 and “larotrectinib” are used interchangeably herein to refer to (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3- hydroxypyrrolidine-1-carboxamide.
  • LOXO-195 and “selitrectinib” are used interchangeably herein to refer to (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24- hexazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7(12),8,10,18(25),19,22- heptaen-17-one or (13E,14E,22R,6R)-35-fluoro-6-methyl-7-aza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(3,2)-pyridina-2(1,2)-pyrrolidinacyclooctaphan-8-one.
  • TPX-005 and “reprotrectinib” are used interchangeably herein to refer to (3R,11S)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21- pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one or (13E,14E,3R,6S)-45-fluoro-3,6-dimethyl-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 4(1,2)-benzenacyclononaphan-9-one.
  • PF06273340 refers to N-[5-[[2-Amino-7-(2-hydroxy-1,1- dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl]-3-pyridinyl]-5-chloro-2- pyridineacetamide.
  • NTRK1, NTRK2, and NTRK3 Neurotrophic receptor tyrosine kinases 1, 2, and 3 have been shown to be critical for various aspects of nervous system function, including nociceptive pain.
  • NTRK2 is upregulated in endometriosis lesions and silencing of NTRK2 in primary endometriotic stromal cells inhibits pro-inflammatory gene expression. NTRK2 contributes to the survival and inflammation associated with endometriosis.
  • NTRK2-selective inhibitors that are non-steroidal drugs and can be used for direct regression of endometriosis - 16 - 55387290.3
  • Attorney Docket No.046641-7063WO1(00172) and reduction of associated pain in girls and women. Girls with a close female relative with endometriosis are 3-7-fold more likely to have endometriosis.
  • Recent genome wide association (GWAS) studies including 60,724 cases and 701,926 controls identified genome wide significant loci (Rahmioglu, et al., 2023, Nature genetics). These genetic associations explained ⁇ 5% of disease variance and regulated expression or methylation of genes in endometrium or blood.
  • the patient with endometriosis has the rs137922923 variant in the NTRK2 gene (the NTRK2 rs137922923 gene variant).
  • the patient with endometriosis has the variant rs78531552 in the BDNF gene (the BDNF rs78531552 gene variant).
  • the present study that compounds of the disclosure have the ability to reduce the expression of certain pro-inflammatory-associated genes.
  • genes include but are not limited to IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, NOS2, CCL28, TNFSF15, CXCL8, DUSP10, CREB3L1, BDNF, and NTRK2.
  • Such effect can be used for monitoring the pharmacological activity of the compounds of the disclosure, including the extent of inhibition of one or more members of the neurotrophic receptor tyrosine kinase (NTRK) family (i.e., NTRK1, NTRK2, and/or NTRK3) and the need to adjust the amount and/or frequency of dosing of the compound of the disclosure to the patient.
  • NTRK neurotrophic receptor tyrosine kinase
  • R 4 is not H;
  • R 2 is selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C 2 -C 8 heterocycl
  • R 4 is not H.
  • R 1 is H.
  • R 2 is H.
  • R 2 is F.
  • R 2 is Br.
  • R 2 is CN.
  • at least one selected from R 3a , R 3b , and R 3c is H.
  • At least two selected from R 3a , R 3b and R 3c are H. In certain embodiments, each of R 3a , R 3b , and R 3c are H. In certain embodiments, at least one selected from R 3a , R 3b , R 3c , R 3d , and R 3e is H. In certain embodiments, at least two selected from R 3a , R 3b , R 3c , R 3d , and R 3e are H. In certain embodiments, at least three selected from R 3a , R 3b , R 3c , R 3d , and R 3e are H.
  • At least four selected from R 3a , R 3b , R 3c , R 3d , and R 3e are H. In certain embodiments, each of R 3a , R 3b , R 3c , R 3d , and R 3e are H.
  • T is In certain embodiments, T . In certain embodiments, T is . In certain embodiments, T is In certain embodiments, In certain certain embodiments, T . In certain embodiments, T . In certain embodiments, T . In certain embodiments, T . In certain embodiments, T . In certain embodiments, T . In certain is H.
  • R 4 is isopropyl. In certain embodiments, R 4 is 1-methylpropyl. In certain embodiments, R 4 is 2-methylpropyl. In certain embodiments, R 4 is 3-methylbutyl. In certain embodiments, R 4 is cyclopropyl. In certain embodiments, R 4 is cyclobutyl. In certain embodiments, R 4 is cyclopentyl. In certain embodiments, R 4 is cyclohexyl. In certain embodiments, R 4 is cycloheptyl. In certain embodiments, R 4 is (CH2)3N(CH3)2.
  • R 4 is phenyl.
  • R 4 is benzyl substituted with at least one C1-C6 alkyl.
  • R 4 is .
  • R 4 is .
  • R 4 is - substituted with at least .
  • R 4 is .
  • R 4 is .
  • a 1 is phenyl substituted with at least one C 1 -C 6 alkyl.
  • a 1 is phenyl substituted with at least one C 1 - C6 alkoxy.
  • a 1 is phenyl substituted with at least one C1-C3 haloalkyl. In certain embodiments, A 1 is phenyl substituted with at least one C 1 -C 3 haloalkoxy. In certain embodiments, A 1 is phenyl substituted with at least one phenoxy. In certain embodiments, A 1 is phenyl substituted with at least one halogen. In certain embodiments, A 1 is phenyl substituted with at least one NO2. . In certain embodiments, A 1 is phenyl substituted with at least one C3-C8 cycloalkyl, which is optionally substituted with at least one C1-C3 haloalkyl.
  • a 1 is C2-C8 heteroaryl. In certain embodiments, A 1 is C2-C8 heteroaryl substituted with at least one C1-C6 alkyl. In certain embodiments, A 1 is C 2 -C 8 heteroaryl fused with a C 2 -C 5 heteroaryl . In certain embodiments, . In certain embodiments, A 1 . In certain embodiments, certain embodiments, A 1 . In certain embodiments, A 1 is . In certain embodiments, A 1 . In certain embodiments, A 1 . In certain embodiments, A 1 . In certain embodiments, A 1 . In certain embodiments, A 1 . In certain embodiments, A 1 . In - 28 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) certain embodiments, A 1 is .
  • X 1 is -NH- In certain embodiments, X 1 is NMe. In certain embodiments, X 1 is O. In certain embodiments, X 1 is a bond. In certain embodiments, R 7 is H. In certain embodiments, R 7 is Me. In certain embodiments, R 5 is H. In certain embodiments, R 5 . In certain - 29 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) certain embodiments, R 5 . In certain embodiments, . In certain embodiments, R 5 . In certain embodiments, R 5 . In certain embodiments, R 5 . In certain In certain In certain . In certain embodiments, R 5 . In certain embodiments, R 5 . In certain embodiments, R 5 . In certain embodiments, R 5 .
  • R 5 is . In certain embodiments, R 5 . In certain embodiments, . In certain embodiments, In - 30 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) certain certain embodiments, R 5 is . In certain embodiments, R 5 is . In certain embodiments, R 5 .
  • the compound of formula (I) is selected from the group 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid; 1-cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea; 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl
  • the present disclosure provides a compound of formula (II) , or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures - 35 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) thereof: , wherein: A 2 is selected from the group ; R 8 is selected from the group optionally substituted C 3-C8 cycloalkyl, R 9a , R 9b , R 9c , and R 9d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 8 heterocyclyl, halogen, CN, and NO2; R 10 is selected from the group consisting of optionally substituted C 1 -C 6 al
  • R 8 is isopropyl. In certain embodiments, R 8 is phenyl. In certain embodiments, R 9a is H. In certain embodiments, R 9a is tert-butyl. In certain embodiments, R 9a is trifluoromethyl. In certain embodiments, R 9b is H. In certain embodiments, R 9b is tert-butyl. In certain embodiments, R 9b is trifluoromethyl. In certain embodiments, R 9c is H. In certain embodiments, R 9c is tert-butyl. In certain embodiments, R 9c is trifluoromethyl. In certain embodiments, R 9d is H. In certain embodiments, R 9d is tert- butyl.
  • R 9d is trifluoromethyl.
  • Z 1 is N and at least two of Z 2 , Z 3 , and Z 4 are CH.
  • Z 1 is N and each of Z 2 , Z 3 , and Z 4 are CH.
  • Z 2 is N and at least one of Z 1 , Z 3 , and Z 4 is CH.
  • Z 2 is N and at least two of Z 1 , Z 3 , and Z 4 are CH.
  • Z 2 is N and each of Z 1 , Z 3 , and Z 4 are CH.
  • X 2 is -O-.
  • X 2 is -NH-.
  • R 14 is H.
  • R 11a is H. In certain embodiments R 11a is methoxy. In certain embodiments, R 11b is H. In certain embodiments R 11b is methoxy. In certain embodiments, R 11c is H. In certain embodiments R 11c is methoxy. In certain embodiments, R 11d is H. In certain embodiments R 11d is methoxy. In certain embodiments, R 11e is H. In certain embodiments R 11e is methoxy. In certain embodiments, R 11f is H. In certain - 37 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) embodiments R 11f is methoxy. In certain embodiments, R 11g is H. In certain embodiments R 11g is methoxy.
  • R 11h is H. In certain embodiments R 11h is methoxy.
  • R 10 is tert-butyl.
  • R 10 is is is selected from the group consisting of: N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)picolinamido)-3-methoxyphenyl)-N 4 -methylterephthalamide; N 1 -(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol- 3-yl)picolinamido)-3-methoxyphenyl)-N 4 -methylterephthalamide; tert-butyl 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinate; tert-butyl 5-(5-(1-(5-
  • the present disclosure provides a compound of formula (III), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures - 38 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) thereof: , wherein: R 15a , selected from the group consisting of H, substituted C 3 -C 8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R 16 is selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R 17a and R 17b are each independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted
  • the compound of formula (III) is a compound of formula (IIIa): (IIIa).
  • the compound of formula (III) is a compound of formula .
  • one of R 15a , R 15b , and R 15c is H.
  • at least two of R 15a , R 15b , and R 15c are H.
  • each of R 15a , R 15b , and R 15c are H.
  • - 39 - 55387290.3 Attorney Docket No.046641-7063WO1(00172)
  • R 16 is benzyl.
  • R 17a is H.
  • R 17b is 1 8a 18a
  • R is H.
  • R 18b is H.
  • R 18b is Me. is .
  • In certain formula (III) is selected from the group consisting of: N-((S)-1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1-(2-(methylamino)-2-oxo-1- phenylethyl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide; (S)-1-benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan- 2-yl)-1H-benzo[d]imidazole-7-carboxamide; and (S)-1-benzyl-N-(1-((4-chlor
  • CDD-2330 5-((1-isopropyl-3-(4- (trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid 2
  • CDD-2301 1-cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 3
  • CDD-2300 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2- (trifluoromethoxy)phenyl)urea
  • CDD-2299 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 5
  • CDD-2299 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically- active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of - 54 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein.
  • compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity.
  • Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form.
  • the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • compounds described herein are prepared as prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic - 55 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
  • isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • substitution with positron emitting isotopes is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. - 56 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.
  • carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.
  • blocking/protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), N-alkoxycarbonyl (Alloc), methyl (Me), ethyl (Et), tert-butyl (t- Bu), tert-butyl dimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), tert- butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), fluorenylmethyloxycarbonyl (FMOC).
  • compositions In one aspect, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure and a pharmaceutically acceptable carrier.
  • compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises Kolliphor EL, and aqueous buffer, or a combination thereof.
  • the aqueous buffer comprises phosphate buffered saline (PBS).
  • the aqueous buffer comprises 1x PBS.
  • the pharmaceutical composition comprises about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% Kolliphor EL.
  • the pharmaceutical composition comprises about 20% Kolliphor EL in 1x PBS.
  • the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • the composition is formulated as a pill, tablet, gelcap, or capsule for oral administration.
  • the present disclosure provides a method of identifying a female human subject that has or is likely to develop endometriosis (such as, but not limited to, ovarian endometrioma). In one aspect, the present disclosure provides a method of identifying a female human subject that has or is likely to develop cancer. In one aspect, the present disclosure provides a method of identifying a female human subject that has or is likely to develop ovarian cancer. In certain embodiments, the ovarian cancer is clear cell ovarian cancer. In certain embodiments, the ovarian cancer is endometrioid ovarian cancer.
  • the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 - 58 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) in the BDNF gene. Such determination can be done using sequencing methods known in the art, using a biological sample obtained from the subject. A person skilled in the art would be able to perform such determination without any undue optimization and/or experimentation.
  • the female human subject has the rs137922923 variant in the NTRK2 gene.
  • the female human subject has the variant rs78531552 in the BDNF gene.
  • the female human subject has or is predisposed to endometriosis. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject has or is predisposed to cancer. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject has or is predisposed to ovarian cancer.
  • the ovarian cancer is clear cell ovarian cancer. In certain embodiments, the ovarian cancer is endometrioid ovarian cancer. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject has or is predisposed to clear cell ovarian cancer and/or endometroid ovarian cancer. In certain embodiments, the female human subject predisposed to have cancer, such as but not limited to ovarian cancer, such as but not limited to clear cell ovarian cancer and/or endometrioid ovarian cancer, benefits by treatment with an NTRK inhibitor.
  • the female human subject if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is counseled to be treated with a therapeutically effective amount of a NTRK inhibitor. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is administered a therapeutically effective amount of a NTRK inhibitor. In one aspect, the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis.
  • Such female human subject has endometriosis and/or is prone to have endometriosis.
  • - 59 - 55387290.3 Attorney Docket No.046641-7063WO1(00172)
  • the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent cancer.
  • Such female human subject has cancer and/or is prone to have endometriosis.
  • the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer.
  • Such female human subject has ovarian cancer and/or is prone to have ovarian cancer.
  • the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent clear cell ovarian cancer.
  • Such female human subject has clear cell ovarian cancer and/or is prone to have clear cell ovarian cancer.
  • the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometrioid ovarian cancer.
  • Such female human subject has endometrioid ovarian cancer and/or is prone to have endometrioid ovarian cancer.
  • the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent clear cell ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometrioid ovarian cancer if the female human subject has the rs137922923 variant in the - 60 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • the present disclosure provides a method of monitoring NTRK inhibition in a female human subject being administered a NTRK inhibitor.
  • the method comprises determining the pre-treatment expression level of at least one gene in the female human patient.
  • the method comprises determining the expression level of the at least one gene in the female human patient after being administered the NTRK inhibitor. In certain embodiments, reduction in expression level of the at least one gene after treatment indicates NTRK inhibition in the female human subject.
  • the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, NOS2, CCL28, TNFSF15, CXCL8, DUSP10, CREB3L1, BDNF, and/or NTRK2.
  • the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, and/or NOS2. In certain embodiments, the at least one gene comprises CXCL10, CXCL11, TNF, and/or NOS2. In certain embodiments, the at least one gene comprises IL1RN. In certain embodiments, the at least one gene comprises CXCL2. In certain embodiments, the at least one gene comprises CXCL10. In certain embodiments, the at least one gene comprises CXCL11. In certain embodiments, the at least one gene comprises CXCL16. In certain embodiments, the at least one gene comprises ALDH1A3. In certain embodiments, the at least one gene comprises TNF.
  • the at least one gene comprises NOS1. In certain embodiments, the at least one gene comprises NOS2. In certain embodiments, the at least one gene comprises CCL28. In certain embodiments, the at least one gene comprises TNFSF15. In certain embodiments, the at least one gene comprises CXCL8. In certain embodiments, the at least one gene comprises DUSP10. In certain embodiments, the at least one gene comprises CREB3L1. In certain embodiments, the at least one gene comprises BDNF. In certain embodiments, the at least one gene comprises NTRK.
  • the amount and/or frequency of dosing of the NTRK inhibitor is modified so as to cause a more intense reduction in expression level of the at least one gene.
  • the amount and/or frequency - 61 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) of dosing of the NTRK inhibitor is modified so as to cause a less intense reduction in expression level of the at least one gene.
  • the therapeutically effective threshold for level alterations in the at least gene should be easily determined using methods known to those skilled in the art.
  • the reduction in expression level of the at least one gene may be determined for a female human subject that is successfully treated for endometriosis.
  • the expression level of the at least one gene is measured before the subject before the subject undergoes treatment and after the subject undergoes successful treatment.
  • the reduction in expression level of the at least one gene may be determined for female human subjects that have experienced various therapeutic outcomes when being treated for endometriosis. Analysis between the NTRK dosing, specifically measured reduction in expression level of the at least one gene, and the corresponding observed therapeutic outcomes may be analyzed to determine how reduction in expression level of the at least one gene correlates with therapeutic outocomes.
  • the NTRK inhibitor is entrectinib, larotrectinib, selitrectinib, reprotrectinib, PF-06273340, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof.
  • the NTRK inhibitor is a compound contemplated within the disclosure.
  • neurotrophic receptor tyrosine kinase 1 (NTRK1) is overexpressed in the subject.
  • NTRK2 neurotrophic receptor tyrosine kinase 2
  • NTRK3 neurotrophic receptor tyrosine kinase 3
  • BDNF Brain Derived Neurotrophic Factor
  • NTF4 neurotrophin 4
  • a combination of NTRK1, NTRK2, NTRK3, BDNF, and/or NTF4 is overexpressed in the subject.
  • administration of the compound of the present disclosure and/or the pharmaceutical composition of the present disclosure results in inhibition of NTRK1 in the subject.
  • inhibition of NTRK1 results in treatment, prevention, and/or amelioration of endometriosis, and/or one or more symptoms thereof, cancer, and/or pain.
  • administration of the compound of the present disclosure and/or the pharmaceutical composition of the present disclosure results in inhibition of NTRK2 in the subject.
  • inhibition of NTRK2 results in treatment, - 62 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) prevention, and/or amelioration of endometriosis, and/or one or more symptoms thereof, cancer, and/or pain.
  • administration of the compound of the present disclosure and/or the pharmaceutical composition of the present disclosure results in inhibition of NTRK3 in the subject.
  • inhibition of NTRK3 results in treatment, prevention, and/or amelioration of endometriosis, and/or one or more symptoms thereof, cancer, and/or pain.
  • a fusion gene comprising at least one selected from the group consisting of NTRK1, NTRK2, and NTRK3 is overexpressed in the subject.
  • the NTRK inhibitor is a NTRK2 inhibitor.
  • the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK1.
  • the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK3.
  • the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK1 and NTRK3.
  • selectivity of a compound for NTRK2 over NTRK1 comprises a half-maximal inhibitory concentration (IC50) of the compound for NTRK2 which is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, or 1000 times lower than the IC50 for the same compound against NTRK1.
  • selectivity of a compound for NTRK2 over NTRK1 comprises a half-maximal inhibitory concentration (IC 50 ) of the compound for NTRK2 which is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, or 1000 times lower than the IC 50 for the same compound against NTRK3.
  • the NTRK2 inhibitor is entrectinib.
  • the NTRK2 inhibitor is larotrectinib. In certain embodiments, the NTRK2 inhibitor is selitrectinib. In certain embodiments, the NTRK2 inhibitor is reprotrectinib. In certain embodiments, the NTRK2 inhibitor is PF-06273340.
  • administration of the compound of the present disclosure and/or the pharmaceutical composition of the present disclosure results in inhibition of the fusion gene product in the subject. In certain embodiments, inhibition of the fusion gene product results in treatment, prevention, and/or amelioration of endometriosis, and/or one or more symptoms thereof, cancer, and/or pain. Administration/Dosage/Formulations The regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the subject either prior to or after the onset - 63 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) of the disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or disorder in the patient.
  • an effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non- limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg/kg of body weight/per day.
  • One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may 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 dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • the compositions described herein are administered to the patient in dosages that range from one to five times per day or more.
  • the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors.
  • the compound(s) described herein for administration may be in the range of from about 1 ⁇ g to about 10,000 mg, about 20 ⁇ g to about 9,500 mg, about 40 ⁇ g to about 9,000 mg, about 75 ⁇ g to about 8,500 mg, about 150 ⁇ g to about 7,500 mg, about 200 ⁇ g to about 7,000 mg, about 350 ⁇ g to about 6,000 mg, about 500 ⁇ g to about 5,000 mg, about 750 ⁇ g to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.
  • the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • a composition as described herein is a packaged pharmaceutical composition
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, - 66 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • transdermal e.g., sublingual, lingual, (trans)buccal, (trans)urethral
  • vaginal e.g., trans- and perivaginally
  • intravesical, intrapulmonary, intraduodenal, intragastrical intrathecal
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or - 67 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose
  • the tablets may be coated using suitable methods and coating materials such as OPADRYTM film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRYTM OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRYTM White, 32K18400).
  • OPADRYTM film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRYTM OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRYTM White, 32K18400).
  • Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions.
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorbic acid.
  • parenteral Administration the compounds as described herein may be formulated for injection or in
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
  • Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S.
  • Additional dosage forms - 68 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos.
  • Controlled Release Formulations and Drug Delivery Systems can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds.
  • the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.
  • the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein can be readily selected for use with the pharmaceutical compositions described herein.
  • single unit dosage forms suitable for oral administration such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein.
  • controlled-release pharmaceutical products have a common goal of improving - 69 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.
  • Controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • controlled-release component is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient.
  • the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 - 70 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • the therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of the disease or disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.
  • a suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day.
  • the dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different.
  • a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, - 71 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both is reduced to a level at which the improved disease is retained.
  • patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, are within the scope of the present application.
  • NRTK inhibitors of the disclosure inhibit BDNF-induced pro-inflammatory signaling in eutopic endometrial epithelial organoids
  • Endometrial epithelial organoids from the eutopic endometrium of a woman with clinical stage 2 endometriosis were grown in 3D cultures. One day prior to treatment, organoid medium was changed to minimal differentiation media overnight. The following morning, organoids were pretreated with vehicle (DMSO), 1 ⁇ M CDD-2737, or 1 ⁇ M CDD- 3031 for 30 minutes, then stimulated with 50ng/ml BDNF for an additional 3 hours.
  • DMSO vehicle
  • 1 ⁇ M CDD-2737 1 ⁇ M CDD-2737
  • 1 ⁇ M CDD- 3031 for 30 minutes
  • mRNA was extracted from the organoids after the 3-hour incubation and subjected to RNA sequencing using the Illumina platform. Reads were aligned to the human genome hg38 build and differentially expressed genes were calculated using DESeq with a cutoff of >1.2, FDR ⁇ .05 or ⁇ 0.8, FDR ⁇ .05. The study showed that, relative to vehicle-treated cells, BDNF stimulated the expression of 688 genes (>1.2, FDR ⁇ .05) and decreased the expression of 555 genes ( ⁇ 0.8, FDR ⁇ .05). This included genes involved in pro-inflammatory pathways (IL32, CXCL10, CXCL11) and oxidative stress response (NOS2, NOS1, SOD1) (FIG.1A).
  • CDD-2737 and CDD-3031 included the pro- - 73 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) inflammatory genes, CXCL10, CXCL11, TNF, and NOS2.
  • Example 2 Genetic analysis of endometriosis patients reveals genetic variants associated with the disease
  • the present study analyzed genetic data from the FinnGen database and searched for genetic associations between BDNF and NTRK2 in various endometriosis subtypes (N14_ENDOMETRIOSIS, N14_ENDOMETRIOSIS_OVARY, N14_ENDOMETRIOSIS_ASRM_STAGE3_4, N14_ENDOMETRIOSIS_PELVICPERITONEUM, N14_ENDOMETRIOSIS_ASRM_STAGE1_2, N14_ENDOMET_INFERT, N14_ENDOMETRIOSIS_RECTPVAGSEPT_VAGINA, N14_ENDOMETRIOSIS_DEEP, N14_ENDOMETRIOSIS_UTERUS, N14_ENDOMETRIOSIS_NOS, N14_ENDOMETRIOSIS_INTESTINE, N14_ENDOMETRIOSIS_FALLOPIAN_TUBE).
  • BDNF variant (rs78531552, yellow circles) was frequently observed in patients with various subtypes of endometriosis (FIG.3B).
  • Example 3 NRTK inhibitors of the disclosure inhibit BDNF-induced pro-inflammatory signaling in eutopic endometrial epithelial organoids
  • Endometrial epithelial organoids from the eutopic endometrium of a woman with clinical stage 2 endometriosis were grown in 3D cultures (see Example 1).
  • Organoids were treated with vehicle; 100 ng/mL BDNF; or 100 ng/mL BDNF and 1 ⁇ M CDD-3031. The study showed that, relative to vehicle-treated, BDNF stimulated the expression of 585 genes.
  • CDD-303196 genes When the epithelial organoids were pretreated with 1 ⁇ M CDD-303196 genes were downregulated. 84 genes were in both groups (i.e., upregulated with BDNF alone, downregulated with BDNF and CDD-3031). Among these 84 were CCL28, CXCL10, NOS2, TNF, IL1RN, TNFSF15, CXCL11, CXCL8, DUSP10, CREB3L1, BDNF, and NTRK2. See FIGS.4A-4B. Gene ontology analysis of pathways suppressed by CDD-3031 indicated suppression - 74 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) of pro-inflammatory pathways. See FIGS.4C-4D.
  • CDD-3031 Inhibition of BDNF-NTRK2 signaling by CDD-3031 impacts several gene pathways that are currently being targeted by molecules undergoing clinical trials or considered pre- clinical candidates for endometriosis. These include (genes impacted by CDD-3031): ⁇ Anti-IL8 antibody (Phase II) - CDD-3031 decreased CXCL8 (the gene encoding interleukin 8 (IL8)) expression. ⁇ CSFR1 antagonist (preclinical candidate) - CDD-3031 decreased several genes stimulated downstream of CSFR1 activation (TNF, CXCL10, IL11RN, CCL28).
  • ⁇ Quinagolide VR-DR2 agonist (Phase II, targeting VEGF/VEGFR1) - CDD-3031 decreased expression of VEGF/VEGFR1 effector gene TNFSF15 (induced by IL1 and TNF); TNFSF15 can induce apoptosis in endothelial cells, inhibit endothelial cell proliferation, and may function as an angiogenesis inhibitor.
  • JNK inhibitors preclinical testing
  • CDD-3031 decreased expression of DUSP10, a phosphatase that dephosphorylates JUN and JNK and correlates with inflammation; the three JNK proteins (JNK1, JNK2, and JNK3, encoded by the MAPK8, MAPK9, and MAPK10 genes, respectively) require phosphorylation to be active.
  • the JNK proteins phosphorylate and activate JUN.
  • Embodiment 1 A method of identifying a female human subject that has developed or is likely to develop endometriosis, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • Embodiment 2 A method of identifying a female human subject that has developed or is likely to develop ovarian cancer, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • Embodiment 3 The method of Embodiment 2, wherein the ovarian cancer comprises clear cell ovarian cancer and/or endometrioid ovarian cancer.
  • Embodiment 4 The method of Embodiment 1, wherein the female human subject has the rs137922923 variant in the NTRK2 gene. - 75 - 55387290.3 Attorney Docket No.046641-7063WO1(00172)
  • Embodiment 5 The method of Embodiment 1, wherein the female human subject has the variant rs78531552 in the BDNF gene.
  • Embodiment 6 The method of any one of Embodiments 1-5, wherein, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is counseled to be treated with a therapeutically effective amount of a NTRK inhibitor.
  • Embodiment 7 The method of any one of Embodiments 1-5, wherein, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is administered a therapeutically effective amount of a NTRK inhibitor.
  • Embodiment 8 A method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, and identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • Embodiment 9 A method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, and identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene.
  • Embodiment 10 The method of Embodiment 9, wherein the ovarian cancer comprises clear cell ovarian cancer or endometrioid ovarian cancer.
  • Embodiment 11 A method of monitoring NTRK inhibition in a female human subject being administered a NTRK inhibitor, the method comprising: determining the pre- treatment expression level of at least one gene in the female human patient, and determining the expression level of the at least one gene in the female human patient after being administered the NTRK inhibitor, wherein reduction in expression level of the at least one gene after treatment indicates NTRK inhibition in the female human subject, wherein the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, NOS2, CCL28, TNFSF15, CXCL8, DUSP10, CREB3L1, BDNF, and/or NTRK2.
  • Embodiment 12 The method of Embodiment 11, wherein the at least one gene comprises CXCL10, CXCL11, TNF, and/or NOS2.
  • Embodiment 13 The method of any one of Embodiments 11-12, wherein, if the reduction in expression level of the at least one gene is determined to be below the therapeutically effective threshold, the amount and/or frequency of dosing of the NTRK inhibitor is modified so as to cause a more intense reduction in expression level of the at least one gene.
  • Embodiment 14 The method of any one of Embodiments 11-12, wherein, if the reduction in expression level of the at least one gene is determined to be above the therapeutically effective threshold, the amount and/or frequency of dosing of the NTRK inhibitor is modified so as to cause a less intense reduction in expression level of the at least one gene.
  • Embodiment 15 The method of any one of Embodiments 1-14, wherein the NTRK inhibitor is entrectinib, larotrectinib, selitrectinib, reprotrectinib, PF-06273340, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof.
  • Embodiment 18 The method of Embodiment 16 or 17, wherein the inhibitor is a compound of formula (I), which is selected from the group consisting of , , is H.
  • Embodiment 21 The method of any one of Embodiments 16-20, wherein at least one of the following applies: (a) at least one selected from R 3a , R 3b , R 3c , R 3d , and R 3e is H; (b) at least two selected from R 3a , R 3b , R 3c , R 3d , and R 3e are H; (c) at least three selected from R 3a , R 3b , R 3c , R 3d , and R 3e are H; (d) at least four selected from R 3a , R 3b , R 3c , R 3d , and R 3e are H; and (e) each of R 3a , R 3b , R 3c , R 3d , and R 3e are H.
  • NC is selected from the group consisting of H, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohept
  • Embodiment 24 The method of any one of Embodiments 16-22, wherein R 4 is selected from the group consisting , and . 25: The method of any one of Embodiments 16-24, wherein A 1 is selected from the group consisting of H; phenyl substituted with at least one substituent - 82 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C 3 -C 8 cycloalkyl optionally substituted with a C 1 -C 3 haloalkyl, phenoxy, halogen, and NO2; phenyl fused with a C2-C6 heterocycloalkyl; and C2-C8 heteroaryl optionally substituted with C 1 -C 6 alkyl or fused with a C 2 -C 5 heteroaryl
  • Embodiment 26 The method of any one of Embodiments 16-25, wherein A 1 is selected from the group consisting of: , is -CH 2 - .
  • Embodiment 30 The method of Embodiment 18, wherein R 7 is selected from the group consisting of H and Me.
  • Embodiment 31 The method of any one of Embodiments 16-30, wherein R 5 is selected from the group consisting of: , - 83 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) , , from the group consisting of: 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid; 1-cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea; 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4
  • Embodiment 33 The method of Embodiment 16 or 17, which is a compound of formula (II).
  • Embodiment 34 The method of Embodiment 33, wherein R 8 is selected from the group consisting of isopropyl and phenyl.
  • Embodiment 35 The method of Embodiment 33 or 34, wherein R 9a , R 9b , R 9c , and R 9d are each independently selected from the group consisting of H, tert-butyl, and trifluoromethyl.
  • Embodiment 36 The method of any one of Embodiments 33-35, wherein A 2 is selected from the group .
  • Embodiment 37 The one of the following applies: (a) Z 1 is N and at least one of Z 2 , Z 3 , and Z 4 is CH; (b) Z 1 is N and at least two of Z 2 , Z 3 , and Z 4 are CH; (c) Z 1 is N and each of Z 2 , Z 3 , and Z 4 are CH; (d) Z 2 is N and at least one of Z 1 , Z 3 , and Z 4 is CH; (e) Z 2 is N and at least two of Z 1 , Z 3 , and Z 4 are CH; or (f) Z 2 is N and each of Z 1 , Z 3 , and Z 4 are CH.
  • Embodiment 38 The method of any one of Embodiments 33-37, wherein X 2 is selected from the group consisting of -O- and -NH-.
  • Embodiment 39 The method of any one of Embodiments 33-38, wherein R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , and R 11h are each independently selected from the group consisting of H and methoxy.
  • Embodiment 41 The method of any one of Embodiments 33-40, wherein R 10 is selected from the group consisting of - 89 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) . which is N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)picolinamido)-3-methoxyphenyl)-N 4 -methylterephthalamide; N 1 -(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol- 3-yl)picolinamido)-3-methoxyphenyl)-N 4 -methylterephthalamide; tert-butyl 5-(5-(5-(tert-butyl)-1
  • Embodiment 43 The method of Embodiment 16 or 17, wherein the compound is a compound of formula (III).
  • Embodiment 44 The method of Embodiment 43, wherein the compound of formula (III) is selected from the group consisting of: . of the following applies: (a) at least one of R 15a , R 15b , and R 15c is H; (b) at least two of R 15a , R 15b , and R 15c are H; and (c) each of R 15a , R 15b , and R 15c are H.
  • Embodiment 46 The method of any one of Embodiments 43-45, wherein R 16 is selected from the group consisting of benzyl .
  • Embodiment 47 The method of any 43-46, wherein R 17a and - 90 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) R 17b are each independently H.
  • Embodiment 48 The method of any one of Embodiments 43-47, wherein R 18a and R 18b are each independently selected from the group consisting of H and Me.
  • Embodiment 49 The method of any one of Embodiments 43-48, wherein A 3 is selected from the group .
  • Embodiment 50 The 43-49, wherein A 4 is .
  • Embodiments 16-17 and 43-50 The method of any one of Embodiments 16-17 and 43-50, which is selected from the group consisting of: N-((S)-1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1-(2-(methylamino)-2-oxo-1- phenylethyl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide; (S)-1-benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan- 2-yl)-1H-benzo[d]imidazole-7-carboxamide; and (S)-1-benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6-trichloroph
  • Embodiment 52 The method of any one of Embodiments 15-51, wherein the NTRK inhibitor is a NTRK2 inhibitor.
  • Embodiment 53 The method of Embodiment 52, wherein the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK1 and/or NTRK3.
  • the terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application.

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Abstract

The present disclosure relates to a method of identifying a female human subject that has developed or is likely to develop endometriosis. The present disclosure further relates to a method of identifying a female human subject that should be administered a NTRK inhibitor, including a selective NTRK2 inhibitor, to treat, ameliorate, and/or prevent endometriosis. The present disclosure further relates to a method of identifying a female human subject that should be administered a NTRK inhibitor, including a selective NTRK2 inhibitor, to treat, ameliorate, and/or prevent endometriosis and the consequences of endometriosis, such as cancer (e.g., clear cell ovarian cancer and/or endometroid ovarian cancer).

Description

Attorney Docket No.046641-7063WO1(00172) TITLE OF THE DISCLOSURE Methods for Treating Endometriosis and/or Other Ovary-Related Diseases and for Monitoring Treatment CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.63/631,850, filed April 9, 2024, which is hereby incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant Number HD110038 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Endometriosis is a debilitating inflammatory disease that is associated with dysmenorrhea, dyspareunia, and menorrhagia, causes infertility, and results in increased incidence of endometrioid and clear-cell ovarian cancer. In women with endometriosis, endometrial tissue enters the peritoneal cavity via retrograde menstruation, leading to the attachment and persistent growth of endometrial tissue outside of the uterine cavity. The disease affects approximately 190 million (~10%) of women ages 15-49 worldwide. Women with endometriosis will typically endure the painful symptoms of the disease for about 10 years before receiving a conclusive diagnosis. Further, even after diagnosis, available treatments for endometriosis are limited and often ineffective long-term. For example, surgical excision of endometriotic implants is not completely curative, as lesions, and associated pain will typically recur. The debilitating pain and host of related side effects of endometriosis prevent women from experiencing productive and vibrant lives during the peak years of their lives. Thus, there is an urgent need in the art for methods for selecting for endometriosis and/or ovarian cancer patients who will benefit from certain therapeutic interventions. Further, there is an urgent need for methods for monitoring therapeutic interventions in endometriosis patients and/or ovarian cancer patients. The present disclosure addresses these needs. - 1 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) SUMMARY In one aspect, disclosed herein is a method of identifying a female human subject that has developed or is likely to develop endometriosis. In certain embodiments, the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In another aspect, disclosed herein is a method of identifying a female human subject that has developed or is likely to develop ovarian cancer. In certain embodiments, the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In another aspect, disclosed herein is a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis. In certain embodiments, the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In another aspect, disclosed herein is a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer. In certain embodiments, the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In another aspect, disclosed herein is a method of monitoring NTRK inhibition in a female human subject being administered a NTRK inhibitor. In certain embodiments, the method comprises determining the pre-treatment expression level of at least one gene in the female human patient. In certain embodiments, the method comprises determining the expression level of the at least one gene in the female human patient after being administered the NTRK inhibitor. In certain embodiments, reduction in expression level of the at least one gene after treatment indicates NTRK inhibition in the female human subject, wherein the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, - 2 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) NOS1, NOS2, CCL28, TNFSF15, CXCL8, DUSP10, CREB3L1, BDNF, and/or NTRK2. BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. FIG.1 illustrates interaction between Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2) and Brain Derived Neurotrophic Factor (BDNF), an extracellular ligand for NTRK2. The binding of BDNF to NTRK2 ultimately induces phosphorylation and activation of CREB (pCREB). Activated CREB acts on the PTGS2 promoter, creating a positive feedback mechanism that results in elevated inflammation. FIGs.2A-2C show Volcano plots displaying differentially expressed genes in eutopic endometrial organoids treated with BDNF and NTRK inhibitors. Organoids were pre-treated with vehicle (DMSO) (FIG.2A), 1µM CDD-2737 (FIG.2B), or 1µM CDD-3031 (FIG.2C) for 30 minutes prior to stimulation with 50ng/ml BDNF for 3 hours. mRNA was extracted and transcriptomic analysis performed using RNA sequencing with the Illumina platform. DEseq was used to identify up and down-regulated genes using a cutoff of >1.2, FDR <.05 or < 0.8, FDR < .05. Genes are displayed in the volcano plot in red (up), green (down), or unchanged (gray). RNAseq shows that Brain Derived Neurotrophic Factor (BDNF), an extracellular ligand for Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2; TRKB), stimulates expression of pro-inflammatory genes (IL32, CXCL10, CXCL11, etc.) and genes involved in oxidative stress (NOS2, NOS1, and SOD1). Inhibition of NTRK2 with kinase inhibitors CDD-2737 and CDD-3031 in the presence of BDNF suppresses these pro- inflammatory genes (IL1RN, TNF, CXCL10, CXCL11, etc.) and oxidative stress pathway genes (NOS2, NOS1). FIGs.3A-3B show plots displaying the association between NTRK2 and BDNF gene variants and endometriosis. FIG.3A: A total of 182 NTRK2 variants were found to be associated more frequently in women with endometriosis relative to controls. FIG.3B: A total of 47 BDNF variants were found to be associated more frequently in women with endometriosis relative to controls. Analyses were performed in patients with endometriosis (n= 62,108) relative to disease-free controls (n= 1,780,044) (p<0.01). FIGS.4A-4D illustrate differentially expressed genes in eutopic endometrial organoids treated with BDNF and NTRK inhibitors. FIG.4A: of 585 genes upregulated by BDNF, and 96 genes downregulated by BDNF+CDD-3031, 84 genes were in both categories. Non-limiting results for 12 genes selected from those 84 are shown. FIG.4B: detailed results - 3 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) for the 12 genes. FIG.4C: gene ontology analysis for genes that were both upregulated by BDNF,and downregulated by BDNF+CDD-3031 reveals genes involved in interferon alpha response, interferon gamma response, TNF-alpha signaling via NF-kB, inflammatory response, allograft rejection, apoptosis, IL-6/JAK/STAT3 signaling, IL-2/STAT5 signaling, hypoxia, epithelial mesenchymal transition, p53 pathway, and KRAS signaling up. FIG.4D details the genes identified in the pathways listed in FIG.4C. DETAILED DESCRIPTION OF THE DISCLOSURE Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. This application incorporates by reference all of the teachings and contents of International Patent Publication No. WO 2024/026410, published February 1, 2024. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by - 4 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) reference herein in their entirety, as though individually incorporated by reference. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Definitions The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a “formyl” group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group. The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups - 5 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term “alkyl” as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “alkylene” or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, inter alia). In certain embodiments, the term may be regarded as a moiety derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g., - CH2-) different (e.g., -CH2CH2-) carbon atoms. The term “alkynyl” as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C^CH, -C^C(CH3), -C^C(CH2CH3), -CH2C^CH, -CH2C^C(CH3), and -CH2C^C(CH2CH3) among others. The term “amine” as used herein refers to primary, secondary, and tertiary amines - 6 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also includes ammonium ions as used herein. The term “amino group” as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3 +, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. The term “aralkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. The term “atm” as used herein refers to a pressure in atmospheres under standard conditions. Thus, 1 atm is a pressure of 101 kPa, 2 atm is a pressure of 202 kPa, and so on. The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, - 7 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. A disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced. As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. The terms “epoxy-functional” or “epoxy-substituted” as used herein refers to a functional group in which an oxygen atom, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system. Examples of epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5- epoxypentyl, 2,3-epoxypropoxy, epoxypropoxypropyl, 2-glycidoxyethyl, 3-glycidoxypropyl, 4-glycidoxybutyl, 2-(glycidoxycarbonyl)propyl, 3-(3,4-epoxycylohexyl)propyl, 2-(3,4- epoxycyclohexyl)ethyl, 2-(2,3-epoxycylopentyl)ethyl, 2-(4-methyl-3,4- epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcylohexyl)-2-methylethyl, and 5,6- - 8 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) epoxyhexyl. The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- - 9 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. The term “heteroarylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein. The term “heterocyclylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. - 10 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. The term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term “hydrocarbyl” refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon - 11 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3 are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3 are all the same, where X1, X2, and X3 are all different, where X1 and X2 are the same but X3 is different, and other analogous permutations. The term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. The term “organic group” as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C100)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted. The term “room temperature” as used herein refers to a temperature of about 15 °C to 28 °C. The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual - 12 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, - 13 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. The term “solvent” as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids. The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term “substantially free of” can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or - 14 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1- C100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. The term “thioalkyl” as used herein refers to a sulfur atom connected to an alkyl group, as defined herein. The alkyl group in the thioalkyl can be straight chained or branched. Examples of linear thioalkyl groups include but are not limited to thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, and the like. Examples of branched alkoxy include but are not limited to iso-thiopropyl, sec-thiobutyl, tert-thiobutyl, iso- thiopentyl, iso-thiohexyl, and the like. The sulfur atom can appear at any suitable position in the alkyl chain, such as at the terminus of the alkyl chain or anywhere within the alkyl chain. - 15 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) The terms “treat,” “treating” and “treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject. The term “entrectinib” refers to N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4- methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide. The terms “LOXO-101” and “larotrectinib” are used interchangeably herein to refer to (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3- hydroxypyrrolidine-1-carboxamide. The terms “LOXO-195” and “selitrectinib” are used interchangeably herein to refer to (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24- hexazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7(12),8,10,18(25),19,22- heptaen-17-one or (13E,14E,22R,6R)-35-fluoro-6-methyl-7-aza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(3,2)-pyridina-2(1,2)-pyrrolidinacyclooctaphan-8-one. The terms “TPX-005” and “reprotrectinib” are used interchangeably herein to refer to (3R,11S)-6-fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21- pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one or (13E,14E,3R,6S)-45-fluoro-3,6-dimethyl-5-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 4(1,2)-benzenacyclononaphan-9-one. The term “PF06273340” as used herein refers to N-[5-[[2-Amino-7-(2-hydroxy-1,1- dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl]-3-pyridinyl]-5-chloro-2- pyridineacetamide. Description Neurotrophic receptor tyrosine kinases 1, 2, and 3 (NTRK1, NTRK2, and NTRK3) have been shown to be critical for various aspects of nervous system function, including nociceptive pain. Gene fusions involving those kinases (e.g., TPM3-NTRK1, MPRIP- NTRK1, TRIM24-NTRK2, and ETV6-NTRK3) are observed in adult and pediatric gliomas and other cancers (e.g., non-small cell lung carcinoma), where they amplify signaling cascades and act as oncogenic drivers. NTRK2 is upregulated in endometriosis lesions and silencing of NTRK2 in primary endometriotic stromal cells inhibits pro-inflammatory gene expression. NTRK2 contributes to the survival and inflammation associated with endometriosis. The present disclosure contemplates peripherally-restricted NTRK2-selective inhibitors that are non-steroidal drugs and can be used for direct regression of endometriosis - 16 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) and reduction of associated pain in girls and women. Girls with a close female relative with endometriosis are 3-7-fold more likely to have endometriosis. Recent genome wide association (GWAS) studies including 60,724 cases and 701,926 controls identified genome wide significant loci (Rahmioglu, et al., 2023, Nature genetics). These genetic associations explained ~5% of disease variance and regulated expression or methylation of genes in endometrium or blood. Importantly, many of these genetic associations corresponded to pain perception or pain maintenance and included genes such as NGF, SRP14, GDAP1, MLLT10, and BMF. The present study used GWAS studies to show patients with endometriosis (n= 62,108) displayed 47 variants in the BDNF gene and 182 variants in the NTRK2 gene (p<0.01) compared to endometriosis-free controls (n= 1,780,044). In one aspect, the patient with endometriosis has the rs137922923 variant in the NTRK2 gene (the NTRK2 rs137922923 gene variant). In one aspect, the patient with endometriosis has the variant rs78531552 in the BDNF gene (the BDNF rs78531552 gene variant). Further, the present study that compounds of the disclosure have the ability to reduce the expression of certain pro-inflammatory-associated genes. Such genes include but are not limited to IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, NOS2, CCL28, TNFSF15, CXCL8, DUSP10, CREB3L1, BDNF, and NTRK2. Such effect can be used for monitoring the pharmacological activity of the compounds of the disclosure, including the extent of inhibition of one or more members of the neurotrophic receptor tyrosine kinase (NTRK) family (i.e., NTRK1, NTRK2, and/or NTRK3) and the need to adjust the amount and/or frequency of dosing of the compound of the disclosure to the patient. Compounds In one aspect, the present disclosure provides a compound of formula (I), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof: , wherein: T is selected from the group , - 17 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) ; substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)ORa, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), CN, and NO2; R2 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), of H, substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(=O)N(Ra)(Rb); R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L1 is -C(R6a)(R6b)-; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; A1 is selected from the group consisting of optionally substituted phenyl, optionally - 18 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl; or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof. In certain H, then R4 is not H; In another aspect, the (Ia), or a salt, solvate, isotopologue, any mixtures thereof: , wherein: R1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)ORa, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), CN, and NO2; R2 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), NRaC(=O)Rb, C(=O)N(Ra)(ORb), C(=NRa)N(Rb)(Rc), C(=NRa)N(Rb)(ORc), and NRaS(=O)2Rb; R3a, R3b, and R3c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; - 19 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) R5 is selected from the group consisting of H and -X1-A1; L1 is -C(R6a)(R6b)-; X1 is selected from the group consisting of a bond, O, and NR7; R6a and R6b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(=O)N(Ra)(Rb); R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; and Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl. In certain embodiments, if -L2-R5 is -H, then R4 is not H. In another aspect, the present disclosure provides a compound of formula (Ib), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof: , wherein: R1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)ORa, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), CN, and NO2; R2 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), - - 55387290.3 Attorney Docket No.046641-7063WO1(00172) NRaS(=O)2Rb; R3a, R3b, and R3c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a and R6b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(=O)N(Ra)(Rb); R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L1 is -C(R6a)(R6b)-; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl. In another aspect, the present disclosure provides a compound of formula (Ic), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof: , wherein: of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally - 21 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)ORa, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), CN, and NO2; R3a, R3b, and R3c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, C6 alkyl, and C(=O)N(Ra)(Rb); - -; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl. In another aspect, the present disclosure provides a compound of formula (Id), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof: , wherein: of H, optionally substituted C1-C6 alkyl, - 22 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)ORa, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), CN, and NO2; R2 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), NRaC(=O)Rb, C(=O)N(Ra)(ORb), C(=NRa)N(Rb)(Rc), C(=NRa)N(Rb)(ORc), and NRaS(=O)2Rb; R3a, R3b, and R3c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(=O)N(Ra)(Rb); L1 is -C(R6a)(R6b)-; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl. - 23 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) In another aspect, the present disclosure provides a compound of formula (Ie), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof: , wherein: selected from the group consisting of H, substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, optionally C(=O)N(Ra)(Rb); L1 is -C(R6a)(R6b)-; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl. In another aspect, the present disclosure provides a compound of formula (If), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures - 24 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) thereof: , wherein: selected from the group consisting of H, substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(=O)N(Ra)(Rb); L1 is -C(R6a)(R6b)-; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl. In another aspect, the present disclosure provides a compound of formula (Ig), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures - 25 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) thereof: , wherein: R3a, selected from the group consisting of H, substituted C3-C8 cycloalkyl, optionally alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(=O)N(Ra)(Rb); R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L1 is -C(R6a)(R6b)-; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl. In certain embodiments, R1 is H. In certain embodiments, R2 is H. In certain embodiments, R2 is F. In certain embodiments, R2 is Br. In certain embodiments, R2 is CN. In certain embodiments, R2 is C(=O)OH. In certain embodiments, R2 is C(=O)NH2. In certain embodiments, R2 is C(=O)NMe. In certain embodiments, R2 is C(=NH)NH(OH). In certain embodiments, R2 is - 26 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) C(=O)NHOH. In certain embodiments, at least one selected from R3a, R3b, and R3c is H. In certain embodiments, at least two selected from R3a, R3b and R3c are H. In certain embodiments, each of R3a, R3b, and R3c are H. In certain embodiments, at least one selected from R3a, R3b, R3c, R3d, and R3e is H. In certain embodiments, at least two selected from R3a, R3b, R3c, R3d, and R3e are H. In certain embodiments, at least three selected from R3a, R3b, R3c, R3d, and R3e are H. In certain embodiments, at least four selected from R3a, R3b, R3c, R3d, and R3e are H. In certain embodiments, each of R3a, R3b, R3c, R3d, and R3e are H. In certain embodiments, T is In certain embodiments, T . In certain embodiments, T is . In certain In certain embodiments, T is In certain embodiments, In certain certain embodiments, T . In certain embodiments, T . In certain embodiments, . In certain embodiments, T . In certain embodiments, T . In certain embodiments, T . In certain embodiments, T . In certain is H. In certain In certain - 27 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) embodiments, R4 is isopropyl. In certain embodiments, R4 is 1-methylpropyl. In certain embodiments, R4 is 2-methylpropyl. In certain embodiments, R4 is 3-methylbutyl. In certain embodiments, R4 is cyclopropyl. In certain embodiments, R4 is cyclobutyl. In certain embodiments, R4 is cyclopentyl. In certain embodiments, R4 is cyclohexyl. In certain embodiments, R4 is cycloheptyl. In certain embodiments, R4 is (CH2)3N(CH3)2. In certain embodiments, R4 is C(=O)CH3. In certain embodiments, R4 is phenyl. In certain embodiments, R4 is benzyl substituted with at least one C1-C6 alkyl. In certain embodiments, R4 is . In certain embodiments, R4 is . In certain embodiments, R4 is - substituted with at least . In certain embodiments, R4 is . In certain embodiments, R4 is . In certain . In certain embodiments, A1 is phenyl substituted with at least one C1-C6 alkyl. In certain embodiments, A1 is phenyl substituted with at least one C1- C6 alkoxy. In certain embodiments, A1 is phenyl substituted with at least one C1-C3 haloalkyl. In certain embodiments, A1 is phenyl substituted with at least one C1-C3 haloalkoxy. In certain embodiments, A1 is phenyl substituted with at least one phenoxy. In certain embodiments, A1 is phenyl substituted with at least one halogen. In certain embodiments, A1 is phenyl substituted with at least one NO2. . In certain embodiments, A1 is phenyl substituted with at least one C3-C8 cycloalkyl, which is optionally substituted with at least one C1-C3 haloalkyl. In certain embodiments, A1 is C2-C8 heteroaryl. In certain embodiments, A1 is C2-C8 heteroaryl substituted with at least one C1-C6 alkyl. In certain embodiments, A1 is C2-C8 heteroaryl fused with a C2-C5 heteroaryl . In certain embodiments, . In certain embodiments, A1 . In certain embodiments, certain embodiments, A1 . In certain embodiments, A1 is . In certain embodiments, A1 . In certain embodiments, A1 . In certain embodiments, A1 . In - 28 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) certain embodiments, A1 is . In certain embodiments, A1 is . In certain . In certain In certain In certain embodiments, A1 is . In certain embodiments, A1 is . In certain embodiments, A1 is . In certain In certain embodiments, A1 is . In certain embodiments, A1 . In certain is H. In certain In certain embodiments, L1 is -CH2-. In certain embodiments, L2 is a bond. In certain embodiments, L2 is -C(=O)-. In certain embodiments, L2 is -S(=O)2-. In certain embodiments, L2 is -C(=S)-. In certain embodiments, L2 is -CH2-. In certain embodiments, L2 . In certain embodiments, . X1 is -NH- In certain embodiments, X1 is NMe. In certain embodiments, X1 is O. In certain embodiments, X1 is a bond. In certain embodiments, R7 is H. In certain embodiments, R7 is Me. In certain embodiments, R5 is H. In certain embodiments, R5 . In certain - 29 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) certain embodiments, R5 . In certain embodiments, . In certain embodiments, R5 . In certain embodiments, R5 . In certain embodiments, R5 . In certain In certain . In certain In certain embodiments, R5 . In certain embodiments, R5 . In certain certain embodiments, R5 is . In certain embodiments, R5 . In certain embodiments, . In certain embodiments, In - 30 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) certain certain embodiments, R5 is . In certain embodiments, R5 is . In certain embodiments, R5 . embodiments, the compound of formula (I) is selected from the group 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid; 1-cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea; 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclobutyl-3-(4-nitrophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 1-phenyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopentyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethyl)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(3-(trifluoromethyl)phenyl)urea; N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; methyl 5-((cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate; 3-(3-chlorophenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)propan-1-amine; N,N-bis(pyrazolo[1,5-a]pyridin-5-ylmethyl)cyclobutanamine; 1-(3-(3-chlorophenoxy)propyl)-3-(4-phenoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5- ylmethyl)urea; 1-(3-(3-chlorophenoxy)propyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea; - 31 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 3-(4-chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 1-cyclobutyl-3-(4-fluorophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)-N-methylpyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxylic acid; methyl 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylate; 1-cyclobutyl-3-(4-methoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; (R)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; (S)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; (S)-1-phenyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)ethan-1-amine; 1-((3-fluoropyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 1-((3-bromopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 5-((1-cyclopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylic acid; 5-((1-isopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-((1-cyclopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-isopropyl-3-methyl-3-(4-(trifluoro methoxy) phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoro methoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 1-((3-cyanopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 5-((1-isobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid; 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine- - 32 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-(4-(trifluoromethoxy) phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboximidamide; 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((2-(4-isopropylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-3-(4-(trifluoromethoxy)phenyl)propanamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-isopropyl-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-(3-(dimethylamino)propyl)-2-(4- isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; (R)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; (S)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-methyl-2-(4-(trifluoromethyl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; - 33 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 5-((N-methyl-2-(3-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((2-(4-(tert-butyl)phenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-(4-(tert-butyl)phenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-((4-(tert-butyl)phenyl)(methyl)amino)-N-methylacetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-(4-(prop-1-en-2-yl)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((2-(4-acetylphenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-(4-acetylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; (S)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; (R)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; (R)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; (S)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; N-((1H-indol-5-yl)methyl)-N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamide; 1-((1H-indol-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea; 2-((6-(tert-butyl)pyridin-3-yl)amino)-N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-((4-(1- (trifluoromethyl)cyclopropyl)phenyl)amino)acetamide; 5-((methyl(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)amino)methyl)pyrazolo[1,5- - 34 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) a]pyridine-3-carboxamide; 1-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-1-cyclopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyrimidin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 5-((N-(3-(3-chlorophenoxy)propyl)-2-(4- isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((N-(4-(trifluoromethoxy)phenyl)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-(((N-isopropyl-4-(trifluoromethyl)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-(((N-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine)-6- sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-(((N-methyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-(((N-isopropyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; (E)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; (Z)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; (E)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; and (Z)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide. In another aspect, the present disclosure provides a compound of formula (II) , or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures - 35 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) thereof: , wherein: A2 is selected from the group ; R8 is selected from the group optionally substituted C 3-C8 cycloalkyl, R9a, R9b, R9c, and R9d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, CN, and NO2; R10 is selected from the group consisting of optionally substituted C1-C6 alkyl, ; selected from the alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), NRaC(=O)Rb, and NRaS(=O)2Rb; R12a, R12b, and R12c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; L3 is selected from the group consisting of ; X2 is selected from the group consisting of R14 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; Z1 is selected from the group consisting of CR13a and N, Z2 is selected from the group consisting of CR13b and N, Z3 is selected from the group consisting of CR13c and N, and Z4 is selected from the group consisting of CR13d and N, wherein at least one selected from the group consisting of Z1, Z2, Z3, and Z4 is N; - 36 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) R13a, R13b, R13c, and R13d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally CN, and NO2; and Ra and Rb are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl. In certain embodiments, R8 is isopropyl. In certain embodiments, R8 is phenyl. In certain embodiments, R9a is H. In certain embodiments, R9a is tert-butyl. In certain embodiments, R9a is trifluoromethyl. In certain embodiments, R9b is H. In certain embodiments, R9b is tert-butyl. In certain embodiments, R9b is trifluoromethyl. In certain embodiments, R9c is H. In certain embodiments, R9c is tert-butyl. In certain embodiments, R9c is trifluoromethyl. In certain embodiments, R9d is H. In certain embodiments, R9d is tert- butyl. In certain embodiments, R9d is trifluoromethyl. is embodiments, Z1 is N and at least two of Z2, Z3, and Z4 are CH. In certain embodiments, Z1 is N and each of Z2, Z3, and Z4 are CH. In certain embodiments, Z2 is N and at least one of Z1, Z3, and Z4 is CH. In certain embodiments, Z2 is N and at least two of Z1, Z3, and Z4 are CH. In certain embodiments, Z2 is N and each of Z1, Z3, and Z4 are CH. In certain embodiments, X2 is -O-. In certain embodiments, X2 is -NH-. In certain embodiments, R14 is H. In certain embodiments, R11a is H. In certain embodiments R11a is methoxy. In certain embodiments, R11b is H. In certain embodiments R11b is methoxy. In certain embodiments, R11c is H. In certain embodiments R11c is methoxy. In certain embodiments, R11d is H. In certain embodiments R11d is methoxy. In certain embodiments, R11e is H. In certain embodiments R11e is methoxy. In certain embodiments, R11f is H. In certain - 37 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) embodiments R11f is methoxy. In certain embodiments, R11g is H. In certain embodiments R11g is methoxy. In certain embodiments, R11h is H. In certain embodiments R11h is methoxy. In certain embodiments, R12a is H. In certain embodiments, R12a is methyl. In certain embodiments, R12a is C(=O)O(C(CH3)3). In certain embodiments, R12b is H. In certain embodiments, R12b is methyl. In certain embodiments, R12b is C(=O)O(C(CH3)3). In certain embodiments, R12c is H. In certain embodiments, R12c is methyl. In certain embodiments, R12c is C(=O)O(C(CH3)3). In certain embodiments, R10 is tert-butyl. In certain embodiments, R10 is is is selected from the group consisting of: N1-(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; N1-(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol- 3-yl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; tert-butyl 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinate; tert-butyl 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazol-3-yl)picolinate; (Z)-N1-(4-(5-(N’-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3- carbonyl)oxy)carbamimidoyl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; and tert-butyl (4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazol-3-yl)picolinamido)-3-methoxyphenyl)carbamate. In another aspect, the present disclosure provides a compound of formula (III), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures - 38 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) thereof: , wherein: R15a, selected from the group consisting of H, substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R16 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R17a and R17b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R18a and R18b are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; A3 is optionally substituted phenyl; and A4 is optionally substituted phenyl. In certain embodiments, the compound of formula (III) is a compound of formula (IIIa): (IIIa). the compound of formula (III) is a compound of formula . one of R15a, R15b, and R15c is H. In certain embodiments, at least two of R15a, R15b, and R15c are H. In certain embodiments, each of R15a, R15b, and R15c are H. - 39 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) In certain embodiments, R16 is benzyl. In certain embodiments, . In certain embodiments, R17a is H. In certain embodiments, R17b is 18a 18a In certain embodiments, R is H. In certain embodiments, R is embodiments, R18b is H. In certain embodiments, R18b is Me. is . In certain formula (III) is selected from the group consisting of: N-((S)-1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1-(2-(methylamino)-2-oxo-1- phenylethyl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide; (S)-1-benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan- 2-yl)-1H-benzo[d]imidazole-7-carboxamide; and (S)-1-benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6-trichlorophenyl)- 1H-benzo[d]imidazole-7-carboxamide. In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heterocyclyl, and optionally substituted alkylenyl, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, OH, N(R’)(R’’), C(=O)R’, C(=O)OR’, OC(=O)OR’, C(=O)N(R’)(R’’), S(=O)2N(R’)(R’’), N(R’)C(=O)R’’, N(R’)S(=O)2R’’, C2-C8 heteroaryl, and phenyl optionally substituted with at least one halogen, wherein each occurrence of R’ and R’’ is independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and phenyl. - 40 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) Table 1. Exemplary compounds Cmpd No. Compound 1 CDD-2330 5-((1-isopropyl-3-(4- (trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid 2 CDD-2301 1-cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 3 CDD-2300 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2- (trifluoromethoxy)phenyl)urea 4 CDD-2299 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 5 CDD-2298 1-cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 6 CDD-2297 1-cyclobutyl-3-(4-nitrophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea - 41 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 7 CDD-2296 1-phenyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 8 CDD-2276 1-cyclopentyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 9 CDD-2275 1-cyclopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 10 CDD-2274 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2- (trifluoromethyl)phenyl)urea 11 CDD-2273 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(3- (trifluoromethyl)phenyl)urea 12 CDD-2271 N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)-N-(pyrazolo[1,5- a]pyridin-5-ylmethyl)acetamide 13 CDD-2270 methyl 5-((cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3- carboxylate - 42 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 14 CDD-2269 3-(3-chlorophenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)propan-1- amine 15 CDD-2268 N,N-bis(pyrazolo[1,5-a]pyridin-5-ylmethyl)cyclobutanamine 16 CDD-2267 1-(3-(3-chlorophenoxy)propyl)-3-(4-phenoxyphenyl)-1-(pyrazolo[1,5- a]pyridin-5-ylmethyl)urea 17 CDD-2266 1-(3-(3-chlorophenoxy)propyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3- (4-(trifluoromethoxy)phenyl)urea 18 CDD-2265 3-(4-chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5- ylmethyl)urea 19 CDD-2264 1-cyclobutyl-3-(4-fluorophenyl)-1-(pyrazolo[1,5-a]pyridin-5- ylmethyl)urea 20 CDD-2263 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)-N- methylpyrazolo[1,5-a]pyridine-3-carboxamide - 43 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 21 CDD-2262 5-((1-cyclobutyl-3-(4- (trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid 22 CDD-2261 methyl 5-((1-cyclobutyl-3-(4- (trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylate 23 CDD-2260 1-cyclobutyl-3-(4-methoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5- ylmethyl)urea 24 CDD-2222 (R)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide 25 CDD-2259 (S)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide 26 CDD-2219 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 27 CDD-2225 - 44 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) (S)-1-phenyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)ethan-1-amine 28 CDD-2734 1-((3-fluoropyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea 29 CDD-2735 1-((3-bromopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea 30 CDD-2736 5-((1-cyclopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid 31 CDD-2737 5-((1-isopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide 32 CDD-2738 5-((1-cyclopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide 33 CDD-2739 5-((1-isopropyl-3-methyl-3-(4-(trifluoro methoxy) phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid 34 CDD-2740 N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoro methoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide - 45 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 35 CDD-2741 1-((3-cyanopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea 36 CDD-2742 5-((1-isobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylic acid 37 CDD-2743 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid 38 CDD-2744 N-hydroxy-5-((1-isopropyl-3-(4-(trifluoromethoxy) phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboximidamide 39 CDD-2241 N1-(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide F H N O F N O N F N N H O 40 N N CDD-2240 O N O H N1-(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)- 1,2,4-oxadiazol-3-yl)picolinamido)-3-methoxyphenyl)-N4- methylterephthalamide - 46 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 41 CDD-2239 tert-butyl 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol- 3-yl)picolinate 42 CDD-2238 tert-butyl 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5- yl)-1,2,4-oxadiazol-3-yl)picolinate 43 CDD-2228 (Z)-N1-(4-(5-(N’-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3- carbonyl)oxy)carbamimidoyl)picolinamido)-3-methoxyphenyl)-N4- methylterephthalamide 44 CDD-2224 tert-butyl (4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol- 5-yl)-1,2,4-oxadiazol-3-yl)picolinamido)-3-methoxyphenyl)carbamate 45 CDD-2218 N-((S)-1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1-(2- (methylamino)-2-oxo-1-phenylethyl)-2-(2,3,6-trichlorophenyl)-1H- benzo[d]imidazole-7-carboxamide - 47 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 46 CDD-2217 (S)-1-benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4- chlorophenyl)amino)-1-oxopropan-2-yl)-1H-benzo[d]imidazole-7- carboxamide 47 CDD-2216 (S)-1-benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6- trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide 48 CDD-3118 5-((1-methyl-3-(4- (trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 49 CDD-3119 5-((1-isopropyl-3-(4- (trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 50 CDD-3120 5-((2-(4-isopropylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 51 CDD-3121 5-((N-methyl-3-(4- (trifluoromethoxy)phenyl)propanamido)methyl)pyrazolo[1,5-a]pyridine- - 48 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 3-carboxamide 52 CDD-3031 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide NH O 2 O O 53 N N N CDD-3032 5-((N-isopropyl-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 54 CDD-3122 5-((N-(3-(dimethylamino)propyl)-2-(4- isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 55 CDD-3129 5-((2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 56 CDD-3130 5-((3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 57 CDD-3131 5-((3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 58 CDD-3132 5-((N-methyl-2-(4- - 49 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) (trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 59 CDD-3133 5-((N-isopropyl-2-(4- (trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 60 CDD-3057 (R)-5-((1-(sec-butyl)-3-(4- (trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 61 CDD-3058 (S)-5-((1-(sec-butyl)-3-(4- (trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 62 CDD-3181 5-((N-methyl-2-(4- (trifluoromethyl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 63 CDD-3182 5-((N-methyl-2-(3- (trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 64 CDD-3183 5-((2-(4-(tert-butyl)phenoxy)-N-methylacetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide - 50 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 65 CDD-3184 5-((2-(4-(tert-butyl)phenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 66 CDD-3185 5-((2-((4-(tert-butyl)phenyl)(methyl)amino)-N- methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide 67 CDD-3254 5-((N-isopropyl-2-((4- (trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 68 CDD-3255 5-((N-isopropyl-2-(4-(prop-1-en-2- yl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide 69 CDD-3256 5-((2-(4-acetylphenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 70 CDD-3257 5-((2-(4-acetylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 71 CDD-3258 - 51 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 5-((N-methyl-2-((4- (trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 72 CDD-3099 (S)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propanamide 73 CDD-3100 (R)-N-methyl-3-(4-nitrophenyl)-2-(3-(4- phenoxyphenyl)ureido)propanamide 74 CDD-3264 N-((1H-indol-5-yl)methyl)-N-isopropyl-2-(4- (trifluoromethoxy)phenoxy)acetamide 75 CDD-3265 1-((1H-indol-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea O H N 76 N N N N CDD-3306 2-((6-(tert-butyl)pyridin-3-yl)amino)-N-isopropyl-N-(pyrazolo[1,5- a]pyridin-5-ylmethyl)acetamide 77 CDD-3307 N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-((4-(1- (trifluoromethyl)cyclopropyl)phenyl)amino)acetamide 78 CDD-3308 5-((methyl(N-(4- (trifluoromethoxy)phenyl)sulfamoyl)amino)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide - 52 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 79 CDD-2837 1-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-1-cyclopropyl-3-(4- (trifluoromethoxy)phenyl)urea 80 CDD-2838 1-cyclopropyl-1-(pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea 81 CDD-2839 1-cyclopropyl-1-(pyrimidin-4-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 82 CDD-2840 1-cyclopropyl-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea 83 CDD-3033 5-((N-(3-(3-chlorophenoxy)propyl)-2-(4- isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 84 CDD-3222 5-((N-(4-(trifluoromethoxy)phenyl)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide 85 CDD-3223 5-(((N-isopropyl-4- (trifluoromethyl)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide - 53 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 86 CDD-3224 5-(((N-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine)-6- sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide 87 CDD-3225 5-(((N-methyl-4- (trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 88 CDD-3226 5-(((N-isopropyl-4- (trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 89 (E)-5-((N-isopropyl-3-(4- methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide 90 (E)-5-((N-isopropyl-3-(4- (trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically- active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of - 54 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic - 55 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to 2H, 3H, 11C, 13C, 14C, 36Cl, 18F, 123I, 125I, 13N, 15N, 15O, 17O, 18O, 32P, and 35S. In certain embodiments, isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as 11C, 18F, 15O, and 13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. - 56 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking/protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), N-alkoxycarbonyl (Alloc), methyl (Me), ethyl (Et), tert-butyl (t- Bu), tert-butyl dimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), tert- butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), fluorenylmethyloxycarbonyl (FMOC). Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated - 57 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) herein by reference for such disclosure. Compositions In one aspect, the present disclosure provides a pharmaceutical composition comprising the compound of the present disclosure and a pharmaceutically acceptable carrier. The compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises Kolliphor EL, and aqueous buffer, or a combination thereof. In certain embodiments, the aqueous buffer comprises phosphate buffered saline (PBS). In some embodiments, the aqueous buffer comprises 1x PBS. In certain embodiments, the pharmaceutical composition comprises about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% Kolliphor EL. In some embodiments, the pharmaceutical composition comprises about 20% Kolliphor EL in 1x PBS. In certain embodiments, the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In some embodiments, the composition is formulated as a pill, tablet, gelcap, or capsule for oral administration. Methods In one aspect, the present disclosure provides a method of identifying a female human subject that has or is likely to develop endometriosis (such as, but not limited to, ovarian endometrioma). In one aspect, the present disclosure provides a method of identifying a female human subject that has or is likely to develop cancer. In one aspect, the present disclosure provides a method of identifying a female human subject that has or is likely to develop ovarian cancer. In certain embodiments, the ovarian cancer is clear cell ovarian cancer. In certain embodiments, the ovarian cancer is endometrioid ovarian cancer. In certain embodiments, the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 - 58 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) in the BDNF gene. Such determination can be done using sequencing methods known in the art, using a biological sample obtained from the subject. A person skilled in the art would be able to perform such determination without any undue optimization and/or experimentation. In certain embodiments, the female human subject has the rs137922923 variant in the NTRK2 gene. In certain embodiments, the female human subject has the variant rs78531552 in the BDNF gene. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject has or is predisposed to endometriosis. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject has or is predisposed to cancer. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject has or is predisposed to ovarian cancer. In certain embodiments, the ovarian cancer is clear cell ovarian cancer. In certain embodiments, the ovarian cancer is endometrioid ovarian cancer. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject has or is predisposed to clear cell ovarian cancer and/or endometroid ovarian cancer. In certain embodiments, the female human subject predisposed to have cancer, such as but not limited to ovarian cancer, such as but not limited to clear cell ovarian cancer and/or endometrioid ovarian cancer, benefits by treatment with an NTRK inhibitor. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is counseled to be treated with a therapeutically effective amount of a NTRK inhibitor. In certain embodiments, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is administered a therapeutically effective amount of a NTRK inhibitor. In one aspect, the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis. Such female human subject has endometriosis and/or is prone to have endometriosis. - 59 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) In one aspect, the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent cancer. Such female human subject has cancer and/or is prone to have endometriosis. In one aspect, the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer. Such female human subject has ovarian cancer and/or is prone to have ovarian cancer. In one aspect, the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent clear cell ovarian cancer. Such female human subject has clear cell ovarian cancer and/or is prone to have clear cell ovarian cancer. In one aspect, the present disclosure provides a method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometrioid ovarian cancer. Such female human subject has endometrioid ovarian cancer and/or is prone to have endometrioid ovarian cancer. In certain embodiments, the method comprises determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent clear cell ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In certain embodiments, the method comprises identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometrioid ovarian cancer if the female human subject has the rs137922923 variant in the - 60 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) NTRK2 gene and/or the variant rs78531552 in the BDNF gene. In one aspect, the present disclosure provides a method of monitoring NTRK inhibition in a female human subject being administered a NTRK inhibitor. In certain embodiments, the method comprises determining the pre-treatment expression level of at least one gene in the female human patient. In certain embodiments, the method comprises determining the expression level of the at least one gene in the female human patient after being administered the NTRK inhibitor. In certain embodiments, reduction in expression level of the at least one gene after treatment indicates NTRK inhibition in the female human subject. In certain embodiments, the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, NOS2, CCL28, TNFSF15, CXCL8, DUSP10, CREB3L1, BDNF, and/or NTRK2. In certain embodiments, the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, and/or NOS2. In certain embodiments, the at least one gene comprises CXCL10, CXCL11, TNF, and/or NOS2. In certain embodiments, the at least one gene comprises IL1RN. In certain embodiments, the at least one gene comprises CXCL2. In certain embodiments, the at least one gene comprises CXCL10. In certain embodiments, the at least one gene comprises CXCL11. In certain embodiments, the at least one gene comprises CXCL16. In certain embodiments, the at least one gene comprises ALDH1A3. In certain embodiments, the at least one gene comprises TNF. In certain embodiments, the at least one gene comprises NOS1. In certain embodiments, the at least one gene comprises NOS2. In certain embodiments, the at least one gene comprises CCL28. In certain embodiments, the at least one gene comprises TNFSF15. In certain embodiments, the at least one gene comprises CXCL8. In certain embodiments, the at least one gene comprises DUSP10. In certain embodiments, the at least one gene comprises CREB3L1. In certain embodiments, the at least one gene comprises BDNF. In certain embodiments, the at least one gene comprises NTRK. In certain embodiments, if the reduction in expression level of the at least one gene is determined to be below the therapeutically effective threshold, the amount and/or frequency of dosing of the NTRK inhibitor is modified so as to cause a more intense reduction in expression level of the at least one gene. In certain embodiments, if the reduction in expression level of the at least one gene is determined to be above the therapeutically effective threshold, the amount and/or frequency - 61 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) of dosing of the NTRK inhibitor is modified so as to cause a less intense reduction in expression level of the at least one gene. The therapeutically effective threshold for level alterations in the at least gene should be easily determined using methods known to those skilled in the art. For example, the reduction in expression level of the at least one gene may be determined for a female human subject that is successfully treated for endometriosis. In such case, the expression level of the at least one gene is measured before the subject before the subject undergoes treatment and after the subject undergoes successful treatment. Further, the reduction in expression level of the at least one gene may be determined for female human subjects that have experienced various therapeutic outcomes when being treated for endometriosis. Analysis between the NTRK dosing, specifically measured reduction in expression level of the at least one gene, and the corresponding observed therapeutic outcomes may be analyzed to determine how reduction in expression level of the at least one gene correlates with therapeutic outocomes. In certain embodiments, the NTRK inhibitor is entrectinib, larotrectinib, selitrectinib, reprotrectinib, PF-06273340, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof. In certain embodiments, the NTRK inhibitor is a compound contemplated within the disclosure. In certain embodiments, neurotrophic receptor tyrosine kinase 1 (NTRK1) is overexpressed in the subject. In certain embodiments, neurotrophic receptor tyrosine kinase 2 (NTRK2) is overexpressed in the subject. In certain embodiments, neurotrophic receptor tyrosine kinase 3 (NTRK3) is overexpressed in the subject. In certain embodiments, Brain Derived Neurotrophic Factor (BDNF) is overexpressed in the subject. In certain embodiments, neurotrophin 4 (NTF4) is overexpressed in the subject. In certain embodiments, a combination of NTRK1, NTRK2, NTRK3, BDNF, and/or NTF4 is overexpressed in the subject. In certain embodiments, administration of the compound of the present disclosure and/or the pharmaceutical composition of the present disclosure results in inhibition of NTRK1 in the subject. In certain embodiments, inhibition of NTRK1 results in treatment, prevention, and/or amelioration of endometriosis, and/or one or more symptoms thereof, cancer, and/or pain. In certain embodiments, administration of the compound of the present disclosure and/or the pharmaceutical composition of the present disclosure results in inhibition of NTRK2 in the subject. In certain embodiments, inhibition of NTRK2 results in treatment, - 62 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) prevention, and/or amelioration of endometriosis, and/or one or more symptoms thereof, cancer, and/or pain. In certain embodiments, administration of the compound of the present disclosure and/or the pharmaceutical composition of the present disclosure results in inhibition of NTRK3 in the subject. In certain embodiments, inhibition of NTRK3 results in treatment, prevention, and/or amelioration of endometriosis, and/or one or more symptoms thereof, cancer, and/or pain. In certain embodiments, a fusion gene comprising at least one selected from the group consisting of NTRK1, NTRK2, and NTRK3 is overexpressed in the subject. In certain embodiments, the NTRK inhibitor is a NTRK2 inhibitor. In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK1. In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK3. In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK1 and NTRK3. In certain embodiments, selectivity of a compound for NTRK2 over NTRK1 comprises a half-maximal inhibitory concentration (IC50) of the compound for NTRK2 which is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, or 1000 times lower than the IC50 for the same compound against NTRK1. In certain embodiments, selectivity of a compound for NTRK2 over NTRK1 comprises a half-maximal inhibitory concentration (IC50) of the compound for NTRK2 which is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, or 1000 times lower than the IC50 for the same compound against NTRK3. In certain embodiments, the NTRK2 inhibitor is entrectinib. In certain embodiments, the NTRK2 inhibitor is larotrectinib. In certain embodiments, the NTRK2 inhibitor is selitrectinib. In certain embodiments, the NTRK2 inhibitor is reprotrectinib. In certain embodiments, the NTRK2 inhibitor is PF-06273340. In certain embodiments, administration of the compound of the present disclosure and/or the pharmaceutical composition of the present disclosure results in inhibition of the fusion gene product in the subject. In certain embodiments, inhibition of the fusion gene product results in treatment, prevention, and/or amelioration of endometriosis, and/or one or more symptoms thereof, cancer, and/or pain. Administration/Dosage/Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset - 63 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) of the disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or disorder in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non- limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. - 64 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound. In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may 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 dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be - 65 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) administered to any patient is determined by the attending physician taking all other factors about the patient into account. The compound(s) described herein for administration may be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, or reduce one or more symptoms of a disease or disorder in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, - 66 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or - 67 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms - 68 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos. WO 03/35041; WO 03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO 02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO 98/11879; WO 97/47285; WO 93/18755; and WO 90/11757. Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein. Most controlled-release pharmaceutical products have a common goal of improving - 69 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects. Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled-release component” is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In some embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 - 70 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of the disease or disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, - 71 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection. The compounds described herein can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the - 72 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein. EXAMPLES Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Example 1. NRTK inhibitors of the disclosure inhibit BDNF-induced pro-inflammatory signaling in eutopic endometrial epithelial organoids Endometrial epithelial organoids from the eutopic endometrium of a woman with clinical stage 2 endometriosis were grown in 3D cultures. One day prior to treatment, organoid medium was changed to minimal differentiation media overnight. The following morning, organoids were pretreated with vehicle (DMSO), 1µM CDD-2737, or 1µM CDD- 3031 for 30 minutes, then stimulated with 50ng/ml BDNF for an additional 3 hours. mRNA was extracted from the organoids after the 3-hour incubation and subjected to RNA sequencing using the Illumina platform. Reads were aligned to the human genome hg38 build and differentially expressed genes were calculated using DESeq with a cutoff of >1.2, FDR <.05 or < 0.8, FDR < .05. The study showed that, relative to vehicle-treated cells, BDNF stimulated the expression of 688 genes (>1.2, FDR <.05) and decreased the expression of 555 genes (< 0.8, FDR < .05). This included genes involved in pro-inflammatory pathways (IL32, CXCL10, CXCL11) and oxidative stress response (NOS2, NOS1, SOD1) (FIG.1A). Pre-treatment with 1µM CDD-2737 before stimulation with 50ng/ml BDNF, increased 183 genes (>1.2, FDR <.05) and decreased 231 genes (< 0.8, FDR < .05) (FIG. 1B). When the epithelial organoids were pretreated with 1µM CDD-3031 prior to stimulation with 50ng/ml BDNF, 276 were upregulated (>1.2, FDR <.05) and 190 genes were downregulated (< 0.8, FDR < .05) (FIG.1C). Genes that were decreased by both CDD-2737 and CDD-3031 included the pro- - 73 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) inflammatory genes, CXCL10, CXCL11, TNF, and NOS2. Example 2: Genetic analysis of endometriosis patients reveals genetic variants associated with the disease The present study analyzed genetic data from the FinnGen database and searched for genetic associations between BDNF and NTRK2 in various endometriosis subtypes (N14_ENDOMETRIOSIS, N14_ENDOMETRIOSIS_OVARY, N14_ENDOMETRIOSIS_ASRM_STAGE3_4, N14_ENDOMETRIOSIS_PELVICPERITONEUM, N14_ENDOMETRIOSIS_ASRM_STAGE1_2, N14_ENDOMET_INFERT, N14_ENDOMETRIOSIS_RECTPVAGSEPT_VAGINA, N14_ENDOMETRIOSIS_DEEP, N14_ENDOMETRIOSIS_UTERUS, N14_ENDOMETRIOSIS_NOS, N14_ENDOMETRIOSIS_INTESTINE, N14_ENDOMETRIOSIS_FALLOPIAN_TUBE). It was found that compared to endometriosis-free controls, individuals with endometriosis displayed several variants in the BDNF and NTRK2 genes that occurred more frequently in this population (FIGs.3A-3B). Specifically, BDNF had 47 variants and NTRK2 had 182 variants across the gene body that were significantly associated in patients with endometriosis (n= 62,108) relative to disease-free controls (n= 1,780,044) (p<0.01). An NTRK2 variant (rs137922923, green circles) was frequently observed with in patients with various subtypes of endometriosis (FIG.3A). A BDNF variant (rs78531552, yellow circles) was frequently observed in patients with various subtypes of endometriosis (FIG.3B). Example 3. NRTK inhibitors of the disclosure inhibit BDNF-induced pro-inflammatory signaling in eutopic endometrial epithelial organoids Endometrial epithelial organoids from the eutopic endometrium of a woman with clinical stage 2 endometriosis were grown in 3D cultures (see Example 1). Organoids were treated with vehicle; 100 ng/mL BDNF; or 100 ng/mL BDNF and 1µM CDD-3031. The study showed that, relative to vehicle-treated, BDNF stimulated the expression of 585 genes. When the epithelial organoids were pretreated with 1µM CDD-303196 genes were downregulated. 84 genes were in both groups (i.e., upregulated with BDNF alone, downregulated with BDNF and CDD-3031). Among these 84 were CCL28, CXCL10, NOS2, TNF, IL1RN, TNFSF15, CXCL11, CXCL8, DUSP10, CREB3L1, BDNF, and NTRK2. See FIGS.4A-4B. Gene ontology analysis of pathways suppressed by CDD-3031 indicated suppression - 74 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) of pro-inflammatory pathways. See FIGS.4C-4D. Inhibition of BDNF-NTRK2 signaling by CDD-3031 impacts several gene pathways that are currently being targeted by molecules undergoing clinical trials or considered pre- clinical candidates for endometriosis. These include (genes impacted by CDD-3031): ^ Anti-IL8 antibody (Phase II) - CDD-3031 decreased CXCL8 (the gene encoding interleukin 8 (IL8)) expression. ^ CSFR1 antagonist (preclinical candidate) - CDD-3031 decreased several genes stimulated downstream of CSFR1 activation (TNF, CXCL10, IL11RN, CCL28). ^ Quinagolide VR-DR2 agonist (Phase II, targeting VEGF/VEGFR1) - CDD-3031 decreased expression of VEGF/VEGFR1 effector gene TNFSF15 (induced by IL1 and TNF); TNFSF15 can induce apoptosis in endothelial cells, inhibit endothelial cell proliferation, and may function as an angiogenesis inhibitor. ^ JNK inhibitors (preclinical testing) - CDD-3031 decreased expression of DUSP10, a phosphatase that dephosphorylates JUN and JNK and correlates with inflammation; the three JNK proteins (JNK1, JNK2, and JNK3, encoded by the MAPK8, MAPK9, and MAPK10 genes, respectively) require phosphorylation to be active. In turn, the JNK proteins phosphorylate and activate JUN. Enumerated Embodiments The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1: A method of identifying a female human subject that has developed or is likely to develop endometriosis, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. Embodiment 2: A method of identifying a female human subject that has developed or is likely to develop ovarian cancer, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. Embodiment 3: The method of Embodiment 2, wherein the ovarian cancer comprises clear cell ovarian cancer and/or endometrioid ovarian cancer. Embodiment 4: The method of Embodiment 1, wherein the female human subject has the rs137922923 variant in the NTRK2 gene. - 75 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) Embodiment 5: The method of Embodiment 1, wherein the female human subject has the variant rs78531552 in the BDNF gene. Embodiment 6: The method of any one of Embodiments 1-5, wherein, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is counseled to be treated with a therapeutically effective amount of a NTRK inhibitor. Embodiment 7: The method of any one of Embodiments 1-5, wherein, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is administered a therapeutically effective amount of a NTRK inhibitor. Embodiment 8: A method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, and identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. Embodiment 9: A method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, and identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. Embodiment 10: The method of Embodiment 9, wherein the ovarian cancer comprises clear cell ovarian cancer or endometrioid ovarian cancer. Embodiment 11: A method of monitoring NTRK inhibition in a female human subject being administered a NTRK inhibitor, the method comprising: determining the pre- treatment expression level of at least one gene in the female human patient, and determining the expression level of the at least one gene in the female human patient after being administered the NTRK inhibitor, wherein reduction in expression level of the at least one gene after treatment indicates NTRK inhibition in the female human subject, wherein the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, NOS2, CCL28, TNFSF15, CXCL8, DUSP10, CREB3L1, BDNF, and/or NTRK2. - 76 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) Embodiment 12: The method of Embodiment 11, wherein the at least one gene comprises CXCL10, CXCL11, TNF, and/or NOS2. Embodiment 13: The method of any one of Embodiments 11-12, wherein, if the reduction in expression level of the at least one gene is determined to be below the therapeutically effective threshold, the amount and/or frequency of dosing of the NTRK inhibitor is modified so as to cause a more intense reduction in expression level of the at least one gene. Embodiment 14: The method of any one of Embodiments 11-12, wherein, if the reduction in expression level of the at least one gene is determined to be above the therapeutically effective threshold, the amount and/or frequency of dosing of the NTRK inhibitor is modified so as to cause a less intense reduction in expression level of the at least one gene. Embodiment 15: The method of any one of Embodiments 1-14, wherein the NTRK inhibitor is entrectinib, larotrectinib, selitrectinib, reprotrectinib, PF-06273340, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof. Embodiment 16: The method of any one of Embodiments 6-15, wherein the inhibitor is selected from the group consisting of: (a) a compound of formula (I): (I), wherein: T is selected from the group consisting of: , optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)ORa, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), CN, and NO2; R2 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, - 77 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), NRaC(=O)Rb, C(=O)N(Ra)(ORb), C(=NRa)N(Rb)(Rc), C(=NRa)N(Rb)(ORc), and NRaS(=O)2Rb; R3a, R3b, R3c, R3d, and R3e are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(=O)N(Ra)(Rb); L1 is -C(R6a)(R6b)-; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl; and then R4 is not H; - - 55387290.3 Attorney Docket No.046641-7063WO1(00172) or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof; (b) a compound of formula (II): (II), wherein: A2 is selected from the group consisting of: ; R8 is selected from substituted C1-C6 alkyl, optionally substituted C3- R9a, R9b, R9c, and R9d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, CN, and NO2; R10 is selected from the group consisting of optionally substituted C1-C6 alkyl, ; selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), NRaC(=O)Rb, and NRaS(=O)2Rb; R12a, R12b, and R12c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R13a, R13b, R13c, and R13d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R14 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; - 79 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) L3 is selected from the group consisting ; X2 is selected from the group consisting 1 Z is selected from the group consisting the group consisting of CR13b and N, Z3 is selected from the group consisting of CR13c and N, and Z4 is selected from the group consisting of CR13d and N, wherein at least one selected from the group consisting of Z1, Z2, Z3, and Z4 are N; and Ra and Rb are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl; or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof; and (c) a compound of , wherein: R15a, R15b, and R15c are each of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R16 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R17a and R17b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R18a and R18b are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; A3 is optionally substituted phenyl; and A4 is optionally substituted phenyl; or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any - 80 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) mixtures thereof. Embodiment 17: The method of Embodiment 16, wherein each occurrence of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heterocyclyl, and optionally substituted alkylenyl, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3- C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, OH, N(R’)(R’’), C(=O)R’, C(=O)OR’, OC(=O)OR’, C(=O)N(R’)(R’’), S(=O)2N(R’)(R’’), N(R’)C(=O)R’’, N(R’)S(=O)2R’’, C2-C8 heteroaryl, and phenyl optionally substituted with at least one halogen, wherein each occurrence of R’ and R’’ is independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and phenyl. Embodiment 18: The method of Embodiment 16 or 17, wherein the inhibitor is a compound of formula (I), which is selected from the group consisting of , , is H. Embodiment 20: The method of any one of Embodiments 16-19, wherein R2 is selected from the group consisting of H, F, Br, CN, C(=O)OH, C(=O)NH2, C(=O)NHMe, C(=O)NHOH, and C(=NH)NH(OH). - 81 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) Embodiment 21: The method of any one of Embodiments 16-20, wherein at least one of the following applies: (a) at least one selected from R3a, R3b, R3c, R3d, and R3e is H; (b) at least two selected from R3a, R3b, R3c, R3d, and R3e are H; (c) at least three selected from R3a, R3b, R3c, R3d, and R3e are H; (d) at least four selected from R3a, R3b, R3c, R3d, and R3e are H; and (e) each of R3a, R3b, R3c, R3d, and R3e are H. Embodiment 22: The method of any one of Embodiments 16-21, wherein T is selected from the group consisting of: NC , is selected from the group consisting of H, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (CH2)3N(CH3)2, C(=O)CH3, phenyl, benzyl substituted with at least one C1-C6 alkyl; and - CH2CH2CH2O(phenyl substituted with at least one halogen). Embodiment 24: The method of any one of Embodiments 16-22, wherein R4 is selected from the group consisting , and . 25: The method of any one of Embodiments 16-24, wherein A1 is selected from the group consisting of H; phenyl substituted with at least one substituent - 82 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C8 cycloalkyl optionally substituted with a C1-C3 haloalkyl, phenoxy, halogen, and NO2; phenyl fused with a C2-C6 heterocycloalkyl; and C2-C8 heteroaryl optionally substituted with C1-C6 alkyl or fused with a C2-C5 heteroaryl. Embodiment 26: The method of any one of Embodiments 16-25, wherein A1 is selected from the group consisting of: , is -CH2- . Embodiment 28: The method of any one of Embodiments 16-27, wherein L2 is selected from the group consisting of a bond, -C(=O)-, -C(=S)-, S(=O)2-, -CH2-, , . method of any one of Embodim 1 ents 16-28, wherein X is selected from the group consisting of a bond, O, and NR7. Embodiment 30: The method of Embodiment 18, wherein R7 is selected from the group consisting of H and Me. Embodiment 31: The method of any one of Embodiments 16-30, wherein R5 is selected from the group consisting of: , - 83 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) , , from the group consisting of: 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid; 1-cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea; 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclobutyl-3-(4-nitrophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 1-phenyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopentyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethyl)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(3-(trifluoromethyl)phenyl)urea; N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; methyl 5-((cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate; - 84 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 3-(3-chlorophenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)propan-1-amine; N,N-bis(pyrazolo[1,5-a]pyridin-5-ylmethyl)cyclobutanamine; 1-(3-(3-chlorophenoxy)propyl)-3-(4-phenoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5- ylmethyl)urea; 1-(3-(3-chlorophenoxy)propyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea; 3-(4-chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 1-cyclobutyl-3-(4-fluorophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)-N-methylpyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxylic acid; methyl 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylate; 1-cyclobutyl-3-(4-methoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; (R)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; (S)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; (S)-1-phenyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)ethan-1-amine; 1-((3-fluoropyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 1-((3-bromopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 5-((1-cyclopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylic acid; 5-((1-isopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-((1-cyclopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-isopropyl-3-methyl-3-(4-(trifluoro methoxy) phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoro - 85 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) methoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 1-((3-cyanopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 5-((1-isobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid; 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-(4-(trifluoromethoxy) phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboximidamide; 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((2-(4-isopropylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-3-(4-(trifluoromethoxy)phenyl)propanamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-isopropyl-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-(3-(dimethylamino)propyl)-2-(4- isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; - 86 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) (R)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; (S)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-methyl-2-(4-(trifluoromethyl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-((N-methyl-2-(3-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((2-(4-(tert-butyl)phenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-(4-(tert-butyl)phenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-((4-(tert-butyl)phenyl)(methyl)amino)-N-methylacetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-(4-(prop-1-en-2-yl)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((2-(4-acetylphenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-(4-acetylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; (S)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; (R)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; (R)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; (S)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; N-((1H-indol-5-yl)methyl)-N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamide; - 87 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 1-((1H-indol-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea; 2-((6-(tert-butyl)pyridin-3-yl)amino)-N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-((4-(1- (trifluoromethyl)cyclopropyl)phenyl)amino)acetamide; 5-((methyl(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)amino)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 1-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-1-cyclopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyrimidin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 5-((N-(3-(3-chlorophenoxy)propyl)-2-(4- isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((N-(4-(trifluoromethoxy)phenyl)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-(((N-isopropyl-4-(trifluoromethyl)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-(((N-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine)-6- sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-(((N-methyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-(((N-isopropyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; (E)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; (Z)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; (E)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; and - 88 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) (Z)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide. Embodiment 33: The method of Embodiment 16 or 17, which is a compound of formula (II). Embodiment 34: The method of Embodiment 33, wherein R8 is selected from the group consisting of isopropyl and phenyl. Embodiment 35: The method of Embodiment 33 or 34, wherein R9a, R9b, R9c, and R9d are each independently selected from the group consisting of H, tert-butyl, and trifluoromethyl. Embodiment 36: The method of any one of Embodiments 33-35, wherein A2 is selected from the group . Embodiment 37: The one of the following applies: (a) Z1 is N and at least one of Z2, Z3, and Z4 is CH; (b) Z1 is N and at least two of Z2, Z3, and Z4 are CH; (c) Z1 is N and each of Z2, Z3, and Z4 are CH; (d) Z2 is N and at least one of Z1, Z3, and Z4 is CH; (e) Z2 is N and at least two of Z1, Z3, and Z4 are CH; or (f) Z2 is N and each of Z1, Z3, and Z4 are CH. Embodiment 38: The method of any one of Embodiments 33-37, wherein X2 is selected from the group consisting of -O- and -NH-. Embodiment 39: The method of any one of Embodiments 33-38, wherein R11a, R11b, R11c, R11d, R11e, R11f, R11g, and R11h are each independently selected from the group consisting of H and methoxy. Embodiment 40: The method of any one of Embodiments 33-39, wherein R12a, R12b, and R12c are each independently selected from the group consisting of H, methyl, and C(=O)O(C(CH3)3). Embodiment 41: The method of any one of Embodiments 33-40, wherein R10 is selected from the group consisting of - 89 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) . which is N1-(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; N1-(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol- 3-yl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; tert-butyl 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinate; tert-butyl 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazol-3-yl)picolinate; (Z)-N1-(4-(5-(N’-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3- carbonyl)oxy)carbamimidoyl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; and tert-butyl (4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazol-3-yl)picolinamido)-3-methoxyphenyl)carbamate. Embodiment 43: The method of Embodiment 16 or 17, wherein the compound is a compound of formula (III). Embodiment 44: The method of Embodiment 43, wherein the compound of formula (III) is selected from the group consisting of: . of the following applies: (a) at least one of R15a, R15b, and R15c is H; (b) at least two of R15a, R15b, and R15c are H; and (c) each of R15a, R15b, and R15c are H. Embodiment 46: The method of any one of Embodiments 43-45, wherein R16 is selected from the group consisting of benzyl . Embodiment 47: The method of any 43-46, wherein R17a and - 90 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) R17b are each independently H. Embodiment 48: The method of any one of Embodiments 43-47, wherein R18a and R18b are each independently selected from the group consisting of H and Me. Embodiment 49: The method of any one of Embodiments 43-48, wherein A3 is selected from the group . Embodiment 50: The 43-49, wherein A4 is . 51: The method of any one of Embodiments 16-17 and 43-50, which is selected from the group consisting of: N-((S)-1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1-(2-(methylamino)-2-oxo-1- phenylethyl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide; (S)-1-benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan- 2-yl)-1H-benzo[d]imidazole-7-carboxamide; and (S)-1-benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6-trichlorophenyl)- 1H-benzo[d]imidazole-7-carboxamide. Embodiment 52: The method of any one of Embodiments 15-51, wherein the NTRK inhibitor is a NTRK2 inhibitor. Embodiment 53: The method of Embodiment 52, wherein the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK1 and/or NTRK3. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application. - 91 - 55387290.3

Claims

Attorney Docket No.046641-7063WO1(00172) CLAIMS What is claimed is: 1. A method of identifying a female human subject that has developed or is likely to develop endometriosis, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. 2. A method of identifying a female human subject that has developed or is likely to develop ovarian cancer, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. 3. The method of claim 2, wherein the ovarian cancer comprises clear cell ovarian cancer and/or endometrioid ovarian cancer. 4. The method of claim 1, wherein the female human subject has the rs137922923 variant in the NTRK2 gene. 5. The method of claim 1, wherein the female human subject has the variant rs78531552 in the BDNF gene. 6. The method of any one of claims 1-5, wherein, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is counseled to be treated with a therapeutically effective amount of a NTRK inhibitor. 7. The method of any one of claims 1-5, wherein, if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, the female human subject is administered a therapeutically effective amount of a NTRK inhibitor. 8. A method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis, the method comprising - 92 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, and identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent endometriosis if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. 9. A method of identifying a female human subject that should be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer, the method comprising determining whether the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene, and identifying the female human subject as a candidate to be administered a NTRK inhibitor to treat, ameliorate, and/or prevent ovarian cancer if the female human subject has the rs137922923 variant in the NTRK2 gene and/or the variant rs78531552 in the BDNF gene. 10. The method of claim 9, wherein the ovarian cancer comprises clear cell ovarian cancer or endometrioid ovarian cancer. 11. A method of monitoring NTRK inhibition in a female human subject being administered a NTRK inhibitor, the method comprising: determining the pre-treatment expression level of at least one gene in the female human patient, and determining the expression level of the at least one gene in the female human patient after being administered the NTRK inhibitor, wherein reduction in expression level of the at least one gene after treatment indicates NTRK inhibition in the female human subject, wherein the at least one gene comprises IL1RN, CXCL2, CXCL10, CXCL11, CXCL16, ALDH1A3, TNF, NOS1, NOS2, CCL28, TNFSF15, CXCL8, DUSP10, CREB3L1, BDNF, and/or NTRK2. 12. The method of claim 11, wherein the at least one gene comprises CXCL10, CXCL11, TNF, and/or NOS2. 13. The method of any one of claims 11-12, wherein, if the reduction in expression level - 93 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) of the at least one gene is determined to be below the therapeutically effective threshold, the amount and/or frequency of dosing of the NTRK inhibitor is modified so as to cause a more intense reduction in expression level of the at least one gene. 14. The method of any one of claims 11-12, wherein, if the reduction in expression level of the at least one gene is determined to be above the therapeutically effective threshold, the amount and/or frequency of dosing of the NTRK inhibitor is modified so as to cause a less intense reduction in expression level of the at least one gene. 15. The method of any one of claims 1-14, wherein the NTRK inhibitor is entrectinib, larotrectinib, selitrectinib, reprotrectinib, PF-06273340, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof. 16. The method of any one of claims 6-15, wherein the inhibitor is selected from the group consisting of: (a) a compound of formula (I): (I), wherein: T is selected from the group consisting of: , optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)ORa, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), CN, and NO2; R2 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, - 94 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), NRaC(=O)Rb, C(=O)N(Ra)(ORb), C(=NRa)N(Rb)(Rc), C(=NRa)N(Rb)(ORc), and NRaS(=O)2Rb; R3a, R3b, R3c, R3d, and R3e are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, C(=O)(optionally substituted C1-C6 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 aminoalkyl, optionally substituted C2-C6 hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R5 is selected from the group consisting of H and -X1-A1; R6a, R6b, R6c, and R6d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and C(=O)N(Ra)(Rb); L1 is -C(R6a)(R6b)-; L2 is selected from the group consisting of a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylenyl), -C(=O)(optionally substituted C2-C3 alkenylenyl), -C(=S)-, - C(=S)(optionally substituted C1-C3 alkylenyl), -C(=S)(optionally substituted C2-C3 alkenylenyl), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylenyl), -S(=O)2(optionally substituted C2-C3 alkenylenyl), optionally substituted C1-C3 alkylenyl, and optionally substituted C2-C3 alkenylenyl; X1 is selected from the group consisting of a bond, O, and NR7; R7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; Ra, Rb, and Rc are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl; and then R4 is not H; - - 55387290.3 Attorney Docket No.046641-7063WO1(00172) or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof; (b) a compound of formula (II): , wherein: A2 is selected from ; R8 is selected from substituted C1-C6 alkyl, optionally substituted C3- R9a, R9b, R9c, and R9d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryl, optionally substituted C2-C8 heterocyclyl, halogen, CN, and NO2; R10 is selected from the group consisting of optionally substituted C1-C6 alkyl, ; selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(=O)Ra, C(=O)ORa, OC(=O)Ra, C(=O)N(Ra)(Rb), S(=O)2N(Ra)(Rb), NRaC(=O)Rb, and NRaS(=O)2Rb; R12a, R12b, and R12c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R13a, R13b, R13c, and R13d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally - 96 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) substituted C1-C6 alkoxy, halogen, CN, and NO2; R14 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L3 is selected from the group consisting of: ; X2 is selected from the Z1 is selected from the N, Z2 is selected from the group consisting of CR13b and N, Z3 is selected from the group consisting of CR13c and N, and Z4 is selected from the group consisting of CR13d and N, wherein at least one selected from the group consisting of Z1, Z2, Z3, and Z4 are N; and Ra and Rb are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl; or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof; and (c) a compound of formula (III): , wherein: R15a, R15b, and R15c are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN, and NO2; R16 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R17a and R17b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally - 97 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) substituted benzyl, and optionally substituted phenyl; R18a and R18b are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; A3 is optionally substituted phenyl; and A4 is optionally substituted phenyl; or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixtures thereof. 17. The method of claim 16, wherein each occurrence of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heterocyclyl, and optionally substituted alkylenyl, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, OH, N(R’)(R’’), C(=O)R’, C(=O)OR’, OC(=O)OR’, C(=O)N(R’)(R’’), S(=O)2N(R’)(R’’), N(R’)C(=O)R’’, N(R’)S(=O)2R’’, C2-C8 heteroaryl, and phenyl optionally substituted with at least one halogen, wherein each occurrence of R’ and R’’ is independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and phenyl. 18. The method of claim 16 or 17, wherein the inhibitor is a compound of formula (I), which is selected from the group consisting of , , - 98 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) . 19. The method of any H. 20. The method of any one of claims 16-19, wherein R2 is selected from the group consisting of H, F, Br, CN, C(=O)OH, C(=O)NH2, C(=O)NHMe, C(=O)NHOH, and C(=NH)NH(OH). 21. The method of any one of claims 16-20, wherein at least one of the following applies: (a) at least one selected from R3a, R3b, R3c, R3d, and R3e is H; (b) at least two selected from R3a, R3b, R3c, R3d, and R3e are H; (c) at least three selected from R3a, R3b, R3c, R3d, and R3e are H; (d) at least four selected from R3a, R3b, R3c, R3d, and R3e are H; and (e) each of R3a, R3b, R3c, R3d, and R3e are H. 22. The method of any one of claims 16-21, wherein T is selected from the group consisting of: NC , - 99 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 23. The method of any one of claims 16-22, wherein R4 is selected from the group consisting of H, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (CH2)3N(CH3)2, C(=O)CH3, phenyl, benzyl substituted with at least one C1-C6 alkyl; and -CH2CH2CH2O(phenyl substituted with at least one halogen). 24. The method of any one of claims 16-22, wherein R4 is selected from the group . 25. the group consisting of H; phenyl substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C8 cycloalkyl optionally substituted with a C1-C3 haloalkyl, phenoxy, halogen, and NO2; phenyl fused with a C2-C6 heterocycloalkyl; and C2-C8 heteroaryl optionally substituted with C1-C6 alkyl or fused with a C2-C5 heteroaryl. 26. The method of any one of claims 16-25, wherein A1 is selected from the group consisting of: , 27. The method of any one of claims 16-26, wherein L1 is -CH2-. 28. The method of any one of claims 16-27, wherein L2 is selected from the group - 100 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) consisting of a bond, -C(=O)-, -C(=S)-, S(=O)2-, -CH2-, , , and any one group consisting of a bond, O, and NR7. 30. The method of claim 18, wherein R7 is selected from the group consisting of H and Me. 31. The method of any one of claims 16-30, wherein R5 is selected from the group consisting of: 32. The method of any one of claims 16-31, which is selected from the group consisting of: - 101 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid; 1-cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea; 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclobutyl-3-(4-nitrophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 1-phenyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopentyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethyl)phenyl)urea; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(3-(trifluoromethyl)phenyl)urea; N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; methyl 5-((cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate; 3-(3-chlorophenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)propan-1-amine; N,N-bis(pyrazolo[1,5-a]pyridin-5-ylmethyl)cyclobutanamine; 1-(3-(3-chlorophenoxy)propyl)-3-(4-phenoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5- ylmethyl)urea; 1-(3-(3-chlorophenoxy)propyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea; 3-(4-chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 1-cyclobutyl-3-(4-fluorophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)-N-methylpyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxylic acid; methyl 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylate; 1-cyclobutyl-3-(4-methoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea; (R)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; (S)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5- - 102 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) ylmethyl)acetamide; 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; (S)-1-phenyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)ethan-1-amine; 1-((3-fluoropyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 1-((3-bromopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 5-((1-cyclopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylic acid; 5-((1-isopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-((1-cyclopropyl-3-(4-(trifluoro methoxy)phenyl) ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-isopropyl-3-methyl-3-(4-(trifluoro methoxy) phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoro methoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 1-((3-cyanopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 5-((1-isobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxylic acid; 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl) ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-(4-(trifluoromethoxy) phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboximidamide; 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((2-(4-isopropylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-3-(4-(trifluoromethoxy)phenyl)propanamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- - 103 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) carboxamide; 5-((N-isopropyl-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-(3-(dimethylamino)propyl)-2-(4- isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; (R)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; (S)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-methyl-2-(4-(trifluoromethyl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-((N-methyl-2-(3-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((2-(4-(tert-butyl)phenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-(4-(tert-butyl)phenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-((4-(tert-butyl)phenyl)(methyl)amino)-N-methylacetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-2-(4-(prop-1-en-2-yl)phenoxy)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; - 104 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 5-((2-(4-acetylphenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((2-(4-acetylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-methyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; (S)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; (R)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3- nitrophenyl)propenamide; N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; (R)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; (S)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)propenamide; N-((1H-indol-5-yl)methyl)-N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamide; 1-((1H-indol-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea; 2-((6-(tert-butyl)pyridin-3-yl)amino)-N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5- ylmethyl)acetamide; N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-((4-(1- (trifluoromethyl)cyclopropyl)phenyl)amino)acetamide; 5-((methyl(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)amino)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 1-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-1-cyclopropyl-3-(4- (trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(pyrimidin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 1-cyclopropyl-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea; 5-((N-(3-(3-chlorophenoxy)propyl)-2-(4- isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((N-(4-(trifluoromethoxy)phenyl)acetamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-(((N-isopropyl-4-(trifluoromethyl)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; - 105 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) 5-(((N-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine)-6- sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-(((N-methyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 5-(((N-isopropyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; 5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; (E)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; (Z)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3- carboxamide; 5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; (E)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide; and (Z)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5- a]pyridine-3-carboxamide. 33. The method of claim 16 or 17, which is a compound of formula (II). 34. The method of claim 33, wherein R8 is selected from the group consisting of isopropyl and phenyl. 35. The method of claim 33 or 34, wherein R9a, R9b, R9c, and R9d are each independently selected from the group consisting of H, tert-butyl, and trifluoromethyl. 36. The method of any one of claims 33-35, wherein A2 is selected from the group . 37. The method of any one of claims 33-35, wherein one of the following applies: - 106 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) (a) Z1 is N and at least one of Z2, Z3, and Z4 is CH; (b) Z1 is N and at least two of Z2, Z3, and Z4 are CH; (c) Z1 is N and each of Z2, Z3, and Z4 are CH; (d) Z2 is N and at least one of Z1, Z3, and Z4 is CH; (e) Z2 is N and at least two of Z1, Z3, and Z4 are CH; or (f) Z2 is N and each of Z1, Z3, and Z4 are CH. 38. The method of any one of claims 33-37, wherein X2 is selected from the group consisting of -O- and -NH-. 39. The method of any one of claims 33-38, wherein R11a, R11b, R11c, R11d, R11e, R11f, R11g, and R11h are each independently selected from the group consisting of H and methoxy. 40. The method of any one of claims 33-39, wherein R12a, R12b, and R12c are each independently selected from the group consisting of H, methyl, and C(=O)O(C(CH3)3). 41. The method of any one of claims 33-40, wherein R10 is selected from the group consisting of tert- . 42. The method of any one of claims 16-17 and 33-41, which is selected from the group consisting of: N1-(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3- yl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; N1-(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol- 3-yl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; tert-butyl 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinate; tert-butyl 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazol-3-yl)picolinate; (Z)-N1-(4-(5-(N’-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3- carbonyl)oxy)carbamimidoyl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide; - 107 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) and tert-butyl (4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- 3-yl)picolinamido)-3-methoxyphenyl)carbamate. 43. The method of claim 16 or 17, wherein the compound is a compound of formula (III). 44. The method of claim 43, wherein the compound of formula (III) is selected from the group consisting of: . 45. or one (a) at least one of R15a, R15b, and R15c is H; (b) at least two of R15a, R15b, and R15c are H; and (c) each of R15a, R15b, and R15c are H. 46. The method of any one of claims 43-45, wherein R16 is selected from the group consisting of . 47. The method of any one of claims 43-46, wherein R17a and R17b are each independently H. 48. The method of any one of claims 43-47, wherein R18a and R18b are each independently selected from the group consisting of H and Me. 49. The method of any one of claims 43-48, wherein A3 is selected from the group - 108 - 55387290.3 Attorney Docket No.046641-7063WO1(00172) consisting . 50. The method of any one of claims 43-49, wherein A4 is . 51. The method of any one of claims 16-17 and 43-50, from the group consisting of: N-((S)-1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1-(2-(methylamino)-2-oxo-1- phenylethyl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide; (S)-1-benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan- 2-yl)-1H-benzo[d]imidazole-7-carboxamide; and (S)-1-benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6-trichlorophenyl)- 1H-benzo[d]imidazole-7-carboxamide. 52. The method of any one of claims 15-51, wherein the NTRK inhibitor is a NTRK2 inhibitor. 53. The method of claim 52, wherein the NTRK2 inhibitor selectively inhibits NTRK2 over NTRK1 and/or NTRK3. - 109 - 55387290.3
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