Neurotrophic factor receptor tyrosine kinase (NTRK) inhibitors and methods of using same

Abstract

The present disclosure relates to compounds that inhibit one or more members of the neurotrophin receptor tyrosine kinase (NTRK) family (i.e., NTRK1, NTRK2, and / or NTRK3), and pharmaceutical compositions thereof. In another aspect, the present disclosure provides a method for treating, preventing, and / or ameliorating at least one disease and / or disorder selected from the group consisting of endometriosis, cancer, and pain in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure. TIFF2025532184000355.tif95138

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 393,557, filed July 29, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] background The human genome encodes 538 protein kinases, most of which are functionally important and involved in the pathogenesis of many diseases. Small molecule inhibition of kinase enzymatic activity is an attractive and tractable approach for treating disease. Currently, there are approximately 73 kinase inhibitors approved by the U.S. Food and Drug Administration (FDA) to treat a variety of diseases. This indicates that kinase inhibition is a validated therapeutic approach with opportunities for significant development and advancement.

[0003] Endometriosis is a debilitating inflammatory disease associated with dysmenorrhea, dyspareunia, and menorrhagia, causing infertility and increasing the incidence of endometrioid and clear cell ovarian cancer. In women with endometriosis, endometrial tissue invades the peritoneal cavity through retrograde menstruation, resulting in the attachment and persistent growth of endometrial tissue outside the uterine cavity. The disease affects approximately 190 million women aged 15–49 years worldwide (approximately 10%).

[0004] Women with endometriosis typically endure the disease's painful symptoms for approximately 10 years before receiving a definitive diagnosis. Furthermore, even after diagnosis, available endometriosis treatments are limited and often ineffective in the long term. For example, surgical removal of endometriotic implants does not completely cure the disease, as the lesions and associated pain typically recur. The debilitating pain of endometriosis and its many associated side effects prevent women from living a vibrant and fulfilling life during their peak years.

[0005] Thus, there is an urgent need in the art for compositions and methods of use for treating, preventing, and / or ameliorating endometriosis. The present disclosure addresses this need. Summary of the Invention

[0006] overview The present disclosure provides, in one aspect, a compound of formula (I), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein T, L 1 , L 2 , R 4 , and R 5 is defined elsewhere herein. TIFF2025532184000002.tif11128

[0007] In another aspect, the present disclosure provides a compound of formula (Ia), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , and R 5 is defined elsewhere herein. TIFF2025532184000003.tif23128

[0008] In another aspect, the present disclosure provides a compound of formula (Ib), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , and R5 is defined elsewhere herein. TIFF2025532184000004.tif23128

[0009] In another aspect, the present disclosure provides a compound of formula (Ic), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein L 1 , L 2 , R 1 , R 3a , R 3b , R 3c , R 4 , and R 5 is defined elsewhere herein. TIFF2025532184000005.tif23128

[0010] In another aspect, the present disclosure provides a compound of formula (Id), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , and R 5 is defined elsewhere herein. TIFF2025532184000006.tif23128

[0011] In another aspect, the present disclosure provides a compound of formula (Ie), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein L 1 , L 2 , R 3a , R 3b , R 3c , R 3d , R 4 , and R 5 is defined elsewhere herein. TIFF2025532184000007.tif23128

[0012] In another aspect, the present disclosure provides a compound of formula (If), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein L 1 , L 2 , R 3a , R 3b , R 4 , and R 5 is defined elsewhere herein. TIFF2025532184000008.tif20128

[0013] In another aspect, the present disclosure provides a compound of formula (Ig), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein L 1 , L 2 , R 3a , R 3b , R 3c , R 3d , R 3e , R 4 , and R 5 is defined elsewhere herein. TIFF2025532184000009.tif23128

[0014] In another aspect, the present disclosure provides a compound of formula (II), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein: A 2 , L 3 , Z 1 , Z 2 , Z 3 , Z 4 , X 2 , and R 10 is defined elsewhere herein. TIFF2025532184000010.tif14128

[0015] In another aspect, the present disclosure provides a compound of formula (III), or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, wherein: A 3 , A 4 , R 15a , R 15b , R 15c , R 16 , R 17a , R 17b , R 18a , and R 18b is defined elsewhere herein. TIFF2025532184000011.tif28128

[0016] In another aspect, the present disclosure provides pharmaceutical compositions comprising at least one compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), or (III) and a pharmaceutically acceptable carrier.

[0017] In another aspect, the present disclosure provides a method for treating, preventing, and / or ameliorating endometriosis in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one neurotrophic receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0018] In another aspect, the present disclosure provides a method for treating, preventing, and / or ameliorating cancer in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one neurotrophin receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0019] In another aspect, the present disclosure provides a method for treating, preventing, and / or ameliorating pain in a subject in need thereof. In certain embodiments, the method comprises administering to the subject at least one neurotrophin receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0020] In certain embodiments, the NTRK inhibitor is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), or (III).

[0021] The NTRK2 inhibitor is selected from the group consisting of staurosporine, entrectinib, ceritrectinib, repotrectinib, and PF-06273340.

[0022] In certain embodiments, the NTRK inhibitor is an NTRK2 inhibitor.

[0023] In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK1 and / or NTRK3. In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK1. In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK3. [Brief explanation of the drawings]

[0024] The drawings illustrate various aspects of the present application generally by way of example, but not by way of limitation.

[0025] [Figure 1A]Figures 1A-1B demonstrate the identification of NTRK2 as a therapeutic target for endometriosis. Gene expression profiling of endometrial tissue from normal women (control endometrium, CE, n=43), endometrial tissue from women with endometriosis (patient endometriosis, PE, n=104), and endometrial tissue from endometriotic lesions (ovarian endometrioma, OMA, n=28; deep endometriosis, DiE, n=91; peritoneal endometriotic lesion, PeL, n=79) identified NTRK2 overexpression in the NTRK2 isoforms NM_006180 (Figure 1A) and NM-001007097 (Figure 1B). NTRK2 overexpression was confirmed in three additional endometriosis datasets: GSE25628, GSE23339, and GSE7305 (fold change >1.4, p<0.05). [Figure 1B] See legend to Figure 1A. [Figure 2-1] Figures 2A-2K show overexpression and activity of NTRK2 in stromal cells of endometriotic lesions. Figure 2A: Western blotting analysis shows that NTRK2 is more abundant in lysates from ectopic peritoneal lesions and ovarian endometriomas than in eutopic normal endometrium or eutopic endometrium from endometriosis patients. Figures 2B-2G: Immunohistochemistry of NTRK2 and negative control (NC) shows staining in stromal and epithelial cells in peritoneal endometriotic lesions. Similar results were observed in endometriotic lesions from endometriomas and rectal endometriotic lesions. Figures 2H-2J: qRT-PCR shows that PGE2-mediated induction of the inflammatory genes PTGS2 / COX2, IL6, and IL8 is reduced after NTRK2 knockdown in primary stromal cells derived from endometriomas. Figure 2K: Western blot analysis of endometriotic stromal cells treated with siNTRK2 ± PGE2 shows that PGE2-induced CREB phosphorylation is suppressed after NTRK2 siRNA treatment. [Figure 2-2] See description of Figure 2-1. [Figure 2-3] See description of Figure 2-1. [Figure 2-4] See description of Figure 2-1. [Figure 2-5] Refer to the description of FIG. 2-1. [Figure 2-6] Refer to the description of FIG. 2-1. [Figure 3] FIG. 3 demonstrates that NTRK2 variants are associated with endometriosis. By analyzing 36,697 endometriosis cases and 116,071 controls from the FinnGen database, 20 NTRK2 variants associated with endometriosis were identified (i.e., -log10p value ≧ 3; p < 0.001). Note that 182 NTRK2 variants were found within the range of 0.001 < p < 0.01. Variants within the NTRK2 gene boundary are more densely shaded than those upstream or downstream of the NTRK2 gene boundary. [Figure 4] FIG. 4 shows the order of steps for using the DEC-Tec platform. (1) Using important chemical reactions, compounds attached to DNA are produced; (2) A library pool consisting of more than 6 billion DNA-encoded drug-like compounds each having a "DNA barcode" is prepared; (3) The library for his-tagged proteins is affinity selected; (4) With the small molecule bound to the his-tagged protein, the his-tagged protein is captured by nickel beads; (5) The protein is separated from the unbound compounds; (6) The DNA barcode is sequenced and informatically analyzed to decipher the molecular structure of the putative selective drug-like "hits"; and (7) The "hits" with / without the DNA tag are resynthesized and tested for binding / inhibition. [Figure 5A]Figures 5A-5B show a non-limiting example of the use of the DEC-Tec platform to identify NTRK2 binders. Parallel DEC-Tec selections were performed with NTRK2, without NTRK2 (control), or in the presence of the promiscuous kinase inhibitor staurosporine (not shown). The enrichment (measured by normalized z-score) of each library member from the selections was compared. A set of analogs consistent with competitive ligand binding was significantly enriched in the NTRK2-only selection but not in either the control or NTRK2 + staurosporine selections. The hits, CDD-2262 and analog CDD-2330, are potent and metabolically stable molecules. [Figure 5B] See legend to Figure 5A. [Figure 6] Figures 6A-6B illustrate the concept of live-cell engagement (Figure 6A) and an NTRK2 example (Figure 6B). Figure 6A: Depiction of Promega's NanoBRET target engagement system according to the Promega website. This system involves cell-based competitive displacement of a fluorescent NanoBRET tracer reversibly bound to a NanoLuc fusion protein. Test compounds displace the tracer depending on their affinity for the target, reducing the loss of NanoBRET signal. Figure 6B: Example using Promega's NTRK2 NanoBRET cell-based system. Each NTRK2 compound (Cpd) was assayed in kinase assays and in cells. Multiple NTRK2 compounds enter cells and are potent nanomolar inhibitors in these assays (normalized to % no Cpd). Staurosporine, a promiscuous kinase inhibitor, is the positive control in these assays. [Figure 7A]Figures 7A-7B show a TREEspot™ plot of KINOMEscan binding data for CDD-2330 across the human kinome tree (Figure 7A) and a Z'-LYTE™ kinase screening assay (Figure 7B) demonstrating the low nanomolar affinity of CDD-2330 for the NTRK subfamily. Figure 7A: The larger the black circle, the higher the affinity of the ligand binding; CDD-2330 is highly specific for NTRK1, NTRK2, and NTRK3, with little off-target binding, even when tested at a concentration of 1 μM. Figure 7B: Kinase specificity for the NTRK subfamily was observed using the ThermoFisher Z'-LYTE™ screening assay. [Figure 7B] See legend to Figure 7A. [Figure 8] 8A-8B provide graphs demonstrating CDD-3031 metabolic stability in mouse liver microsomes (MLM) (FIG. 8A) and human liver microsomes (FIG. 8B). [Figure 9] Figures 9A-9B show the distribution of CDD-2330 in mouse brain (Figure 9A) and testis (Figure 9B). Mice (n=3 per time point) were intraperitoneally treated with CDD-2330, and brain, testis, and blood samples were collected. Samples were processed and analyzed by LC-MS. [Figure 10] Figures 10A-10C show the distribution of hydroxyzine (Figure 10A), chlorpromazine (Figure 10B), and CDD-3031 (Figure 10C) in the brain and plasma of mice 24 hours after administration, demonstrating low brain penetration. [Figure 11]Figures 11A-11B show the pharmacokinetics of CDD-2330 (Figure 11A) and CDD-3031 (Figure 11B) in mice. CDD-2330 was dissolved in 10% DMSO + 0.5% methylcellulose at 5 mg / mL. 50 mg / kg of CDD-2330 was orally delivered to mice (n=4). Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were analyzed by LC-MS, and CDD-2330 concentrations were quantified using a calibration curve (range: 0-10 μM). A dose of 50 mg / kg of CDD-3031 was administered by oral gavage. Blood samples were collected at 0, 0.83, 0.167, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. [Figure 12A] Figures 12A-12C show that NTRK2 stimulates proinflammatory signaling and pain in endometriosis. Figure 12A: Estrogen secreted by the ovaries and endometriotic lesions signals macrophages and nerve fibers, including the production of BDNF / NT-3 and proinflammatory cytokines, respectively. Figure 12B: At the cellular level, our studies show that proinflammatory prostaglandin E2 (PGE2) signals through EP2 / EP4 receptors on endometriotic stromal cells, inducing the phosphorylation and activation of CREB (pCREB). Activated CREB acts on the PTGS2 promoter, creating a positive feedback mechanism that increases inflammation. PGE2 signaling also stimulates PKA / PKC signaling, inducing BDNF production and NTF3 expression. Figure 12C: Endometriotic stromal cells were pretreated with 1 μM entrectinib or various doses of CDD-2262, followed by stimulation with 1 μM PGE2 for 6 hours. PTGS2 gene expression was quantified using quantitative real-time PCR (RT-PCR). [Figure 12B] See legend to Figure 12A. [Figure 12C] See legend to Figure 12A. [Figure 13] FIG. 13 provides the chemical structures of CDD-2330 metabolites in mouse plasma. [Figure 14]FIG. 14 provides a schematic illustrating the experimental procedure for studies utilizing the endometriosis mouse model described herein. [Figure 15A] Figures 15A-15E provide photographs (Figures 15A-15C) and graphs (Figures 15D-15E) demonstrating that CDD-2737 reduces lesion number and lesion size in a mouse model of endometriosis. [Figure 15B] See legend to Figure 15A. [Figure 15C] See legend to Figure 15A. [Figure 15D] See legend to Figure 15A. [Figure 15E] See legend to Figure 15A. [Figure 16] Figures 16A-16B provide graphs demonstrating that CDD-2737 has no gross or serum effects on the liver and kidney. [Figure 17-1] Figures 17A-17F illustrate the robust efficacy of inhibitory compounds of the present disclosure as NTRK2 inhibitors for inhibiting endometriotic lesion growth in mice, utilizing CDD-3132 as an example. Figure 17A provides a schematic overview of the experiment performed. Figures 17B-17C provide photographs showing excised lesions administered with control (Figure 17B) or CDD-3132 (10 mg / kg / day) (Figure 17C). Figures 17D-17F provide graphs showing the number of lesions (Figure 17D), lesion volume (Figure 17E), and lesion mass (Figure 17F) per mouse administered certain compounds (i.e., CDD-3031, CDD-3119, CDD-3132, and PF-06273340 at 10 mg / kg / day) or control (vehicle). [Figure 17-2] See description of Figure 17-1. [Figure 17-3] See description of Figure 17-1. [Figure 18A]Figures 18A-18B provide microscopic images of excised lesions from mice treated with vehicle or CDD-3132, by H&E staining (Figure 18A) or confocal microscopy (Figure 18B), demonstrating that NTRK2 inhibitors reduce proliferation and inflammation in endometriotic lesions. [Figure 18B] See legend to Figure 18A. [Figure 19] FIG. 19 provides photographs of excised lesions from mice administered CDD-3031, CDD-3119, and PF-06273340 (10 mg / kg). [Figure 20] Figures 20A-20B provide graphs illustrating the total liver (Figure 20A) and kidney (Figure 20B) weights in mice administered certain compounds, demonstrating that NTRK2 inhibitors had no significant effect on liver and kidney weights in mice treated with certain compounds, including CDD-3031, CDD-3119, and CDD-3132, for 14 days. DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description of the Disclosure Reference will now be made in detail to certain aspects of the presently disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the presently disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the illustrated subject matter is not intended to limit the scope of the claims to the presently disclosed subject matter.

[0027] Throughout this document, values ​​expressed in range format should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or subranges within that range, as if each numerical value and subrange were expressly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the stated range. The term "about X to Y" has the same meaning as "about X to about Y" unless otherwise specified. Similarly, the term "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise specified.

[0028] Unless otherwise clearly indicated by context, the terms "a," "an," or "the" are used in this document to include one or more. The term "or" is used to refer to a non-exclusive "or" unless otherwise specified. The phrases "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B." It should further be understood that any phraseology or terminology used herein and not specifically defined is for descriptive purposes only and not for limiting purposes. Any use of section headings is intended to aid in the reading of this document and should not be construed as limiting. Information associated with a section heading may be found within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if individually incorporated by reference.

[0029] In the methods described herein, acts may be performed in any order unless a time or order of operations is expressly recited. Furthermore, specified acts may be performed simultaneously unless express claim language recites the specified acts as being performed separately. For example, a claimed act of performing X and a claimed act of performing Y may be performed simultaneously in a single operation, and the resulting process would fall within the literal scope of the claimed process.

[0030] definition As used herein, the term "about" can allow for a degree of variation in a value or range, for example, within 10%, within 5%, or within 1% of a specified value or a specified limit of a range, and includes the exact specified value or range.

[0031] As used herein, the term "about" can allow for a degree of variation in a value or range, for example, within 10%, within 5%, or within 1% of a specified value or a specified limit of a range, and includes the exact specified value or range.

[0032] The term "acyl," as used herein, refers to a group containing a carbonyl moiety and bonded through the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or to another carbon atom, which may be part of an alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group, etc. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may contain double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group may also contain 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, etc. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. An example is the trifluoroacetyl group.

[0033] The term "alkenyl," as used herein, refers to straight-chain, branched-chain, and cyclic alkyl groups, as defined herein, except that there is at least one double bond between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or from 2 to about 20 carbon atoms, or from 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.

[0034] The term "alkoxy," as used herein, refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched-chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may contain from about 1 to about 12, from about 1 to about 20, or from about 1 to about 40 carbon atoms bonded to the oxygen atom, and may further contain double or triple bonds and heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein; similarly, a methylenedioxy group is also an alkoxy group within the meaning herein when two adjacent atoms of the structure are substituted together.

[0035] As used herein, the term "alkyl" refers to straight- and branched-chain alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbon atoms, or, in some embodiments, 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include those having 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-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, 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 may be substituted one or more times with any of the groups enumerated herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0036] The term "alkylene" or "alkylenyl," as used herein, refers to a divalent saturated aliphatic radical (e.g., -CH-, -CHCH-, and -CHCHCH-, among others). In certain embodiments, the term may be considered to refer to a moiety derived from an alkene by opening a double bond, or to a moiety derived from an alkane by removal of two hydrogen atoms from the same (e.g., -CH-) or different (e.g., -CHCH-) carbon atom.

[0037] 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, from 2 to about 20 carbon atoms, or from 2 to 12 carbon atoms, or in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CHCH), and -CHC≡C(CHCH), among others.

[0038] The term "amine" as used herein refers to primary amines, secondary amines, and tertiary amines, for example, having the formula N(group). Each group in the formula may independently be H or a non-H group, such as an alkyl or aryl. Amines include, but are not limited to, R-NH, e.g., alkylamines, arylamines, alkylarylamines; RNH, where each R is independently selected, e.g., dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and RN, where each R is independently selected, e.g., trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" as used herein also includes ammonium ions.

[0039] As used herein, the term "amino group" refers to any of -NH2, -NHR, -NR2, -NR3, where each R is independently selected. + and non-protonatable -NR3 + "Amino" refers to the protonated form of each of these, excluding the protonated forms of the amino groups. Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be a primary amino group, a secondary amino group, a tertiary amino group, or a quaternary amino group. An "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0040] The term "aralkyl" as used herein refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by 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. An aralkenyl group is an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group, as defined herein.

[0041] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group that does 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 from about 6 to about 14 carbon atoms in the ring portion of the group. Aryl groups can be unsubstituted or substituted as defined herein. Representative substituted aryl groups can be mono- or multiply substituted, and include, but are not limited to, phenyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or naphthyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring.

[0042] As used herein, the term "atm" refers to the pressure in the atmosphere under standard conditions. Thus, 1 atm is a pressure of 101 kPa and 2 atm is a pressure of 202 kPa.

[0043] As used herein, the term "cycloalkyl" refers to cyclic alkyl groups, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments, the number of ring carbon atoms is from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups, including, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, including, but not limited to, decalinyl. Cycloalkyl groups also include rings substituted with straight- or branched-chain alkyl groups, as defined herein. Representative substituted cycloalkyl groups may be mono- or multiply substituted and include, but are 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 may be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0044] A "disease" is a state of health in an animal in which the animal is unable to maintain homeostasis, and unless the disease is remitted, the animal's health continues to deteriorate.

[0045] 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 health is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily result in a further deterioration of the animal's health.

[0046] A disease or disorder is "alleviated" if the severity of a symptom of the disease or disorder, the frequency with which such symptoms are experienced by a patient, or both, are reduced.

[0047] 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 produce a desired biological result. This result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of skill in the art using routine experimentation.

[0048] As used herein, the term "epoxy functional group" or "epoxy-substituted" refers to a functional group in which an oxygen atom, an epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring structure. 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-epoxycyclohexyl)propyl, 2-(3,4-epoxycyclohexyl)ethyl, 2-(2,3-epoxycyclopentyl)ethyl, 2-(4-methyl-3,4-epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcyclohexyl)-2-methylethyl, and 5,6-epoxyhexyl.

[0049] 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.

[0050] As used herein, the term "haloalkyl" group includes monohaloalkyl groups, polyhaloalkyl groups where all halo atoms may be the same or different, and perhaloalkyl groups where all hydrogen atoms are replaced with 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.

[0051] As used herein, the term "heteroaryl" refers to an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. For example, a heteroaryl ring may have from five to about 8-12 ring members. Heteroaryl groups are various heterocyclyl groups with aromatic electronic structures. A heteroaryl group referred to as a C2-heteroaryl may be a pentacyclic ring with two carbon atoms and three heteroatoms, a hexacyclic ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4-heteroaryl may be a pentacyclic ring with one heteroatom, a hexacyclic ring with two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. Heteroaryl groups include, but are not limited to, 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 substituted with the groups discussed herein.Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein.

[0052] Further examples of aryl and heteroaryl groups include 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, benzyl, and the like. Hydryl, 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-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]thiof phenyl), 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 midazolyl, 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]azepin-2-yl, 5H -dibenz[b,f]azepin-3-yl, 5H-dibenz[b,f]azepin-4-yl, 5H-dibenz[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepin-5-yl), and the like.

[0053] The term "heteroarylalkyl," as used herein, refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group, as defined herein.

[0054] As used herein, the term "heterocyclylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0055] As used herein, the term "heterocyclyl" refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, including, but not limited to, N, O, and S. Thus, heterocyclyl can be cycloheteroalkyl, heteroaryl, or any combination thereof, provided it is polycyclic. In some embodiments, heterocyclyl groups contain from 3 to about 20 ring members, while other such groups have from 3 to about 15 ring members. A heterocyclyl group referred to as a C2-heterocyclyl can be a pentacyclic ring with two carbon atoms and three heteroatoms, a hexacyclic ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4-heterocyclyl can be a pentacyclic ring with one heteroatom, a hexacyclic ring with two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also contain 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 containing fused aromatic and non-aromatic groups. For example, dioxolanyl and benzdioxolanyl ring structures (methylenedioxyphenyl ring structures) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring structures containing heteroatoms, such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted or 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 may be mono- or multiply substituted, such as, but not limited to, piperidinyl or quinolinyl groups, which may be 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted, with groups such as those enumerated herein.

[0056] As used herein, the term "hydrocarbon" or "hydrocarbyl" refers to a molecule or functional group that contains carbon and hydrogen atoms. The term typically contains both carbon and hydrogen atoms, but can also refer to a molecule or functional group in which all hydrogen atoms have been replaced with other functional groups.

[0057] As used herein, the term "hydrocarbyl" refers to a functional group derived from a straight chain, branched chain, or cyclic hydrocarbon, and may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. A hydrocarbyl group is (C a ~C b (C1-C4)hydrocarbyl, where a and b are integers, means that the hydrocarbyl group can be any number of carbon atoms from a to b. For example, (C1-C4)hydrocarbyl means that the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4). (C0-C b) Hydrocarbyl means that in certain embodiments there are no hydrocarbyl groups.

[0058] As used herein, the term "independently selected from" means that the referenced groups are the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, "X 1 , X 2 , and X 3 The phrase "independently selected from the noble gases" refers to, for example, X 1 , X 2 , and X 3 are all the same, X 1 , X 2 , and X 3 are all different, X 1 and X 2 is the same, but X 3 This will include different scenarios and other similar combinations.

[0059] As used herein, the term "monovalent" refers to a substituent that is connected to the substituted molecule through a single bond. For example, when a substituent, such as F or Cl, is monovalent, it is attached to the atom it replaces by a single bond.

[0060] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples may include oxygen-containing groups such as alkoxy groups, aryloxy groups, aralkyloxy groups, and oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylic acid esters; sulfur-containing groups, such as alkyl and aryl sulfide groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R), CN, CF, OCF, R, C(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0-2N(R)C(O)R, (CH2) 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)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~C 100 ) hydrocarbyl, where R can be hydrogen (including other carbon atoms in the examples) or a carbon-based moiety, which can be substituted or unsubstituted.

[0061] As used herein, the term "room temperature" refers to a temperature between about 15°C and 28°C.

[0062] The terms "patient," "subject," or "individual" are used interchangeably herein and refer to any animal or cells thereof amenable to the methods described herein, whether in vitro or in situ. In non-limiting aspects, the patient, subject, or individual is a human.

[0063] As used herein, the term "pharmaceutically acceptable" refers to a material, e.g., a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., it can be administered to an individual without causing undesired biological effects or deleteriously interacting with any of the components of the composition in which it is contained.

[0064] As used herein, the term "pharmaceutically acceptable salts" refers to salts of the compound being administered prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.

[0065] Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfate and hydrogen sulfate), and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxyl-containing, and sulfonic acid classes of organic acids. Examples include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharin, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0066] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, metal salts including ammonium salts, alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compound, for example, by reacting the compound with an appropriate acid or base.

[0067] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or carrier, e.g., a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, involved in carrying or transporting a compound described herein into or to a patient so that the compound described herein can perform its intended function. Typically, such compounds are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound described herein, and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution, ethyl alcohol; phosphate buffers; and other non-toxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds described herein and are physiologically acceptable to patients. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds described herein.Other additional ingredients that may be included in pharmaceutical compositions used in conjunction with the methods or compounds described herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0068] As used herein, the term "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.

[0069] As used herein, the term "substantially" refers to a majority or majority, such as 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%. As used herein, the term "substantially free" can mean that there is no, or only such a small amount of a substance present that the amount of the substance does not affect the material properties of a composition containing the substance, and can mean that the substance in the composition is from about 0 wt% to about 5 wt%, or from about 0 wt% to about 1 wt%, or not more than about 5 wt%, or less than about 4.5 wt%, equal to about 4.5 wt%, or more 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 not more than about 0.001 wt% of the substance. The term "substantially free" can mean that the substance in the composition has only trace amounts such as from about 0 wt% to about 5 wt%, or from about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than about 4.5 wt%, equal to about 4.5 wt%, 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%.

[0070] The term "substituted" as used herein in conjunction with a molecule or organic group defined herein refers to a state in which one or more hydrogen atoms contained therein are replaced with one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that can be substituted or is substituted on a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxyl groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxylic acids, carboxylates, and carboxylic acid esters; sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxylamine, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be attached to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R), CN, NO, NO, ONO, azido, CF, OCF, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R), SR, SOR, SO, SO, N(R), SO, R, C(O)R, C(O)C(O)R, C(O)CHC(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R), OC(O)N(R), C(S)N(R), (CH) 0-2 N(R)C(O)R, (CH2) 0-2Examples include N(R)N(R), N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R), N(R)SOR, N(R)SON(R), N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R), N(R)C(S)N(R), N(COR)COR, N(OR)R, C(=NH)N(R), C(O)N(OR)R, and C(=NOR)R, where R can be hydrogen or a carbon-based moiety. For example, R can be hydrogen, (C1-C 100 ) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to the nitrogen atom or adjacent nitrogen atoms may together with one or more nitrogen atoms form a heterocyclyl.

[0071] A "therapeutic" treatment is a treatment administered to a subject who exhibits symptoms of a pathological condition with the intent of reducing or eliminating the symptoms of the condition.

[0072] The term "thioalkyl," as used herein, refers to a sulfur atom connected to an alkyl group, as defined herein. The alkyl group in a thioalkyl may be straight or branched. Examples of straight-chain thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, and the like. Examples of branched-chain alkoxy groups include, but are not limited to, iso-thiopropyl, sec-thiobutyl, tert-thiobutyl, iso-thiopentyl, iso-thiohexyl, and the like. The sulfur atom may appear at any suitable position in the alkyl chain, for example, at the terminus of the alkyl chain or anywhere within the alkyl chain.

[0073] As used herein, the terms "treat," "treating," and "treatment" refer to reducing the frequency or severity with which a subject experiences symptoms of a disease or condition by administering an agent or compound to the subject.

[0074] The term "staurosporine" refers to (5S,6R,7R,9S)-6-methoxy-5-methyl-7-(methylamino)-6,7,8,9,15,16-hexahydro-5H,14H-17-oxa-4b,9a,15-triaza-5,9-methanodibenzo[b,h]cyclonona[jkl]cyclopenta[e]-as-indacen-14-one.

[0075] 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.

[0076] The terms "LOXO-101" and "lamotrectinib" 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.

[0077] The terms "LOXO-195" and "ceritrectinib" 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)-pyrrolinacyclooctaphan-8-one.

[0078] The terms "TPX-005" and "repotrectinib" 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.

[0079] 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.

[0080] explanation Neurotrophin receptor tyrosine kinases 1, 2, and 3 (NTRK1, NTRK2, and NTRK3) have been shown to be important for various aspects of nervous system function, including nociceptive pain. Gene fusions involving these kinases (e.g., TPM3-NTRK1, MPRIP-NTRK1, TRIM24-NTRK2, and ETV6-NTRK3) have been observed in adult and pediatric gliomas and other cancers (e.g., non-small cell lung cancer), amplifying signaling cascades and acting as oncogenic drivers.

[0081] In one aspect, the present disclosure relates to the identification of the target for treating patients with endometriosis and the inflammation and pain associated with endometriosis.Therefore, the present disclosure describes the bioinformatics analysis of the kinase that is overexpressed in endometriosis tissue.By this bioinformatics analysis, NTRK2 is identified as the potential therapeutic target for endometriosis.

[0082] As demonstrated herein, NTRK2 is upregulated in endometriotic lesions, and silencing NTRK2 in primary endometriotic stromal cells inhibits the expression of proinflammatory genes. Furthermore, administration of ANA-12, a selective NTRK2 inhibitor that rapidly crosses the blood-brain barrier and exerts antidepressant and anxiolytic effects, induces regression of endometriotic lesions in mice. These studies indicate that NTRK2 contributes to endometriosis-associated survival and inflammation.

[0083] Additionally, the present disclosure describes the identification, preparation, and validation of NTRK2 inhibitors for treating, preventing, and / or ameliorating endometriosis and / or its symptoms, cancer, and pain in a subject.

[0084] compound In one aspect, the present disclosure provides a compound of formula (I): TIFF2025532184000012.tif11128 or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof, During the ceremony, T is TIFF2025532184000013.tif49148; R 1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C 10 Aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)OR a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), CN, and NO2; R 2is 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, OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), NR a C(=O)R b , C(=O)N(R a )(OR b ), C(=NR a )N(R b )(R c ), C(=NR a )N(R b )(OR c ), and NR a S(=O)2R b selected from the group consisting of R 3a , R 3b , R 3c , R 3d , and R 3e 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; R 4 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; R 5 is H and -X 1 -A 1 selected from the group consisting of R 6a , R 6b , R 6c , and R 6d are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L 1 -C(R 6a )(R 6b )- and L 2 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; X 1 is a bond, O, and NR 7 selected from the group consisting of A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , R b , and R c 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0085] In certain embodiments, T is TIFF2025532184000014.tif22128 and -L 2 -R 5 If is -H, R 4 is not H.

[0086] In another aspect, the present disclosure provides a compound of formula (Ia): The compound of TIFF2025532184000015.tif23128, During the ceremony, R 1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C 10 Aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)OR a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), CN, and NO2; R 2 is 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, OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), NR a C(=O)R b, C(=O)N(R a )(OR b ), C(=NR a )N(R b )(R c ), C(=NR a )N(R b )(OR c ), and NR a S(=O)2R b selected from the group consisting of R 3a , R 3b , and R 3c 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; R 4 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; R 5 is H and -X 1 -A 1 selected from the group consisting of L 1 -C(R 6a )(R 6b )- and X 1 is a bond, O, and NR 7 selected from the group consisting of R 6a and R 6b are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L 2is 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; A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , R b , and R c 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0087] In certain embodiments, -L 2 -R 5 is -H, then R 4 is not H.

[0088] In another aspect, the present disclosure provides a compound of formula (Ib): The compound of TIFF2025532184000016.tif23128, During the ceremony, R 1 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)OR a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), CN, and NO2; R 2 is 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, OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), NR a C(=O)R b , C(=O)N(R a )(OR b ), C(=NR a )N(R b )(R c ), C(=NR a )N(R b )(OR c ), and NR a S(=O)2R b selected from the group consisting of R 3a , R 3b , and R 3c 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; R 4is 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; R 5 is H and -X 1 -A 1 selected from the group consisting of R 6a and R 6b are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L 1 -C(R 6a )(R 6b )- and L 2 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; X 1 is a bond, O, and NR 7 selected from the group consisting of A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , Rb , and R c 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0089] In another aspect, the present disclosure provides a compound of formula (Ic): The compound of TIFF2025532184000017.tif23128, During the ceremony, R 1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C 10 Aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)OR a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), CN, and NO2; R 3a , R 3b , and R 3c 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; R 4is 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; R 5 is H and -X 1 -A 1 selected from the group consisting of R 6a , R 6b , R 6c , and R 6d are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of L 1 -C(R 6a )(R 6b )- and L 2 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; X 1 is a bond, O, and NR 7 selected from the group consisting of R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , R b , and R c 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0090] In another aspect, the present disclosure provides a compound of formula (Id): The compound of TIFF2025532184000018.tif23128, During the ceremony, R 1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C 10 Aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)OR a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), CN, and NO2; R 2 is 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, OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O)2N(R a)(R b ), NR a C(=O)R b , C(=O)N(R a )(OR b ), C(=NR a )N(R b )(R c ), C(=NR a )N(R b )(OR c ), and NR a S(=O)2R b selected from the group consisting of R 3a , R 3b , and R 3c 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; R 4 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; R 5 is H and -X 1 -A 1 selected from the group consisting of R 6a , R 6b , R 6c , and R 6d are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of L 1 -C(R 6a )(R 6b )- and L 2is 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; X 1 is a bond, O, and NR 7 selected from the group consisting of R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , R b , and R c 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0091] In another aspect, the present disclosure provides a compound of formula (Ie): The compound of TIFF2025532184000019.tif23128, During the ceremony, R 3a , R 3b , R 3c , and R 3dare 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; R 4 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; R 5 is H and -X 1 -A 1 selected from the group consisting of R 6a , R 6b , R 6c , and R 6d are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of L 1 -C(R 6a )(R 6b )- and L 2 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; X 1 is a bond, O, and NR 7 selected from the group consisting of R 7is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , R b , and R c 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0092] In another aspect, the present disclosure provides a compound of formula (If): The compound of TIFF2025532184000020.tif21128, During the ceremony, R 3a , R 3b , and R 3c 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; R 4 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; R 5 is H and -X 1 -A 1 selected from the group consisting of R 6a, R 6b , R 6c , and R 6d are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of L 1 -C(R 6a )(R 6b )- and L 2 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; X 1 is a bond, O, and NR 7 selected from the group consisting of R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , R b , and R c 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0093] In another aspect, the present disclosure provides a compound of formula (Ig): The compound of TIFF2025532184000021.tif23128, During the ceremony, R 3a , R 3b , R 3c , R 3d , and R 3e 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; R 4 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; R 5 is H and -X 1 -A 1 selected from the group consisting of R 6a , R 6b , R 6c , and R 6d are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of R 7 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L 1 -C(R 6a )(R 6b )- and L 2is 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; X 1 is a bond, O, and NR 7 selected from the group consisting of A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , R b , and R c 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0094] In certain embodiments, R 1 is H.

[0095] In certain embodiments, R 2 is H. In certain embodiments, R 2 is F. In certain embodiments, R 2 is Br. In certain embodiments, R 2 is CN. In certain embodiments, R 2 is C(=O)OH. In certain embodiments, R2 is C(=O)NH2. In certain embodiments, R 2 is C(=O)NMe. In certain embodiments, R 2 is C(=NH)NH(OH). In certain embodiments, R 2 is C(=O)NHOH.

[0096] In certain embodiments, R 3a , R 3b , and R 3c At least one selected from R is H. In certain embodiments, R 3a , R 3b and R 3c At least two selected from R 3a , R 3b , and R 3c is H. In certain embodiments, each of R 3a , R 3b , R 3c , R 3d , and R 3e At least one selected from R is H. In certain embodiments, R 3a , R 3b , R 3c , R 3d , and R 3e At least two selected from R 3a , R 3b , R 3c , R 3d , and R 3e At least three selected from R are H. In certain embodiments, 3a , R 3b , R 3c , R 3d , and R 3e At least four selected from R are H. In certain embodiments, 3a , R 3b , R 3c , R 3d , and R 3e Each of these is H.

[0097] In certain embodiments, T is TIFF2025532184000022.tif11128. In certain embodiments, T is TIFF2025532184000023.tif15128. In certain embodiments, T is TIFF2025532184000024.tif15128. In certain embodiments, T is TIFF2025532184000025.tif15128. In certain embodiments, T is TIFF2025532184000026.tif18128. In certain embodiments, T is TIFF2025532184000027.tif18128. In certain embodiments, T is TIFF2025532184000028.tif18128. In certain embodiments, T is TIFF2025532184000029.tif18128. In certain embodiments, T is TIFF2025532184000030.tif18128. In certain embodiments, T is TIFF2025532184000031.tif18128. In certain embodiments, T is TIFF2025532184000032.tif11128. In certain embodiments, T is TIFF2025532184000033.tif11128. In certain embodiments, T is TIFF2025532184000034.tif14128. In certain embodiments, T is TIFF2025532184000035.tif11128. In certain embodiments, T is TIFF2025532184000036.tif11128. In certain embodiments, T is TIFF2025532184000037.tif11128. In certain embodiments, T is TIFF2025532184000038.tif11128.

[0098] In certain embodiments, R 4 is H. In certain embodiments, R 4 is methyl. In certain embodiments, 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. In certain embodiments, R 4 is C(=O)CH3. In certain embodiments, R 4 is phenyl. In certain embodiments, R 4 is benzyl substituted with at least one C1-C6 alkyl.

[0099] In certain embodiments, R 4 teeth, TIFF2025532184000039.tif7128. In certain embodiments, R 4 teeth, TIFF2025532184000040.tif7128. In certain embodiments, R 4 is —CH2CH2CH2O (phenyl substituted with at least one halogen). In certain embodiments, R 4 teeth, TIFF2025532184000041.tif8128. In certain embodiments, R 4 teeth, TIFF2025532184000042.tif8128. In certain embodiments, R 4 teeth, The file is TIFF2025532184000043.tif11128.

[0100] In certain embodiments, A 1 is H. In certain embodiments, A 1 is phenyl substituted with at least one C1-C6 alkyl. 1 is phenyl substituted with at least one C1-C6 alkoxy. 1 is phenyl substituted with at least one C1-C3 haloalkyl. 1 is phenyl substituted with at least one C1-C3 haloalkoxy. 1 is phenyl substituted with at least one phenoxy. 1 is phenyl substituted with at least one halogen. 1 is phenyl substituted with at least one NO. In certain embodiments, A 1 is phenyl substituted with at least one C3-C8 cycloalkyl, optionally substituted with at least one C1-C3 haloalkyl. 1 is C2-C8 heteroaryl. 1 is a C2-C8 heteroaryl substituted with at least one C1-C6 alkyl. 1 is a C2-C8 heteroaryl fused with a C2-C5 heteroaryl. 1 teeth, TIFF2025532184000044.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000045.tif13128. In certain embodiments, A 1 teeth, TIFF2025532184000046.tif11128. In certain embodiments, A 1 teeth, TIFF2025532184000047.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000048.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000049.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000050.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000051.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000052.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000053.tif10128. In certain embodiments, A 1 teeth, TIFF2025532184000054.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000055.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000056.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000057.tif13128. In certain embodiments, A 1 teeth, TIFF2025532184000058.tif13128. In certain embodiments, A 1 teeth, TIFF2025532184000059.tif18128. In certain embodiments, A 1 teeth, TIFF2025532184000060.tif11128. In certain embodiments, A 1 teeth, TIFF2025532184000061.tif9128. In certain embodiments, A 1 teeth, TIFF2025532184000062.tif10128. In certain embodiments, A 1 teeth, TIFF2025532184000063.tif18128. In certain embodiments, A 1 teeth, TIFF2025532184000064.tif10128. In certain embodiments, A 1 teeth, TIFF2025532184000065.tif15128.

[0101] In certain embodiments, R 6a is H. In certain embodiments, R 6b is H.

[0102] In certain embodiments, L 1 is -CH2-.

[0103] In certain embodiments, L 2 is a bond. In certain embodiments, L 2 is —C(═O)—. In certain embodiments, L 2 is -S(=O)2-. In certain embodiments, L 2 is -C(=S)-. In certain embodiments, L 2 is -CH2-. In certain embodiments, L 2 teeth, TIFF2025532184000066.tif8128. In certain embodiments, L 2 teeth, TIFF2025532184000067.tif8128. In certain embodiments, L 2 teeth, TIFF2025532184000068.tif8128.

[0104] In certain embodiments, X 1 is NR7 In certain embodiments, 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.

[0105] In certain embodiments, R 7 is H. In certain embodiments, R 7 is Me.

[0106] In certain embodiments, R 5 is H. In certain embodiments, R 5 teeth, TIFF2025532184000069.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000070.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000071.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000072.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000073.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000074.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000075.tif14128. In certain embodiments, R 5 teeth, TIFF2025532184000076.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000077.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000078.tif16128. In certain embodiments, R 5 teeth, TIFF2025532184000079.tif11128. In certain embodiments, R 5 teeth, TIFF2025532184000080.tif11128. In certain embodiments, R 5 teeth, TIFF2025532184000081.tif18128. In certain embodiments, R 5 teeth, TIFF2025532184000082.tif18128. In certain embodiments, R 5 teeth, TIFF2025532184000083.tif18128. In certain embodiments, R 5 teeth, TIFF2025532184000084.tif16128. In certain embodiments, R 5 teeth, TIFF2025532184000085.tif16128. In certain embodiments, R 5 teeth, TIFF2025532184000086.tif18128. In certain embodiments, R 5 teeth, TIFF2025532184000087.tif13128. In certain embodiments, R 5 teeth, TIFF2025532184000088.tif11128. In certain embodiments, R 5 teeth, TIFF2025532184000089.tif13128. In certain embodiments, R 5 teeth, TIFF2025532184000090.tif11128. In certain embodiments, R 5 teeth, TIFF2025532184000091.tif20128. In certain embodiments, R 5 teeth, TIFF2025532184000092.tif15128. In certain embodiments, R 5 teeth, TIFF2025532184000093.tif11128. In certain embodiments, R 5 teeth, TIFF2025532184000094.tif15128.

[0107] In certain embodiments, the compound of formula (I) is: 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-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-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid; 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((1-Isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)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; (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; 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 (Z)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide is selected from the group consisting of:

[0108] In another aspect, the present disclosure provides a compound of formula (II): The compound of TIFF2025532184000095.tif14128, During the ceremony, A 2 teeth, TIFF2025532184000096.tif23128; R 8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted phenyl; R 9a , R 9b , R 9c , and R 9dare each independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C 10 selected from the group consisting of aryl, optionally substituted C2-C8 heterocyclyl, halogen, CN, and NO2; R 10 represents an optionally substituted C1-C6 alkyl, TIFF2025532184000097.tif21128; R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , and R 11h are each independently 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, OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), NR a C(=O)R b , and N.R. a S(=O)2R b selected from the group consisting of R 12a , R 12b , and R 12c 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; L 3 teeth, TIFF2025532184000098.tif14128; X 2 O and NR 14 selected from the group consisting of R 14 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; Z 1 is CR 13a and N, and Z 2 is CR 13b and N, and Z 3 is CR 13c and N, and Z 4 is CR 13d and N, Z 1 , Z 2 , Z 3 , and Z 4 At least one selected from the group consisting of is N; R 13a , R 13b , R 13c , and R 13d 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; R a and R b 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; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0109] In certain embodiments, R 8 is isopropyl. In certain embodiments, R8 is phenyl.

[0110] 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. In certain embodiments, R 9d is trifluoromethyl.

[0111] In certain embodiments, A 2 teeth, TIFF2025532184000099.tif18128. In certain embodiments, A 2 teeth, TIFF2025532184000100.tif23128.

[0112] In certain embodiments, Z 1 is N and Z 2 , Z 3 , and Z 4 At least one of Z is CH. 1 is N and Z 2 , Z 3 , and Z 4 At least two of Z are CH. 1 is N and Z 2 , Z 3 , and Z 4 In certain embodiments, each of Z 2is N and Z 1 , Z 3 , and Z 4 At least one of Z is CH. 2 is N and Z 1 , Z 3 , and Z 4 At least two of Z are CH. 2 is N and Z 1 , Z 3 , and Z 4 Each of these is CH.

[0113] In certain embodiments, X 2 is —O—. In certain embodiments, X 2 is -NH-.

[0114] In certain embodiments, R 14 is H.

[0115] In certain embodiments, 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 embodiments, R 11f is methoxy. In certain embodiments, R 11g is H. In certain embodiments, R 11g is methoxy. In certain embodiments, R 11h is H. In certain embodiments, R 11h is methoxy.

[0116] In certain embodiments, R 12a is H. In certain embodiments, R 12a is methyl. In certain embodiments, R 12a is C(=O)O(C(CH3)3). In certain embodiments, R 12b is H. In certain embodiments, R 12b is methyl. In certain embodiments, R 12b is C(=O)O(C(CH3)3). In certain embodiments, R 12c is H. In certain embodiments, R 12c is methyl. In certain embodiments, R 12c is C(=O)O(C(CH3)3).

[0117] In certain embodiments, R 10 is tert-butyl. In certain embodiments, R 10 teeth, TIFF2025532184000101.tif18128. In certain embodiments, R 10 teeth, The file is TIFF2025532184000102.tif18128.

[0118] In certain embodiments, the compound of formula (II) 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 -methyl terephthalamide; 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 -methyl terephthalamide; 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)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamimidoyl)picolinamido)-3-methoxyphenyl)-N 4 -methyl terephthalamide; 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 is selected from the group consisting of:

[0119] In another aspect, the present disclosure provides a compound of formula (III): The compound of TIFF2025532184000103.tif28128, During the ceremony, R 15a , R 15b , and R 15c 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; R 16 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; R 17a and R 17b 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; R 18a and R 18bare each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; A 3 is optionally substituted phenyl, A 4 is optionally substituted phenyl; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0120] In certain embodiments, the compound of formula (III) has the formula (IIIa): The compound is TIFF2025532184000104.tif28128.

[0121] In certain embodiments, the compound of formula (III) has formula (IIIb): The compound is TIFF2025532184000105.tif28128.

[0122] In certain embodiments, R 15a , R 15b , and R 15c At least one of R 15a , R 15b , and R 15c At least two of R 15a , R 15b , and R 15c Each of these is H.

[0123] In certain embodiments, R 16 is benzyl. In certain embodiments, R 16 teeth, The file is TIFF2025532184000106.tif15128.

[0124] In certain embodiments, R 17a is H. In certain embodiments, R 17b is H.

[0125] In certain embodiments, R 18a is H. In certain embodiments, R 18a is Me. In certain embodiments, R 18b is H. In certain embodiments, R 18b is Me.

[0126] In certain embodiments, A 3 teeth, TIFF2025532184000107.tif20128. In certain embodiments, A 3 teeth, TIFF2025532184000108.tif11128

[0127] In certain embodiments, A 4 teeth, The file is TIFF2025532184000109.tif9128.

[0128] In certain embodiments, the compound of formula (III) is 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 is selected from the group consisting of:

[0129] In certain embodiments, each 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, when present, is independently selected from C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, OH, N(R')( and optionally substituted with at least one substituent selected from the group consisting of R′, C(═O)R′, C(═O)OR′, OC(═O)OR′, C(═O)N(R′)(R″), S(═O)N(R′)(R″), N(R′)C(═O)R″, N(R′)S(═O)R″, C-C heteroaryl, and phenyl optionally substituted with at least one halogen, wherein each of R′ and R″ is independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, C-C haloalkyl, benzyl, and phenyl.

[0130] Table 1: Exemplary compounds TIFF2025532184000110.tif123146TIFF2025532184000111.tif225146TIFF2025532184000112.tif220146TIFF20255321840 00113.tif208146TIFF2025532184000114.tif223146TIFF2025532184000115.tif224146TIFF2025532184000116.tif208146 TIFF2025532184000117.tif208146TIFF2025532184000118.tif222146TIFF2025532184000119.tif219146TIFF20255321840 00120.tif222146TIFF2025532184000121.tif222146TIFF2025532184000122.tif222146TIFF2025532184000123.tif232146

[0131] The compounds described herein can have one or more stereocenters, and each stereocenter can independently exist in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. The compounds described herein should be understood to encompass racemic, optically active, regioisomeric, and stereoisomeric forms, or combinations thereof, that possess the therapeutically useful properties described herein. Preparation of optically active forms can be accomplished in any suitable manner, including, but not limited to, resolution of racemic forms by recrystallization methods, 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 isomers is utilized as a therapeutic compound described herein. In other embodiments, the 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 their isomers can be accomplished by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0132] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any of the compounds 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, acetate salts, 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 forms.

[0133] In certain embodiments, the compounds described herein may exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0134] In certain embodiments, the 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, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized by one or more steps or processes into a biologically, pharmaceutically, or therapeutically active form of the compound.

[0135] In certain embodiments, moieties in the compounds described herein, such as the aromatic ring moieties of the compounds described herein, are susceptible to various metabolic reactions. Incorporation of appropriate substituents into the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions include, by way of example only, deuterium, halogen, or alkyl groups.

[0136] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 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 35Isotopically labeled compounds include, but are not limited to, S. In certain embodiments, isotopically labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavy isotopes such as deuterium provides increased metabolic stability (e.g., longer in vivo half-life or reduced dosage requirements). In yet other embodiments, 11 C. 18 F, 15 O, and 13 Substitution with positron-emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process in which a suitable isotopically labeled reagent is substituted for a non-labeled reagent otherwise used in the method.

[0137] In certain aspects, the compounds described herein are labeled by other means, including non-virtually chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0138] The compounds described herein, and other related compounds having different substituents, can be synthesized using the techniques and materials described herein, e.g., 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), Advanced Organic Chemistry 4 (March, 1994), and others. thEd., (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 disclosures). The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to introduce the various moieties found in the formulas provided herein.

[0139] The compounds described herein are synthesized using any suitable procedure, starting from compounds available from commercial suppliers or prepared using the procedures described herein.

[0140] In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxy groups, are protected to prevent their undesired participation in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in a chemical reaction until the protecting group is removed. In other embodiments, each protecting group can be removed by a different means. Protecting groups that are cleaved under completely different reaction conditions meet the requirement for differential removal.

[0141] In certain embodiments, protecting groups are removed by acid, base, reducing conditions (e.g., 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 amino groups protected with the base-labile Fmoc group. Carboxylic acid and hydroxy reactive moieties are blocked with base-labile groups, including, but not limited to, methyl, ethyl, and acetyl, in the presence of amines blocked with acid-labile groups such as t-butyl carbamate, or amines blocked with carbamates, which are stable to acid and base but removable by hydrolysis.

[0142] In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protecting groups such as benzyl groups, 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 exemplified herein, including conversion to alkyl esters, or blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride-labile silyl carbamates.

[0143] Allyl blocking groups are useful in the presence of acid- and base-protecting groups because the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected by 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, the functional group is blocked and cannot react. Once released from the resin, the functional group can react.

[0144] Typically, the blocking / protecting group may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), N-alkoxycarbonyl (Alloc), methyl (Me), ethyl (Et), tert-butyl (t-Bu), tert-butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), tert-butyloxycarbonyl (Boc), paramethoxybenzyl (PMB), triphenylmethyl (trityl), fluorenylmethyloxycarbonyl (FMOC).

[0145] Detailed descriptions of other protecting groups and applicable techniques for their creation and removal are found 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 herein by reference for such disclosures.

[0146] composition In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0147] Compositions containing the compounds described herein include pharmaceutical compositions comprising at least one compound described herein and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises Kolliphor EL and an 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 dissolved in 1x PBS.

[0148] In certain embodiments, the compositions are formulated for oral or parenteral administration, e.g., transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., transvaginal and perivaginal), nasal (intranasal) and rectal (transrectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. In some embodiments, the compositions are formulated as a pill, tablet, gelcap, or capsule for oral administration.

[0149] method In one aspect, the present disclosure provides a method for treating, preventing, and / or ameliorating endometriosis in a subject in need thereof. In certain embodiments, the method comprises administering to the subject a neurotrophic factor receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0150] In certain embodiments, the NTRK inhibitor is a compound of the present disclosure.

[0151] In another aspect, the present disclosure provides a method of treating, preventing, and / or ameliorating endometriosis in a subject in need thereof, comprising administering to the subject a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure.

[0152] In certain embodiments, at least one selected from the group consisting of chronic pelvic pain, inflammation, and infertility is treated, prevented, and / or ameliorated in the subject.

[0153] In certain embodiments, the subject is female.

[0154] In another aspect, the present disclosure provides a method for treating, preventing, and / or ameliorating cancer in a subject in need thereof. In certain embodiments, the method comprises administering to the subject a neurotrophic factor receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0155] In certain embodiments, the NTRK inhibitor is a compound of the present disclosure.

[0156] In another aspect, the present disclosure provides a method of treating, preventing, and / or ameliorating cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure.

[0157] In another aspect, the present disclosure provides a method for treating, preventing, and / or ameliorating pain in a subject in need thereof. In certain embodiments, the method comprises administering to the subject a neurotrophic factor receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0158] In certain embodiments, the NTRK inhibitor is a compound of the present disclosure.

[0159] In another aspect, the present disclosure provides a method of treating, preventing, and / or ameliorating pain in a subject in need thereof, comprising administering to the subject a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure.

[0160] In certain embodiments, neurotrophin receptor tyrosine kinase 1 (NTRK1) is overexpressed in the subject. In certain embodiments, neurotrophin receptor tyrosine kinase 2 (NTRK2) is overexpressed in the subject. In certain embodiments, neurotrophin receptor tyrosine kinase 3 (NTRK3) is overexpressed in the subject.

[0161] In certain embodiments, administration of a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure results in inhibition of NTRK1 in a subject. In certain embodiments, inhibition of NTRK1 results in the treatment, prevention, and / or amelioration of endometriosis and / or one or more symptoms thereof, cancer, and / or pain.

[0162] In certain embodiments, administration of a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure results in inhibition of NTRK2 in a subject. In certain embodiments, inhibition of NTRK2 results in the treatment, prevention, and / or amelioration of endometriosis and / or one or more symptoms thereof, cancer, and / or pain.

[0163] In certain embodiments, administration of a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure results in inhibition of NTRK3 in a subject. In certain embodiments, inhibition of NTRK3 results in the treatment, prevention, and / or amelioration of endometriosis and / or one or more symptoms thereof, cancer, and / or pain.

[0164] 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.

[0165] In certain embodiments, the NTRK inhibitor is an NTRK2 inhibitor.

[0166] In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK1. In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK3. In certain embodiments, the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK1 and NTRK3.

[0167] In certain embodiments, the selectivity of a compound for NTRK2 relative to NTRK1 is measured by the half maximal inhibitory concentration (IC) of the compound for NTRK2. 50 ) but the IC of the same compound against NTRK1 50 In certain embodiments, the selectivity of a compound for NTRK2 over NTRK1 is measured by the half maximal inhibitory concentration (IC) of the compound for NTRK2. 50 ) but the IC of the same compound against NTRK3 50 including at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, or 1000-fold lower than

[0168] In certain embodiments, the NTRK2 inhibitor is staurosporine.In certain embodiments, the NTRK2 inhibitor is entrectinib.In certain embodiments, the NTRK2 inhibitor is larotrectinib.In certain embodiments, the NTRK2 inhibitor is ceritrectinib.In certain embodiments, the NTRK2 inhibitor is repotrectinib.In certain embodiments, the NTRK2 inhibitor is PF-06273340.

[0169] In certain embodiments, administration of a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure results in inhibition of the fusion gene product in a subject, hi certain embodiments, inhibition of the fusion gene product results in the treatment, prevention, and / or amelioration of endometriosis and / or one or more symptoms thereof, cancer, and / or pain.

[0170] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

[0171] Administration / Dosage / Formulation The dosage regimen may affect what constitutes an effective amount. The therapeutic formulation may be administered to a subject before or after the onset of the disease or disorder. Furthermore, several divided doses and staggered doses may be administered daily or continuously. Alternatively, the dose may be continuously infused or bolus injected. Furthermore, the dosage of the therapeutic formulation may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0172] The compositions described herein can be administered to a subject, preferably a mammal, more preferably a human, using known procedures at a dosage and duration effective to treat a disease or disorder in the patient. The effective amount of the therapeutic compound required to achieve a therapeutic effect can 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. The dosage regimen can be adjusted to provide an optimal therapeutic response. For example, several divided doses can be administered daily. Alternatively, the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for the therapeutic compounds described herein is about 1 and 5,000 mg / kg body weight / day. Those skilled in the art will be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0173] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied to provide an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration without toxicity to the subject.

[0174] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of 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 similar factors well known in the medical arts.

[0175] A medical doctor, e.g., a physician or veterinarian, having ordinary skill in the art can readily determine the effective amount of the pharmaceutical composition required and prescribe an effective amount of the pharmaceutical composition. For example, the physician or veterinarian could start dosing the compounds described herein used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0176] In certain embodiments, it is particularly advantageous to formulate the compound in a unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to a physically discrete unit suitable for unitary administration to a patient to be treated. Each unit contains a predetermined amount of therapeutic compound calculated to produce a desired therapeutic effect in combination with the required pharmaceutical vehicle. The unit dosage form of the compound described herein is determined by and directly influenced by (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the constraints inherent in the field of compounding / formulating such therapeutic compounds.

[0177] In certain embodiments, the compositions described herein are formulated with one or more pharmaceutically acceptable excipients or carriers.In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compounds described herein and a pharmaceutically acceptable carrier.

[0178] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. The activity of microorganisms can be prevented 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 injectable compositions can be achieved by including absorption delaying agents, for example, aluminum monostearate and gelatin in the composition.

[0179] In certain embodiments, the compositions described herein are administered to a patient in one to five or more doses per day. In other embodiments, the compositions described herein are administered to a patient in a range of doses, including, but not limited to, once daily, once every two days, once every three days, to once weekly and once every two weeks. It will be readily apparent to those skilled in the art that the frequency of administration of the various combination compositions described herein will vary between individuals depending on many factors, including, but not limited to, age, the disease or disorder being treated, gender, general health, and other factors. Therefore, administration of the compounds and compositions described herein should not be construed as limited to any particular dosage regime, and the exact dosage and composition administered to any patient will be determined by the attending physician, taking into account all other factors relevant to the patient.

[0180] The compounds described herein for administration may be administered in doses ranging 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 It may be within the range of 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, as well as any and all whole or partial increments therebetween.

[0181] In some embodiments, the dosage of the compounds described herein is about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compounds described herein used in the 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, the dose of the second compound 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.

[0182] In certain embodiments, the compositions described herein are packaged pharmaceutical compositions comprising a container for housing 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.

[0183] The formulations may be used in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable administration method known in the art. Pharmaceutical preparations may be sterilized and, if desired, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, flavoring substances, and / or aromatic substances. These may, if desired, be combined with other active agents, such as other analgesics.

[0184] The administration route of any of the compositions described herein includes oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical administration. The compounds for use in the compositions described herein may be formulated for administration by any suitable route, such as oral or parenteral administration, for example, transdermal, transmucosal (e.g., sublingual, lingual, (buccal), (urethral), vaginal (e.g., vaginal and perivaginal), nasal (intranasal), and rectal (rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0185] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelcaps, 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, etc. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions described herein.

[0186] Oral administration For oral application, tablets, sugar-coated tablets, liquids, drops, suppositories, or capsules, caplets, and gel caps are particularly suitable.Compositions intended for oral use can 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 pharmaceutical excipients suitable for tablet manufacture.Such excipients include, for example, inert diluents, such as lactose; granulating and disintegrating agents, such as corn starch; binders, such as starch; and lubricants, such as magnesium stearate.Tablets may be uncoated, or may be coated using known methods to ensure accurate or delayed release of active ingredients.Preparations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0187] For oral administration, the compounds described herein may take the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets may be coated using appropriate methods and coating materials, such as the OPADRY™ film coating system 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 preparations for oral administration may take the form of solutions, syrups, or suspensions. Liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifying agents (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-hydroxybenzoate or sorbic acid).

[0188] Parenteral administration For parenteral administration, the compounds described herein may be formulated for injection or infusion, e.g., intravenous, intramuscular, or subcutaneous, and may be formulated for administration in a bolus dose and / or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles, optionally containing other formulatory agents such as suspending, stabilizing, and / or dispersing agents, may also be used.

[0189] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable solutions, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0190] Further dosage forms Further dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Further dosage forms suitable for use with the compounds and compositions described herein also include those described in U.S. Patent Application Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compounds and compositions described herein include those described in PCT Application Nos. WO03 / 35041; WO03 / 35040; WO03 / 35029; WO03 / 35177; WO03 / 35039; WO02 / 96404; WO02 / 32416; WO01 / 97783; WO01 / 56544; WO01 / 32217; WO98 / 55107; WO98 / 11879; WO97 / 47285; WO93 / 18755; and WO90 / 11757.

[0191] Sustained-Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein may be, but are not limited to, short-acting formulations, rapid-offset formulations, and sustained release formulations, including sustained release formulations, delayed release formulations, and pulsatile release formulations.

[0192] The term sustained release is used in its conventional sense to refer to a drug formulation that gradually releases drug over an extended period of time, which may, but does not necessarily, result in substantially constant blood levels of drug over an extended period of time, which may be as long as a month or more and should result in a longer release than an equivalent amount of drug administered in bolus form.

[0193] For sustained release, the compounds may be formulated with suitable polymeric or hydrophobic materials that impart sustained release properties to the compounds. Thus, the compounds for use with the methods described herein may be administered in the form of microparticles, for example, by injection, or in the form of a wafer or disk by implantation.

[0194] In some cases, the dosage form used can be provided as one or more active ingredients contained in the dosage form that slowly releases or sustained releases, for example, by using hydropropylmethylcellulose, other polymer matrices, gels, dialysis membranes, osmotic systems, multi-layer coatings, microparticles, liposomes or microspheres, or their combinations, which produce desired release profiles in various ratios.Suitable sustained-release formulations known to those skilled in the art, including the sustained-release formulations described herein, can be easily selected for use with the pharmaceutical compositions described herein.Therefore, the single-unit dosage form that is adapted for sustained release and is suitable for oral administration, such as tablets, capsules, gel caps and caplets, are included in the compositions and dosage forms described herein.

[0195] Most sustained-release pharmaceutical products share a common goal of improving drug therapy compared to that achieved by their non-sustained-release counterparts. Ideally, the use of an optimally designed sustained-release preparation during medical treatment is characterized by the use of a minimum amount of active ingredient and the cure or management of the condition in the shortest possible time. Advantages of sustained-release formulations include a longer duration of drug activity, less frequent administration, and increased patient compliance. Furthermore, sustained-release formulations can be used to affect the onset of action or other characteristics of the drug, such as blood levels, and therefore the occurrence of side effects.

[0196] Most sustained-release formulations are designed to initially release an amount of drug that rapidly produces the desired therapeutic effect, and then gradually and continuously release another amount of drug that maintains this level of therapeutic effect over an extended period of time. In order 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.

[0197] The sustained release of active ingredients can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds.The term "sustained release component" is defined herein as a compound that unintentionally comprises a polymer, a polymer matrix, a gel, a dialysis membrane, a liposome, or a microsphere, or a combination thereof, which facilitates the sustained release of active ingredients.In some embodiments, the compounds described herein are administered to patients alone or in combination with other pharmaceutical agents using sustained release formulations.In some embodiments, the compounds described herein are administered to patients alone or in combination with other pharmaceutical agents using sustained release formulations.

[0198] The term delayed release is used herein in its conventional sense to refer to a drug formulation that first releases the drug after some delay after the drug is administered, which may include, but is not necessarily, from about 10 minutes to about 12 hours.

[0199] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that releases drug in a manner that produces a pulsatile plasma profile of the drug after the drug is administered.

[0200] The term immediate release is used in its conventional sense to refer to a drug formulation that releases the drug immediately after administration.

[0201] As used herein, short-term 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 or all whole or partial increments thereof, after the drug is administered.

[0202] As used herein, rapid off-action 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 the drug is administered.

[0203] dosage The therapeutically effective amount or dose of the compounds described herein depends on the age, sex, weight, current medical condition of the patient, and the progression of the disease or disorder in the patient being treated. Those skilled in the art can determine the appropriate dosage depending on these and other factors.

[0204] A suitable dose of the compound of the present invention may be within the range of about 0.01 mg to about 5,000 mg per day, e.g., about 0.1 mg to about 1,000 mg, e.g., about 1 mg to about 500 mg, e.g., about 5 mg to about 250 mg per day. This dose may be administered in a single dose or in multiple doses, e.g., 1 to 4 or more times per day. When multiple doses are used, the amount of each dose may be the same or different. For example, a 1 mg dose per day may be administered as two 0.5 mg doses, spaced about 12 hours apart.

[0205] It is understood that the amount of compound administered daily may be, for example, administered every day, every other day, every two days, every three days, every four days, or every five days. For example, when administered every other day, a dose of 5 mg per day may be administered starting on Monday, a first dose of 5 mg per subsequent day may be administered on Wednesday, and a second dose of 5 mg per subsequent day may be administered on Friday.

[0206] If the subject's condition improves, optionally, the compound described herein can be continuously administered at the discretion of a physician. Alternatively, the dose of the administered drug can be temporarily reduced or temporarily suspended for a certain period of time (i.e., a "drug holiday"). Optionally, the length of the drug holiday can be from 2 days to 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. Dose reductions during drug holidays include, by way of example only, 10% to 100%, including 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0207] Once the subject's condition has improved, a maintenance dose is administered if necessary. Thereafter, the dosage and / or frequency of administration are reduced to a level at which the improved condition is maintained. In certain embodiments, if symptoms and / or infection recur, the subject will require intermittent treatment on a long-term basis.

[0208] The compounds described herein can be formulated in unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary administration to a patient undergoing treatment. Each unit contains a predetermined amount of active material calculated to produce a desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or for 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.

[0209] Optionally, LD 50 (the dose that causes death in 50% of the population) and ED 50The toxicity and therapeutic efficacy of such treatment regimens are determined in cell cultures or experimental animals, which impractically involves determining the LD (dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 The dosage range for human use is preferably expressed as a ratio of ED . Data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for human use. The dosage of such compounds is preferably determined to be within the range of ED . 50 Optionally, the dosage varies within this range depending upon the dosage form employed and the route of administration utilized.

[0210] Those skilled in the art will recognize, or can recognize 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 are covered by the accompanying claims. For example, variations in reaction conditions, including reaction times, reaction sizes / volumes, and experimental reagents, e.g., solvents, catalysts, pressure, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, unrealistically, based on art-recognized alternatives and using no more than routine experimentation, should be understood to be within the scope of this application.

[0211] Whenever values ​​and ranges are provided herein, it should be understood that all values ​​and ranges encompassed by these values ​​and ranges are intended to be included within the scope of the disclosure. Furthermore, all values ​​within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by this application.

[0212] The following examples further illustrate aspects of the present disclosure, but do not limit the teachings or disclosure of the present disclosure presented herein. [Example]

[0213] Various aspects of the present application can be better understood by reference to the following examples, which are provided by way of illustration and are not intended to limit the scope of the present application to the examples set forth herein.

[0214] material and method Materials and Measurements All reactions involving air-sensitive reagents were carried out in anhydrous solvents under a nitrogen atmosphere. Reagents and solvents purchased from commercial suppliers were used as received. Reactions were monitored by thin-layer chromatography (TLC) or high-performance liquid chromatography / mass spectrometry (HPLC-MS) on BAKER-FLEX® silica gel plates (IB2-F) with UV light (254 and 365 nm) detection. Column chromatography was performed using a Teledyne ISCO CombiFlash system equipped with a silica or C-18 column. NMR spectra were recorded on a Bruker Avance III HD 600 MHz spectrometer (at 600 MHz). 1 H NMR) at room temperature. Chemical shifts (δ) were recorded relative to the solvent signal [ 1 H-NMR: reported in parts per million (ppm) relative to DMSO-d (2.50 ppm) and CDCl (7.26 ppm). Signal patterns are reported as s (singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Coupling constants (J) are given in Hz. HRMS measurements were performed using a ThermoFisher Scientific Q Exactive instrument. Abbreviations used in the experimental procedures are defined as follows: NaBH(OAc)3, sodium triacetoxyborohydride; CHCl3, chloroform; DCM, dichloromethane; CH3CN, acetonitrile; MeOH, methanol; NaHCO3, sodium bicarbonate; DMF, N,N-dimethylformamide; EtOAc, ethyl acetate; HATU, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; LiOH, lithium hydroxide; NaOH (aq); TEA, triethylamine; THF, tetrahydrofuran; HCl, hydrochloric acid.

[0215] Example 1: Novel kinases as therapeutic targets in endometriosis Balanced phosphorylation activity mediated by kinases and phosphatases encoded in the human genome is crucial for regulating intracellular responses to internal and external cues. This balanced kinase and phosphatase activity is crucial for maintaining cellular function and preventing dysregulated cell proliferation. Identifying inhibitors of overactive kinases and phosphatases in cancer is an area of ​​great interest in academic and industrial drug discovery. There are approximately 538 kinases and 200 phosphatases in the human genome, and 73 FDA-approved kinase inhibitors are currently available. In addition to the 73 FDA-approved kinase inhibitors targeting 42 different major kinases, there are hundreds of ongoing clinical trials targeting another 15–20 protein kinases. Therefore, of the 538 known kinases, only approximately 70 kinases are currently targeted for drug inhibition. This indicates that numerous therapeutic opportunities exist through targeting the kinase domain. Furthermore, these FDA-approved kinase inhibitors are often promiscuous, inhibiting multiple related kinases. For example, the pan-NTRK inhibitor entrectinib is a potent 7 nM inhibitor of ROS1 and a 12 nM inhibitor of anaplastic lymphoma kinase (ALK). Pexidartinib inhibits FLT3-ITD, KIT, and CSF1R with IC values ​​of 9 nM, 12 nM, and 17 nM, respectively. 50 Ripretinib inhibits at IC values ​​of 3-7 nM. 50 It targets KIT, PDRFα, BRAF, and DDR2 in a range of

[0216] To identify kinases overexpressed in endometriosis, we analyzed a comprehensive database comparing endometrial biopsies from 53 controls with endometriosis subtype lesions from 115 patients (i.e., peritoneal lesions (PeL), ovarian endometriomas (OMA), and deep endometriosis (DiE)). To identify differentially expressed kinases, we analyzed normalized microarray values ​​to identify upregulated (>1.4-fold, p<0.05) kinase-encoding genes and selected those highly expressed across all three subtypes. From this analysis, 20 kinases were identified for validation and therapeutic targeting in endometriosis (Figures 1A-1B).

[0217] Example 2: Identification of NTRK2 as a target kinase for endometriosis NTRK2 is among the kinases identified in the studies described herein and is the target of an FDA-approved small molecule inhibitor (i.e., entrectinib). Thus, NTRK2 is a kinase target with a corresponding FDA-approved inhibitor that can be evaluated as a tool compound for endometriosis.

[0218] NTRK1, NTRK2, and NTRK3 are tyrosine kinase receptors for the extracellular ligands nerve growth factor (NGF), brain-derived nerve growth factor (BDNF), and neurotrophin 4 (NT-4) and neurotrophin 3 (NT-3), respectively. Furthermore, previous data have demonstrated a risk of on-target adverse events associated with both NTRK1 and NTRK2 due to pharmacologically relevant exposure in the CNS. Therefore, the development of safer, peripherally restricted NTRK2 inhibitors for this non-fatal indication must be considered.

[0219] Western blot analysis revealed that NTRK2 protein levels were higher in endometriotic tissues than in eutopic tissues (Figure 2A). Expression of NTRK2 in lysates from ectopic peritoneal lesions and ovarian endometriomas was higher than that in eutopic normal endometrium (Figures 2B–2G). We also confirmed that siRNA-mediated knockdown of NTRK2 in primary endometriotic stromal cells derived from endometriomas reduced prostaglandin E2 (PGE2)-mediated induction of proinflammatory genes (PTGS2 / COX2, IL6, and IL8) (Figures 2H–2J). Western blot analysis revealed that this NTRK2-mediated reduction in proinflammatory genes also reduced phosphorylation of cAMP response element-binding protein (CREB) (Figure 2K).

[0220] Furthermore, by analyzing 36,697 endometriosis cases and 116,071 controls from the FinnGen database, we identified 20 (p<0.001) associations of NTRK2 variants with various subtypes and stages of endometriosis (Figure 3).

[0221] Example 3: Identification of NTRK2 inhibitors To identify NTRK2 selective inhibitors, we used a DNA-Encoded Chemistry Technology (DEC-Tec) strategy. DEC-Tec is a platform for identifying drug-like molecules with high affinity binding to target proteins. The DEC-Tec platform allows for the exploration of chemical space at a greater level than traditional high-throughput screening methods. By using a "split and pool" combinatorial synthesis method, DEC-Tec has developed a 10 9 Up to 10 uniquely encoded compounds can be used to effectively generate screening libraries (Figure 4).

[0222] Parallel selections were performed on 4.25 billion DNA-encoded small molecules using NTRK2, without NTRK2 (i.e., control), or in the presence of the promiscuous kinase inhibitor staurosporine. These selections included kinase-biased molecules. The enrichment of each library member, as measured by normalized z-scores from the selections, was compared. Consistent with competitive ligand binding, a set of compounds was identified that was significantly enriched in the NTRK2-only selection but not in the control or NTRK2 + staurosporine selections.

[0223] Because this NTRK2 hit series had many drug-like features, we selected several tricynthon hits and analogs, including CDD-2262 and its smaller analog, CDD-2330, for synthetic off-DNA for in vitro testing (Figure 5).

[0224] Example 4: Synthesis of Compounds General Procedure I: Reductive Amination TIFF2025532184000124.tif17128 An oven-dried microwave vial equipped with a magnetic stir bar was charged with aryl aldehyde (1.0 equiv.), primary amine (2.0 equiv.), and CHCl3 (0.2–0.4 M). The solution was stirred at room temperature for at least 2 h, and then NaBH(OAc)3 (1.5 equiv.) was added portionwise. After overnight, additional NaBH(OAc)3 (1.5 equiv.) was added. After 4 h, the reaction mixture was quenched by adding NaOH (1.0 M) until pH = 9. The aqueous layer was extracted three times with DCM / MeOH (9:1). The combined organic layers were concentrated, and the residue was chromatographed to give the desired secondary amine products. Compounds 13–15 and 27 were prepared according to general procedure I.

[0225] General Procedure II: Synthesis of Urea TIFF2025532184000125.tif18128 A secondary amine (1.0 equiv.) was dissolved in DCM (0.2 M), and then an isocyanate (2.0 equiv.) was added. The reaction was allowed to proceed overnight, and then the solution was concentrated and the crude product was purified by chromatography to obtain the desired urea product. In certain embodiments, secondary amines may be obtained as described in General Procedure I. Compounds 2-11, 16-19, 21-23, and 25-26 were prepared according to General Procedure II.

[0226] General Procedure III: Amide Coupling TIFF2025532184000126.tif13128 Carboxylic acid (1.0 equiv.) was dissolved in DMF (0.2 M), followed by the addition of HATU (1.2 equiv.). After stirring at room temperature for 5 minutes, a secondary amine (1.3 equiv.) was added, followed by EtN (1.8 equiv.). The reaction was allowed to proceed overnight, quenched with saturated NaHCO3, and extracted three times with EtOAc. The combined organic layers were evaporated to obtain the crude product, which was purified by chromatography to yield the desired amide product. In certain embodiments, secondary amines may be obtained as described in General Procedure I. Compounds 12 and 24-25 were prepared according to General Procedure III.

[0227] General Procedure IV: Ester Hydrolysis The TIFF2025532184000127.tif20143 methyl ester was dissolved in a solvent mixture containing THF / MeOH / HO (4:1:1, 0.2 M), and then aqueous LiOH (2.0 M, 5 equiv.) was added dropwise at room temperature. The reaction proceeded for 4 h, after which additional aqueous LiOH was added. The reaction proceeded overnight, after which it was quenched with 1 M HCl and the pH was adjusted to pH = 2-3. The mixture was concentrated to give the crude product. The crude product was purified by C-18 column chromatography to give the desired carboxylic acid product. Compounds 1 and 21 were prepared according to general procedure IV.

[0228] General Procedure V: Amide Coupling TIFF2025532184000128.tif24128 The carboxylic acid (1.0 equiv.) was dissolved in DMF (0.2 M) and then HATU (1.2 equiv.) was added. After stirring at room temperature for 5 minutes, ammonium chloride or methylamine salt (1.3 equiv.) was added, followed by EtN (1.8 equiv.). The reaction was allowed to proceed overnight, quenched with saturated NaHCO3, and extracted three times with EtOAc. The combined organic layers were evaporated to give the crude product, which was purified by chromatography to give the desired amide product.

[0229] TIFF2025532184000129.tif181285-((1-Isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-4-carboxylic acid (1) TIFF2025532184000130.tif31158

[0230] TIFF2025532184000131.tif271281-Cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(2) TIFF2025532184000132.tif25143

[0231] TIFF2025532184000133.tif201281-Cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea(3) TIFF2025532184000134.tif24145

[0232] TIFF2025532184000135.tif181281-Isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(4) TIFF2025532184000136.tif38144

[0233] TIFF2025532184000137.tif251281-Cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(5) TIFF2025532184000138.tif31144

[0234] TIFF2025532184000139.tif221281-Cyclobutyl-3-(4-nitrophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea (6) TIFF2025532184000140.tif25146

[0235] TIFF2025532184000141.tif251281-Phenyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea (7) TIFF2025532184000142.tif18144

[0236] TIFF2025532184000143.tif221281-Cyclopentyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea (8) TIFF2025532184000144.tif31144

[0237] TIFF2025532184000145.tif201281-Cyclopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea (9) TIFF2025532184000146.tif24144

[0238] TIFF2025532184000147.tif201281-Cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethyl)phenyl)urea (10) TIFF2025532184000148.tif24146

[0239] TIFF2025532184000149.tif201281-Cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(3-(trifluoromethyl)phenyl)urea (11) TIFF2025532184000150.tif24144

[0240] TIFF2025532184000151.tif25128N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide (12) TIFF2025532184000152.tif38145

[0241] TIFF2025532184000153.tif22128 Methyl 5-((cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (13) TIFF2025532184000154.tif18145

[0242] TIFF2025532184000155.tif181283-(3-Chlorophenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)propan-1-amine (14) TIFF2025532184000156.tif24145

[0243] TIFF2025532184000157.tif13128N,N-bis(pyrazolo[1,5-a]pyridin-5-ylmethyl)cyclobutanamine (15) This compound is the over-reduced amination product. TIFF2025532184000158.tif18138

[0244] TIFF2025532184000159.tif271281-(3-(3-chlorophenoxy)propyl)-3-(4-phenoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea (16) TIFF2025532184000160.tif18144

[0245] TIFF2025532184000161.tif271281-(3-(3-chlorophenoxy)propyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-trifluoromethoxy)phenyl)urea (17) TIFF2025532184000162.tif24146

[0246] TIFF2025532184000163.tif221283-(4-Chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea (18) TIFF2025532184000164.tif18144

[0247] TIFF2025532184000165.tif221281-Cyclobutyl-3-(4-fluorophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea (19) TIFF2025532184000166.tif25143

[0248] TIFF2025532184000167.tif251285-((1-Cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (20) TIFF2025532184000168.tif18145

[0249] TIFF2025532184000169.tif221285-((1-Cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (21) TIFF2025532184000170.tif25145

[0250] TIFF2025532184000171.tif22128 Methyl 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (22) TIFF2025532184000172.tif18146

[0251] TIFF2025532184000173.tif221281-Cyclobutyl-3-(4-methoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea (23) TIFF2025532184000174.tif24145

[0252] TIFF2025532184000175.tif25128(R)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide (24) TIFF2025532184000176.tif25142

[0253] TIFF2025532184000177.tif25128(S)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide (25) TIFF2025532184000178.tif31145

[0254] TIFF2025532184000179.tif221281-Cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea (26) TIFF2025532184000180.tif24145

[0255] TIFF2025532184000181.tif16128(S)-1-Phenyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)ethan-1-amine (27) TIFF2025532184000182.tif18143

[0256] TIFF2025532184000183.tif181281-((3-Fluoropyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea (28) TIFF2025532184000184.tif18144

[0257] TIFF2025532184000185.tif181281-((3-Bromopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea (29) TIFF2025532184000186.tif18145

[0258] TIFF2025532184000187.tif201285-((1-Cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (30) TIFF2025532184000188.tif18146

[0259] TIFF2025532184000189.tif181285-((1-Isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (31) TIFF2025532184000190.tif18143

[0260] TIFF2025532184000191.tif201285-((1-Cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (32) TIFF2025532184000192.tif18144

[0261] TIFF2025532184000193.tif181285-((1-Isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (33) TIFF2025532184000194.tif18143

[0262] TIFF2025532184000195.tif20128N-Hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (34) TIFF2025532184000196.tif18145

[0263] TIFF2025532184000197.tif201281-((3-cyanopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea (35) TIFF2025532184000198.tif18143

[0264] TIFF2025532184000199.tif221285-((1-Isobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (36) TIFF2025532184000200.tif18143

[0265] TIFF2025532184000201.tif221285-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (37) TIFF2025532184000202.tif24145

[0266] TIFF2025532184000203.tif20128N-Hydroxy-5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboximidamide (38) TIFF2025532184000204.tif18144

[0267] TIFF2025532184000205.tif31128N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinamido)-3-methoxyphenyl)-N 4 -Methyl terephthalamide (39) TIFF2025532184000206.tif24145

[0268] TIFF2025532184000207.tif31128N 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 -Methyl terephthalamide (40) TIFF2025532184000208.tif24145

[0269] TIFF2025532184000209.tif25128tert-Butyl 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinate (41) TIFF2025532184000210.tif18145

[0270] TIFF2025532184000211.tif25128 tert-Butyl 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-3-yl)picolinate (42) TIFF2025532184000212.tif18145

[0271] TIFF2025532184000213.tif39128(Z)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamimidoyl)picolinamido)-3-methoxyphenyl)-N 4 -Methyl terephthalamide (43) TIFF2025532184000214.tif18143

[0272] TIFF2025532184000215.tif20128N1-(4-(5-(N-hydroxycarbamimidoyl)picolinamido)-3-methoxyphenyl)-N4-methylterephthalamide (Int-1) TIFF2025532184000216.tif24145

[0273] TIFF2025532184000217.tif20128 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 (44) TIFF2025532184000218.tif18144

[0274] TIFF2025532184000219.tif34128N-((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 (45) TIFF2025532184000220.tif18144

[0275] TIFF2025532184000221.tif38128(S)-1-Benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1H-benzo[d]imidazole-7-carboxamide (46) TIFF2025532184000222.tif18144

[0276] TIFF2025532184000223.tif32128(S)-1-Benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide (47) TIFF2025532184000224.tif18141

[0277] TIFF2025532184000225.tif30128(S)-2-(benzylamino)-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-3-nitrobenzamide (Int-2) TIFF2025532184000226.tif18144

[0278] TIFF2025532184000227.tif181285-((1-methyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (48) TIFF2025532184000228.tif11143

[0279] TIFF2025532184000229.tif181285-((1-Isopropyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (49) TIFF2025532184000230.tif18143

[0280] TIFF2025532184000231.tif201285-((N-methyl-3-(4-(trifluoromethoxy)phenyl)propanamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (51) TIFF2025532184000232.tif18146

[0281] TIFF2025532184000233.tif181285-((1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (52) TIFF2025532184000234.tif11143

[0282] TIFF2025532184000235.tif221285-((N-Isopropyl-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (53) TIFF2025532184000236.tif18140

[0283] TIFF2025532184000237.tif291285-((N-(3-(dimethylamino)propyl)-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (54) TIFF2025532184000238.tif31144

[0284] TIFF2025532184000239.tif221285-((2-(4-Isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (55) TIFF2025532184000240.tif18144

[0285] TIFF2025532184000241.tif181285-((3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (56) TIFF2025532184000242.tif11147

[0286] TIFF2025532184000243.tif181285-((3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (57) TIFF2025532184000244.tif11139

[0287] TIFF2025532184000245.tif201285-((N-methyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (58) TIFF2025532184000246.tif18145

[0288] TIFF2025532184000247.tif201285-((N-Isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (59) TIFF2025532184000248.tif18142

[0289] TIFF2025532184000249.tif22128(R)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (60) TIFF2025532184000250.tif24145

[0290] TIFF2025532184000251.tif22128(S)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (61) TIFF2025532184000252.tif24145

[0291] TIFF2025532184000253.tif251285-((N-methyl-2-(4-(trifluoromethyl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (62) TIFF2025532184000254.tif18143

[0292] TIFF2025532184000255.tif181285-((N-methyl-2-(3-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (63) TIFF2025532184000256.tif11145

[0293] TIFF2025532184000257.tif221285-((2-(4-(tert-butyl)phenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (64) TIFF2025532184000258.tif18145

[0294] TIFF2025532184000259.tif221285-((2-(4-(tert-butyl)phenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (65) TIFF2025532184000260.tif18143

[0295] TIFF2025532184000261.tif221285-((2-((4-(tert-butyl)phenyl)(methyl)amino)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (66) TIFF2025532184000262.tif18144

[0296] TIFF2025532184000263.tif201285-((N-Isopropyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (67) TIFF2025532184000264.tif18143

[0297] TIFF2025532184000265.tif221285-((N-Isopropyl-2-(4-(prop-1-en-2-yl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (68) TIFF2025532184000266.tif18144

[0298] TIFF2025532184000267.tif251285-((2-(4-acetylphenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (69) TIFF2025532184000268.tif18145

[0299] TIFF2025532184000269.tif251285-((2-(4-acetylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (70) TIFF2025532184000270.tif18146

[0300] TIFF2025532184000271.tif201285-((N-methyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (71) TIFF2025532184000272.tif18145

[0301] TIFF2025532184000273.tif18128N-((1H-indol-5-yl)methyl)-N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamide (74) TIFF2025532184000274.tif18144

[0302] TIFF2025532184000275.tif201281-((1H-indol-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea (75) TIFF2025532184000276.tif18140

[0303] TIFF2025532184000277.tif201282-((6-(tert-butyl)pyridin-3-yl)amino)-N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide (76) TIFF2025532184000278.tif24145

[0304] TIFF2025532184000279.tif22128N-Isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-((4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)acetamide (77) TIFF2025532184000280.tif24145

[0305] TIFF2025532184000281.tif181285-((methyl(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)amino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (78) TIFF2025532184000282.tif11140

[0306] TIFF2025532184000283.tif201281-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)urea (79) TIFF2025532184000284.tif18143

[0307] TIFF2025532184000285.tif201281-Cyclopropyl-1-(pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea (80) TIFF2025532184000286.tif18146

[0308] TIFF2025532184000287.tif201281-Cyclopropyl-1-(methylpyrimidin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea (81) TIFF2025532184000288.tif18143

[0309] TIFF2025532184000289.tif201281-Cyclopropyl-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea (82) TIFF2025532184000290.tif18143

[0310] TIFF2025532184000291.tif271285-((N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (83) TIFF2025532184000292.tif18148

[0311] TIFF2025532184000293.tif201285-((N-(4-(trifluoromethoxy)phenyl)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (84) TIFF2025532184000294.tif18143

[0312] TIFF2025532184000295.tif201285-(((N-Isopropyl-4-(trifluoromethyl)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (85) TIFF2025532184000296.tif18145

[0313] TIFF2025532184000297.tif201285-(((N-Isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine)-6-sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (86) TIFF2025532184000298.tif11140

[0314] TIFF2025532184000299.tif201285-(((N-methyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (87) TIFF2025532184000300.tif11146

[0315] TIFF2025532184000301.tif361285-(((N-Isopropyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (88) TIFF2025532184000302.tif18145

[0316] Example 5: Verification of NTRK (NTRK1, NTRK2, and / or NTRK3) activity of selected compounds As described elsewhere herein, hit compounds, including CDD-2262 and its smaller analog, CDD-2330, were subjected to DNA synthesis and evaluated for NTRK2 activity. Selected compounds (i.e., CDD-2299, CDD-2219, CDD-2330, CDD-2262, CDD-2737, and CDD-3032, among others) exhibited low nanomolar potency (IC of 3.7 nM, 13 nM, 3.5 nM, 32 nM, 2.3 nM, and 6.1 nM, respectively). 50 ; see Table 2), and were also able to penetrate the cell membrane and induce effects in a NanoBRET assay (Figures 6A-6B).

[0317] The inhibitory properties of selected compounds of the present disclosure against NTRK1, NTRK2, and NTRK3 were analyzed (Table 2). Additionally, the apparent inhibitory constants (K i app ) was calculated (Table 3). 50 Compounds with a ≥ 10,000 nM were considered inactive herein.

[0318] Table 2. Exemplary NTRK2 inhibition data for certain compounds TIFF2025532184000303.tif158146TIFF2025532184000304.tif254146

[0319] Table 3. Apparent NTRK2 inhibition constants (K i app )data TIFF2025532184000305.tif22146

[0320] Example 6: Verification of NTRK2 specificity of CDD-2330 To broadly evaluate the kinome-wide selectivity of CDD-2330, we used the KINOMEscan profiling platform (Figure 7A). At a concentration of 1 μM, CDD-2330 demonstrated high specificity for NTRK, with MAP3K19 being the only potential off-target. Further dose-response evaluation of CDD-2330 in the ThermoFisher Z'-LYTE assay (Figure 7B) revealed that CDD-2330 binds to NTRK with single-digit nanomolar activity (IC). 50 : 1.2-3.8 nM), MAP3K19 (IC 50 It was confirmed that it showed >100-fold selectivity compared to the α-glucan (401 nM).

[0321] Similarly, the selectivity of CDD-3031 for NTRK kinases was assessed in a kinase occupancy assay (Promega K192 cell-based NanoBRET assay) using 192 kinases (Table 4). In this assay, CDD-3031 was delivered at 1 μM and showed significant selectivity for NTRK2 and NTRK1, confirming the findings in Table 2.

[0322] Table 4: CDD-3031 kinase occupancy (%) TIFF2025532184000306.tif172146

[0323] Example 7: Pharmacokinetic data of compounds of the present disclosure Previous data have demonstrated the risk of on-target adverse events associated with NTRK1 and NTRK2 due to pharmacologically relevant exposure in the central nervous system. Both FDA-approved small molecule pan-NTRK inhibitors (i.e., entrectinib and larotrectinib) have been shown to cross the blood-brain barrier, which is considered a major problem in the treatment of endometriosis, a non-fatal condition. Therefore, in certain non-limiting embodiments, peripherally restricted NTRK-specific inhibitors with novel chemotypes are a safer option and hold great potential for the treatment of both inflammation and pain associated with endometriosis.

[0324] CDD-2262 was shown to be a metabolically stable compound using mouse and human liver microsomes in vitro, whereas (t 1 / 2 >7 hr), the analog CDD-2330 was found to be even more stable (t 1 / 2 >25 hr) (Table 5). Certain pharmacokinetic properties (eg, clearance) of the exemplary compound CDD-3031 are further provided herein (Tables 6-7 and Figures 8A-8B).

[0325] Taken together, the data demonstrate that the compounds described herein are potent, metabolically stable, and NTRK-specific compounds.

[0326] Table 5. Half-lives in mouse liver microsomes (MLM) and human liver microsomes (HLM) TIFF2025532184000307.tif84146

[0327] Table 6. Exemplary clearance data for CDD-3031 TIFF2025532184000308.tif21146

[0328] Table 7. Exemplary pharmacokinetic data for CDD-3031 (n=3, mean±SD) TIFF2025532184000309.tif69146

[0329] CDD-2330 brain uptake was low (brain:plasma ratio of 0.31 at 4 hours) compared to antidepressants such as atomextine (brain:plasma ratio of 20 at 4 hours) (Figure 9A), and testis uptake was also low (testis:plasma ratio of 0.31 at 4 hours) (Figure 9B). Similarly, CDD-3031 brain uptake was relatively low compared to chlorpromazine (positive control) but high compared to hydroxyzine (negative control) (Figures 10A-10C).

[0330] Table 8. Exemplary brain uptake data for certain compounds TIFF2025532184000310.tif32146

[0331] Furthermore, analysis of potential liver and other tissue toxicity following high doses of certain exemplary compounds, including CDD-2330 and CDD-3031 (i.e., 50 mg / kg), shows minimal effects (Tables 9-10).

[0332] Table 9. Evaluation of potential liver and other tissue toxicity in mice treated with high doses of CDD-2330 a TIFF2025532184000311.tif42146 a Plasma ALT and AST levels were assessed 48 hours after oral administration of 50 mg / kg CDD-2330 to mice (n=4).

[0333] Table 10. Evaluation of potential liver and other tissue toxicity in mice treated with high doses of CDD-3031 a TIFF2025532184000312.tif49146 a Plasma ALT and AST levels were assessed 24 hours after administering 50 mg / kg CDD-3031 to mice by oral gavage.

[0334] Furthermore, initial pharmacokinetic analysis of orally administered CDD-2330 demonstrated rapid elimination from the blood, which may be at least partially due to metabolism ( FIG. 11A ). Thus, the present disclosure indicates that CDD-2330 and its analogs may be safer, peripherally restricted pan-NTRK inhibitors for treating endometriosis and multiple cancers.

[0335] In certain embodiments, compounds of the present invention containing a carboxyl group at the 3-position of the pyrazolo[1,5-a]pyridine scaffold have potent NTRK1, NTRK2, and / or NTRK3 activity. In certain embodiments, replacing the carboxyl functionality at the 3-position of the pyrazolo[1,5-a]pyridine scaffold with any of a number of substituents, including non-realistically halogens, amidines, N-hydroxyamidines, and N-hydroxyamides (e.g., Weinreb amides), improves the pharmacokinetic properties of the compound. Without wishing to be bound by theory, it is believed that replacing the carboxylic acid group with any of a number of substituents improves the pharmacokinetics of the compound by reducing glucuronidation.

[0336] Example 8: CDD-2330 administration leads to downregulation of inflammation-related markers in endometriotic cells Estrogen, produced by the ovaries and endometriotic lesions, is a key molecule that induces BDNF / NT3 secretion from macrophages and proinflammatory signaling from nerve fibers (Figure 12A). This signaling mechanism exacerbates the proinflammatory state in endometriotic lesions, promoting nerve fiber growth and pain. At the cellular level, PGE2 and BDNF / NT-3 signaling have been shown to stimulate PTGS2 expression via the phosphorylation and activation of CREB (Figure 12B). Furthermore, inhibiting NTRK2 with siRNA attenuates the expression of proinflammatory genes.

[0337] Preliminary studies with CDD-2262 (i.e., a CDD-2330 analog) demonstrated that NTRK2 inhibition statistically suppressed prostaglandin-endoperoxidase synthase 2 (PTGS2) mRNA at concentrations >100 nM over a 6-hour period (FIG. 12C). Thus, the present disclosure provides evidence that CDD-2330 administration suppresses inflammation-related markers and is therefore suitable for the treatment of endometriosis.

[0338] Example 9: Exemplary data for certain NTRK2 inhibitors in endometriosis mouse models In one aspect, the present disclosure provides exemplary data relating to the administration of NTRK2 inhibitors in endometriosis mouse models (Figure 14).In certain embodiments, 14 days after intraperitoneal injection of donor mouse endometrium, recipient mice are administered NTRK2 inhibitors and / or controls.In certain embodiments, recipient mice are sacrificed and quantitatively evaluated on the 28th day.

[0339] This disclosure provides exemplary data demonstrating that administration of CDD-2737 to a mouse model of endometriosis resulted in a reduction in the number and size of lesions compared to controls (Figures 15A-15E). Furthermore, CDD-2737 administration did not show any gross effects on the liver and / or kidneys (Figures 16A-16B) or potential liver or other tissue toxicity (Table 11).

[0340] Table 11. Evaluation of potential liver and other tissue toxicity in mice treated with 10 mg / kg / day CDD-2737 for 14 days TIFF2025532184000313.tif117146

[0341] The present disclosure further demonstrates the robust efficacy of NTRK inhibitors (e.g., CDD-3132) for inhibiting endometriotic lesion growth in mice (Figure 17A). In certain embodiments, a decrease in endometriotic lesion size was observed with administration of CDD-3132 (10 mg / kg) compared to vehicle control (Figures 17B-17C). In certain embodiments, a decrease in lesion area, lesion volume, and lesion mass was observed with administration of CDD-3132, CDD-3119, CDD-3132, and PF-06273340 (10 mg / kg) compared to vehicle control (Figures 17D-17F).

[0342] The present disclosure further demonstrates, for example, that administration of CDD-3132 (10 mg / kg) reduces proliferation, angiogenesis, macrophage infiltration, and / or inflammation within endometriotic lesions (FIGS. 18A-18B).

[0343] The present disclosure further demonstrates the efficacy of certain NTRK inhibitors, including, by way of non-limiting examples, CDD-3031, CDD-3119, CDD-3132, and PF-06273340 (10 mg / kg), to inhibit endometriotic lesion growth in mice (Figure 19).

[0344] The present disclosure further demonstrates that certain NTRK2 inhibitors, including by way of non-limiting examples CDD-3031, CDD-3119, CDD-3132, and PF-0672 (10 mg / kg), have little to no effect on liver and / or kidney weight and / or serum ALT and AST elevation in mice bearing endometriotic lesions (Figures 20A-20B and Table 12).

[0345] Table 12. Evaluation of potential liver and other tissue toxicity (ALT and AST levels) in mice treated with exemplary NTRK inhibitors (10 mg / kg / day ip dosed for 14 days) or control (vehicle). TIFF2025532184000314.tif42146

[0346] Enumerated Aspects The following exemplary aspects are provided: The numbering of the following exemplary aspects should not be construed as indicating any level of importance.

[0347] Aspect 1 is a compound selected from the group consisting of: (a) Formula (I): The compound of TIFF2025532184000315.tif11128, During the ceremony, T is TIFF2025532184000316.tif49128; R 1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C 10 Aryl, optionally substituted C2-C8 heterocyclyl, halogen, C(=O)OR a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), CN, and NO2; R 2 is 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, OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), NR a C(=O)R b , C(=O)N(R a )(OR b ), C(=NR a )N(R b )(R c ), C(=NR a )N(R b )(OR c ), and NR a S(=O)2R b selected from the group consisting of R 3a , R 3b , R 3c , R 3d , and R 3eare 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; R 4 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; R 5 H and -X 1 -A 1 selected from the group consisting of R 6a , R 6b , R 6c , and R 6d are each independently H, an optionally substituted C1-C6 alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of L 1 is -C(R 6a )(R 6b )- and L 2 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; X 1 is a bond, O, and NR 7 selected from the group consisting of R 7is selected from the group consisting of H and optionally substituted C1-C6 alkyl; A 1 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted C2-C8 heterocyclyl; R a , R b , and R c 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; T TIFF2025532184000317.tif22128 and -L 2 -R 5 is -H, then R 4 is not H, a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof; (b) Formula (II): The compound of TIFF2025532184000318.tif14128, During the ceremony, A 2 teeth, TIFF2025532184000319.tif23128; R 8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted phenyl; R 9a , R 9b , R 9c , and R 9d are each independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C 10selected from the group consisting of aryl, optionally substituted C2-C8 heterocyclyl, halogen, CN, and NO2; R 10 represents an optionally substituted C1-C6 alkyl, TIFF2025532184000320.tif21128; R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , and R 11h are each independently 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, OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O)2N(R a )(R b ), NR a C(=O)R b , and N.R. a S(=O)2R b selected from the group consisting of R 12a , R 12b , and R 12c 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; R 13a , R 13b , R 13c , and R 13dare 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; R 14 is selected from the group consisting of H and optionally substituted C1-C6 alkyl; L 3 teeth, TIFF2025532184000321.tif14128; X 2 O and NR 14 selected from the group consisting of Z 1 is CR 13a and N, and Z 2 is CR 13b and N, and Z 3 is CR 13c and N, and Z 4 is CR 13d and N, Z 1 , Z 2 , Z 3 , and Z 4 At least one selected from the group consisting of is N; R a and R b 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; a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof; (c) Formula (III): The compound of TIFF2025532184000322.tif28128, During the ceremony, R 15a , R15b , and R 15c 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; R 16 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; R 17a and R 17b 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; R 18a and R 18b are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl; A 3 is optionally substituted phenyl, A 4 is optionally substituted phenyl; Provided is a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

[0348] Aspect 2 is an embodiment in which each 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, when 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; each 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; A compound according to embodiment 1 is provided.

[0349] Aspect 3 is TIFF2025532184000323.tif102128.

[0350] Aspect 4 is R 1 is H.

[0351] Aspect 5 is R 2 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).

[0352] Aspect 6 is (a)R 3a , R 3b , R 3c , R 3d , and R 3e at least one selected from is H; (b)R 3a , R 3b , R 3c , R 3d , and R 3e at least two selected from are H; (c)R 3a , R 3b , R 3c , R 3d , and R 3e at least three selected from the following are H; (d)R 3a , R 3b , R 3c , R 3d , and R 3e at least four selected from are H; and (e)R 3a , R 3b , R 3c , R 3d , and R 3e Each of the following is H The present invention provides a compound according to any one of Aspects 1 to 5, which corresponds to at least one of the following:

[0353] Aspect 7 is where T is TIFF2025532184000324.tif79136.

[0354] Aspect 8 is R 4is selected from the group consisting of H, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (CH)N(CH), C(=O)CH, phenyl, benzyl substituted with at least one C-C alkyl; and -CHCHCHO (phenyl substituted with at least one halogen).

[0355] Aspect 9 is R 4 but, The present invention provides a compound according to any one of aspects 1 to 7, wherein the compound is selected from the group consisting of: TIFF2025532184000325.tif11128.

[0356] Aspect 10 is A 1 but, 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 C1-C3 haloalkyl, phenoxy, halogen, and NO2; phenyl fused with C2-C6 heterocycloalkyl; and C2-C8 heteroaryl optionally substituted with C1-C6 alkyl and optionally fused with C2-C5 heteroaryl. The present invention provides a compound according to any one of aspects 1 to 9, selected from the group consisting of:

[0357] Aspect 11 is A 1 but, 11. The compound according to any one of aspects 1 to 10, wherein the compound is selected from the group consisting of: TIFF2025532184000326.tif68136.

[0358] Aspect 12 is L 1 is —CH 2 —.

[0359] Aspect 13 is L2 is a bond, -C(=O)-, -C(=S)-, S(=O)2-, -CH2-, 13. The compound according to any one of aspects 1 to 12, wherein the compound is selected from the group consisting of: TIFF2025532184000327.tif10128.

[0360] Aspect 14 is X 1 , bond, O, and NR 7 The compound according to any one of aspects 1 to 13 is selected from the group consisting of:

[0361] Aspect 15 is R 7 is selected from the group consisting of H and Me.

[0362] Aspect 16 is R 5 but, 16. The compound according to any one of aspects 1 to 15, wherein the compound is selected from the group consisting of: TIFF2025532184000328.tif118145.

[0363] Aspect 17 is 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-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-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid; 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((1-Isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)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; (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; 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 (Z)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide The present invention provides a compound according to any one of aspects 1 to 16, selected from the group consisting of:

[0364] Aspect 18 provides a compound according to aspect 1 or 2, which is a compound of formula (II).

[0365] Aspect 19 is R 8 is selected from the group consisting of isopropyl and phenyl.

[0366] Aspect 20 is R 9a , R 9b , R 9c , and R 9d is each independently selected from the group consisting of H, tert-butyl, and trifluoromethyl.

[0367] Aspect 21 is A 2 but, 21. The compound according to any one of embodiments 18 to 20, wherein the compound is selected from the group consisting of: TIFF2025532184000329.tif24128.

[0368] Aspect 22 is (a)Z 1 is N and Z 2 , Z 3 , and Z 4 At least one of the following is CH: (b)Z 1 is N and Z 2 , Z 3 , and Z 4 At least two of the (c)Z 1 is N and Z 2 , Z 3 , and Z 4 each of which is CH; (d)Z 2 is N and Z 1 , Z 3 , and Z 4 At least one of the following is CH: (e)Z 2 is N and Z 1 , Z 3 , and Z4 At least two of the (f)Z 2 is N and Z 1 , Z 3 , and Z 4 Each of the above is CH. The present invention provides a compound according to any one of aspects 17 to 20, wherein the compound corresponds to one of the following:

[0369] Aspect 23 is X 2 is selected from the group consisting of —O— and —NH—.

[0370] Aspect 24 is 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.

[0371] Aspect 25 is R 12a , R 12b , and R 12c are each independently selected from the group consisting of H, methyl, and C(=O)O(C(CH3)3).

[0372] Aspect 26 is R 10 But tert-butyl, 26. The compound of any one of aspects 18 to 25, wherein the compound is selected from the group consisting of: TIFF2025532184000330.tif19128.

[0373] Aspect 27 is N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinamido)-3-methoxyphenyl)-N4 -methyl terephthalamide; 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 -methyl terephthalamide; 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)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamimidoyl)picolinamido)-3-methoxyphenyl)-N 4 -methyl terephthalamide; 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 The present invention provides a compound according to any one of aspects 1-2 and 18-26, selected from the group consisting of:

[0374] Aspect 28 provides a compound according to aspect 1 or 2, which is a compound of formula (III).

[0375] Aspect 29 is directed to compounds of formula (III) TIFF2025532184000331.tif28128.

[0376] Aspect 30 is (a)R 15a , R 15b , and R15c At least one of the following is H: (b)R 15a , R 15b , and R 15c at least two of are H, and (c)R 15a , R 15b , and R 15c Each of the following is H 30. The compound according to claim 28 or 29, wherein the compound corresponds to one of:

[0377] Aspect 31 is R 16 However, benzyl and The present invention provides a compound according to any one of aspects 28 to 30, wherein the compound is selected from the group consisting of: TIFF2025532184000332.tif15128.

[0378] Aspect 32 is R 17a and R 17b is each independently H.

[0379] Aspect 33 is R 18a and R 18b are each independently selected from the group consisting of H and Me.

[0380] Aspect 34 is A 3 but, TIFF2025532184000333.tif21128.

[0381] Aspect 35 is A 4 but, The compound according to any one of Aspects 28 to 34 is provided, wherein the compound is TIFF2025532184000334.tif9128.

[0382] Aspect 36 is 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 The present invention provides a compound according to any one of aspects 1-2 and 28-35, selected from the group consisting of:

[0383] Aspect 37 provides a pharmaceutical composition comprising a compound according to any one of aspects 1 to 36 and a pharmaceutically acceptable carrier.

[0384] Embodiment 38 provides a method of treating, preventing, and / or ameliorating endometriosis in a subject in need thereof, comprising administering to the subject at least one neurotrophin receptor tyrosine kinase (NTRK) inhibitor, or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

[0385] Example 39 provides a method according to Example 38, wherein at least one selected from the group consisting of chronic pelvic pain, inflammation, and infertility is treated, prevented, and / or ameliorated in said subject.

[0386] Aspect 40 provides a method according to aspect 38 or 39, wherein the subject is female.

[0387] Embodiment 41 provides a method of treating, preventing, and / or ameliorating cancer in a subject in need thereof, comprising administering to the subject at least one neurotrophin receptor tyrosine kinase (NTRK) inhibitor, or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

[0388] Embodiment 42 provides a method of treating, preventing, and / or ameliorating pain in a subject in need thereof, comprising administering to the subject at least one neurotrophin receptor tyrosine kinase (NTRK) inhibitor, or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

[0389] Aspect 43 provides a method according to any one of Aspects 38 to 42, wherein the subject has overexpression of at least one selected from the group consisting of neurotrophin receptor tyrosine kinase 1 (NTRK1), neurotrophin receptor tyrosine kinase 2 (NTRK2), and neurotrophin receptor tyrosine kinase 3 (NTRK3).

[0390] Aspect 44 provides a method according to any one of Aspects 38 to 44, wherein at least one selected from the group consisting of NTRK1, NTRK2, and NTRK3 is inhibited in the subject.

[0391] Aspect 45 provides a method according to any one of Aspects 38 to 44, wherein a fusion gene comprising at least one selected from the group consisting of NTRK1, NTRK2, and NTRK3 is overexpressed in the subject.

[0392] Example 46 provides a method according to example 45, wherein the product of the fusion gene is inhibited in the subject.

[0393] Aspect 47 provides a method of any one of Aspects 38 to 46, wherein the NTRK inhibitor comprises a compound of any one of Aspects 1 to 35, or the pharmaceutical composition thereof comprises a pharmaceutical composition of Aspect 36.

[0394] Aspect 48 provides the method of any one of Aspects 38 to 47, wherein the NTRK inhibitor is an NTRK2 inhibitor.

[0395] Example 49 provides a method of example 48, wherein the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK1 and / or NTRK3.

[0396] Example 50 provides a method of any one of Examples 38 to 49, wherein the at least one NTRK2 inhibitor is selected from the group consisting of staurosporine, larotrectinib, entrectinib, ceritrectinib, repotrectinib, and PF-06273340.

[0397] Example 51 provides a method according to any one of Examples 38 to 50, wherein the subject is a mammal.

[0398] Aspect 52 provides the method of aspect 51, wherein the mammal is a human.

[0399] The terms and expressions used in this specification are used as terms of description and not as terms of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the embodiments of this application. Thus, although this application has described specific embodiments and optional features, it should be understood that modifications and / or variations of the compositions, methods, and concepts disclosed herein may be employed by those skilled in the art, and such modifications and variations are considered to be within the scope of the embodiments of this application.

Claims

1. A compound selected from the group consisting of: (a) Formula (I): A compound of the formula: During the ceremony, T is selected from the group consisting of R 1 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 Alkoxy, optionally substituted C 6 ~C 10 Aryl, optionally substituted C 2 ~C 8 Heterocyclyl, halogen, C(=O)OR a , C(=O)N(R a )(R b ), S(=O) 2 N(R a )(R b ), CN, and NO 2 selected from the group consisting of R 2 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 Alkoxy, optionally substituted phenyl, optionally substituted C 2 ~C 8 Heterocyclyl, halogen, CN, NO 2 , OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O) 2 N(R a )(R b ), NR a C(=O)R b , C(=O)N(R a )(OR b ), C(=NR a )N(R b )(R c ), C(=NR a )N(R b )(OR c ), and NR a S(=O) 2 R b selected from the group consisting of R 3a , R 3b , R 3c , R 3d , and R 3e are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 Alkoxy, halogen, CN, and NO 2 selected from the group consisting of R 4 is H, optionally substituted C 1 ~C 6 Alkyl, C(=O)(optionally substituted C 1 ~C 6 alkyl), optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 Aminoalkyl, optionally substituted C 2 ~C 6 is selected from the group consisting of hydroxyalkyl, optionally substituted benzyl, and optionally substituted phenyl; R 5 H and -X 1 -A 1 selected from the group consisting of R 6a , R 6b , R 6c , and R 6d are each independently H, optionally substituted C, 1 ~C 6 Alkyl, and C(=O)N(R a )(R b ) selected from the group consisting of L 1 is -C(R 6a )(R 6b )- and L 2 represents a bond, -C(=O)-, -C(=O)(optionally substituted C 1 ~C 3 alkylenyl), -C(=O)(optionally substituted C 2 ~C 3 alkenylenyl), -C(=S)-, -C(=S)(optionally substituted C 1 ~C 3 alkylenyl), -C(=S) (optionally substituted C 2 ~C 3 alkenylenyl), -S(=O) 2 -, -S(=O) 2 (Optionally substituted C 1 ~C 3 alkylenyl), -S(=O) 2 (Optionally substituted C 2 ~C 3 alkenylenyl), optionally substituted C 1 ~C 3 Alkylene, and optionally substituted C 2 ~C 3 alkenylenyl; X 1 is a bond, O, and NR 7 selected from the group consisting of R 7 is H and optionally substituted C 1 ~C 6 alkyl, A 1 is an optionally substituted phenyl, an optionally substituted naphthyl, and an optionally substituted C 2 ~C 8 heterocyclyl; R a , R b , and R c are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 ~C 8 heterocyclyl; T and -L 2 -R 5 is -H, then R 4 is not H, a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof; (b) Formula (II): A compound of the formula: During the ceremony, A 2 teeth, selected from the group consisting of R 8 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 cycloalkyl, and optionally substituted phenyl; R 9a , R 9b , R 9c , and R 9d are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 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 NO 2 selected from the group consisting of R 10 may be substituted C 1 ~C 6 Alkyl, selected from the group consisting of R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , and R 11h are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 Alkoxy, optionally substituted phenyl, optionally substituted C 2 ~C 8 Heterocyclyl, halogen, CN, NO 2 , OR a , N(R a )(R b ), C(=O)R a , C(=O)OR a , OC(=O)R a , C(=O)N(R a )(R b ), S(=O) 2 N(R a )(R b ), NR a C(=O)R b , and N.R. a S(=O) 2 R b selected from the group consisting of R 12a , R 12b , and R 12c are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 selected from the group consisting of cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R 13a , R 13b , R 13c , and R 13d are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 Alkoxy, halogen, CN, and NO 2 selected from the group consisting of R 14 is H and optionally substituted C 1 ~C 6 alkyl, L 3 teeth, selected from the group consisting of X 2 O and NR 14 selected from the group consisting of Z 1 is CR 13a and N, and Z 2 is CR 13b and N, and Z 3 is CR 13c and N, and Z 4 is CR 13d and N, Z 1 , Z 2 , Z 3 , and Z 4 At least one selected from the group consisting of is N; R a and R b are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C 2 ~C 8 heterocyclyl, a compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof; (c) Formula (III): A compound of the formula: During the ceremony, R 15a , R 15b , and R 15c are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 Cycloalkyl, optionally substituted C 1 ~C 6 Alkoxy, halogen, CN, and NO 2 selected from the group consisting of R 16 is H, optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 selected from the group consisting of cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R 17a and R 17b are each independently H, optionally substituted C, 1 ~C 6 Alkyl, optionally substituted C 3 ~C 8 selected from the group consisting of cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl; R 18a and R 18b are each independently H and optionally substituted C 1 ~C 6 alkyl, A 3 is optionally substituted phenyl, A 4 is optionally substituted phenyl; A compound, or a salt, solvate, isotopologue, prodrug, stereoisomer, or tautomer thereof, or any mixture thereof.

2. Each 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, when present, independently is selected from the group consisting of C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 3 Haloalkoxy, phenoxy, halogen, CN, NO 2 , OH, N(R')(R''), C(=O)R', C(=O)OR', OC(=O)OR', C(=O)N(R')(R''), S(=O) 2 N(R')(R''), N(R')C(=O)R'', N(R')S(=O) 2 R'', C 2 ~C 8 optionally substituted with at least one substituent selected from the group consisting of heteroaryl, and phenyl optionally substituted with at least one halogen; Each of R' and R'' is independently H, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 6 selected from the group consisting of haloalkyl, benzyl, and phenyl; The compound of claim 1.

3. The compound of claim 1 or 2, which is a compound of formula (I) selected from the group consisting of:

4. R 1 The compound of any one of claims 1 to 3, wherein is H.

5. R 2 is H, F, Br, CN, C(=O)OH, C(=O)NH 2 5. The compound of any one of claims 1 to 4, wherein the compound is selected from the group consisting of: C(=O)NHMe, C(=O)NHOH, and C(=NH)NH(OH).

6. (a) R 3a , R 3b , R 3c , R 3d , and R 3e at least one selected from is H; (b) R 3a , R 3b , R 3c , R 3d , and R 3e at least two selected from are H; (c) R 3a , R 3b , R 3c , R 3d , and R 3e at least three selected from the following are H; (d) R 3a , R 3b , R 3c , R 3d , and R 3e at least four selected from are H; and (e) R 3a , R 3b , R 3c , R 3d , and R 3e Each of the following is H The compound according to any one of claims 1 to 5, wherein the compound satisfies at least one of the following conditions:

7. T, 7. The compound of any one of claims 1 to 6, selected from the group consisting of:

8. R 4 H, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (CH 2 ) 3 N(CH 3 ) 2 , C(=O)CH 3 , phenyl, at least one C 1 ~C 6 Alkyl-substituted benzyl; and -CH 2 CH 2 CH 2 8. The compound of any one of claims 1 to 7, wherein the compound is selected from the group consisting of O (phenyl substituted with at least one halogen).

9. R 4 but, 8. The compound of any one of claims 1 to 7, selected from the group consisting of:

10. A 1 but, H;C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Haloalkoxy, C 1 ~C 3 C optionally substituted with haloalkyl 3 ~C 8 Cycloalkyl, phenoxy, halogen, and NO 2 phenyl, substituted with at least one substituent selected from the group consisting of: 2 ~C 6 phenyl fused to a heterocycloalkyl; and C 1 ~C 6 may be substituted with alkyl, or 2 ~C 5 optionally fused with heteroaryl, C 2 ~C 8 Heteroaryl 10. The compound of any one of claims 1 to 9, selected from the group consisting of:

11. A 1 but, 11. The compound of any one of claims 1 to 10, selected from the group consisting of:

12. L 1 Ga-CH 2 12. The compound of any one of claims 1 to 11, wherein:

13. L 2 is a bond, -C(=O)-, -C(=S)-, S(=O) 2 -, -CH 2 -, 13. The compound of any one of claims 1 to 12, selected from the group consisting of:

14. X 1 , bond, O, and NR 7 14. The compound of any one of claims 1 to 13, selected from the group consisting of:

15. R 7 15. The compound of claim 14, wherein is selected from the group consisting of H and Me.

16. R 5 but, 16. The compound of any one of claims 1 to 15, selected from the group consisting of:

17. 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-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-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid; 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((1-Isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid; N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)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; (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; 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 (Z)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide 17. The compound of any one of claims 1 to 16, selected from the group consisting of:

18. 3. The compound of claim 1 or 2, which is a compound of formula (II).

19. R 8 19. The compound of claim 18, wherein is selected from the group consisting of isopropyl and phenyl.

20. R 9a , R 9b , R 9c , and R 9d is each independently selected from the group consisting of H, tert-butyl, and trifluoromethyl.

21. A 2 but, 21. The compound of any one of claims 18 to 20, selected from the group consisting of:

22. (a) Z 1 is N and Z 2 , Z 3 , and Z 4 At least one of the following is CH: (b) Z 1 is N and Z 2 , Z 3 , and Z 4 At least two of the (c) Z 1 is N and Z 2 , Z 3 , and Z 4 each of which is CH; (d) Z 2 is N and Z 1 , Z 3 , and Z 4 At least one of the following is CH: (e) Z 2 is N and Z 1 , Z 3 , and Z 4 At least two of the (f) Z 2 is N and Z 1 , Z 3 , and Z 4 Each of the above is CH.

21. The compound according to any one of claims 17 to 20, wherein

23. X 2 23. The compound of any one of claims 18-22, wherein is selected from the group consisting of -O- and -NH-.

24. R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , and R 11h is independently selected from the group consisting of H and methoxy.

25. R 12a , R 12b , and R 12c are each independently H, methyl, and C(=O)O(C(CH 3 ) 3 25. The compound of any one of claims 18 to 24, selected from the group consisting of:

26. R 10 But tert-butyl, 26. The compound of any one of claims 18 to 25, selected from the group consisting of:

27. 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 -methyl terephthalamide; 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 -methyl terephthalamide; 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)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamimidoyl)picolinamido)-3-methoxyphenyl)-N 4 -methyl terephthalamide; 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 27. The compound of any one of claims 1-2 and 18-26, selected from the group consisting of:

28. 3. The compound of claim 1 or 2, which is a compound of formula (III).

29. The compound of formula (III) 29. The compound of claim 28, selected from the group consisting of:

30. (a) R 15a , R 15b , and R 15c At least one of the following is H: (b) R 15a , R 15b , and R 15c at least two of are H, and (c) R 15a , R 15b , and R 15c Each of the following is H 30. The compound of claim 28 or 29, wherein:

31. R 16 However, benzyl and 31. The compound of any one of claims 28 to 30, selected from the group consisting of:

32. R 17a and R 17b is each independently H.

33. R 18a and R 18b is each independently selected from the group consisting of H and Me.

34. A 3 but, 34. The compound of any one of claims 28 to 33, selected from the group consisting of:

35. A 4 but, 35. The compound of any one of claims 28 to 34, wherein:

36. 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 36. The compound of any one of claims 1-2 and 28-35, selected from the group consisting of:

37. 37. A pharmaceutical composition comprising a compound of any one of claims 1 to 36 and a pharmaceutically acceptable carrier.

38. A method for treating, preventing, and / or ameliorating endometriosis in a subject in need thereof, comprising administering to the subject at least one neurotrophin receptor tyrosine kinase (NTRK) inhibitor, or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

39. 39. The method of claim 38, wherein at least one selected from the group consisting of chronic pelvic pain, inflammation, and infertility is treated, prevented, and / or ameliorated in the subject.

40. 40. The method of claim 38 or 39, wherein the subject is female.

41. A method for treating, preventing, and / or ameliorating cancer in a subject in need thereof, comprising administering to the subject at least one neurotrophin receptor tyrosine kinase (NTRK) inhibitor, or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

42. A method of treating, preventing, and / or ameliorating pain in a subject in need thereof, comprising administering to the subject at least one neurotrophin receptor tyrosine kinase (NTRK) inhibitor, or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

43. The method of any one of claims 38 to 42, wherein the subject has overexpression of at least one selected from the group consisting of neurotrophin receptor tyrosine kinase 1 (NTRK1), neurotrophin receptor tyrosine kinase 2 (NTRK2), and neurotrophin receptor tyrosine kinase 3 (NTRK3).

44. The method of any one of claims 38 to 44, wherein at least one selected from the group consisting of NTRK1, NTRK2, and NTRK3 is inhibited in the subject.

45. The method of any one of claims 38 to 44, wherein a fusion gene comprising at least one selected from the group consisting of NTRK1, NTRK2, and NTRK3 is overexpressed in the subject.

46. 46. ​​The method of claim 45, wherein the product of the fusion gene is inhibited in the subject.

47. The method of any one of claims 38-46, wherein the NTRK inhibitor comprises a compound of any one of claims 1-35, or wherein the pharmaceutical composition thereof comprises the pharmaceutical composition of claim 36.

48. The method of any one of claims 38 to 47, wherein the NTRK inhibitor is an NTRK2 inhibitor.

49. The method of claim 48, wherein the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK1 and / or NTRK3.

50. 50. The method of any one of claims 38-49, wherein said at least one NTRK2 inhibitor is selected from the group consisting of staurosporine, larotrectinib, entrectinib, ceritrectinib, repotrectinib, and PF-06273340.

51. The method of any one of claims 38 to 50, wherein the subject is a mammal.

52. 52. The method of claim 51, wherein the mammal is a human.

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