Neurotrophic receptor tyrosine kinase (NTRK) inhibitors and methods of use thereof

Abstract

The present disclosure relates to compounds and pharmaceutical compositions thereof that inhibit one or more members of the neurotrophic receptor tyrosine kinase (NTRK) family (i.e., NTRK1, NTRK2 and / or NTRK3). In another aspect, the disclosure provides a method of treating, preventing and / or ameliorating at least one disease and / or disorder selected from endometrial tissue ectopic, 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 disclosure and / or a pharmaceutical composition of the disclosure.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 USC §119(e) to U.S. Provisional Patent Application No. 63 / 393,557, filed on July 29, 2022 (which is incorporated herein by reference in its entirety). Background Art

[0003] The human genome encodes 538 protein kinases, most of which have important functions and are involved in the pathogenesis of many diseases. Small molecule inhibition of the enzymatic activity of kinases is an attractive and tractable approach to treat diseases. Currently, about 73 kinase inhibitors are approved by the U.S. Food and Drug Administration (FDA) for the treatment of various diseases, indicating that kinase inhibition is a proven therapeutic approach with the opportunity for great progress and advancement.

[0004] Endometriosis is a debilitating inflammatory disease associated with dysmenorrhea, dyspareunia and menorrhagia, leading to infertility and an increased incidence of endometrioid and clear cell ovarian cancer. In women with endometriosis, endometrial tissue enters the peritoneal cavity via retrograde menstruation, resulting in the attachment and continued growth of endometrial tissue outside the uterine cavity. The disease affects approximately 190 million women (approximately 10%) aged 15-49 years worldwide.

[0005] Women with endometriosis typically endure the painful symptoms of the disease for about 10 years before receiving a conclusive diagnosis. Furthermore, even after diagnosis, available treatments for endometriosis are limited and often ineffective in the long term. For example, surgical removal of endometriotic implants is not a complete cure, as the lesions and associated pain typically recur. The debilitating pain of endometriosis and the myriad of associated side effects prevent women from experiencing a productive and vibrant life in the prime of their lives.

[0006] Therefore, there is an urgent need in the art for compositions and methods of use for treating, preventing and / or improving endometrial tissue ectopic tissue. The present disclosure addresses this need. Summary of the invention

[0007] In one aspect, the present disclosure provides 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 Defined elsewhere in this document:

[0008]

[0009] In another aspect, the present disclosure provides a compound of formula (Ia), or a salt, solvate, isotopomer, 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 Defined elsewhere in this document:

[0010]

[0011] In another aspect, the present disclosure provides a compound of formula (Ib), or a salt, solvate, isotopomer, 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 Defined elsewhere in this document:

[0012]

[0013] In another aspect, the present disclosure provides a compound of formula (Ic), or a salt, solvate, isotopomer, 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 Defined elsewhere in this document:

[0014]

[0015] In another aspect, the present disclosure provides a compound of formula (Id), or a salt, solvate, isotopomer, 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 5Defined elsewhere in this document:

[0016]

[0017] In another aspect, the present disclosure provides a compound of formula (Ie), or a salt, solvate, isotopomer, 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 Defined elsewhere in this document:

[0018]

[0019] In another aspect, the present disclosure provides a compound of formula (If), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof, wherein L 1 , L 2 , R 3a , R 3b , R 4 and R 5 Defined elsewhere in this document:

[0020]

[0021] In another aspect, the present disclosure provides a compound of formula (Ig), or a salt, solvate, isotopomer, 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 Defined elsewhere in this document:

[0022]

[0023] In another aspect, the present disclosure provides a compound of formula (II), or a salt, solvate, isotopomer, 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 Defined elsewhere in this document:

[0024]

[0025] In another aspect, the present disclosure provides a compound of formula (III), or a salt, solvate, isotopomer, 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 Defined elsewhere herein.

[0026]

[0027] In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (II) or (III) and a pharmaceutically acceptable carrier.

[0028] In another aspect, the present disclosure provides a method for treating, preventing and / or ameliorating endometrial tissue ectopic 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 the NTRK inhibitor and a pharmaceutically acceptable carrier.

[0029] In another aspect, the present disclosure provides methods 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 neurotrophic receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

[0030] 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 neurotrophic receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

[0031] In certain embodiments, the NTRK inhibitor is a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (II), or (III).

[0032] The NTRK2 inhibitor is selected from staurosporine, entrectinib, selitrectinib, reprotrectinib and PF-06273340.

[0033] In certain embodiments, the NTRK inhibitor is an NTRK2 inhibitor.

[0034] 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 DESCRIPTION OF THE DRAWINGS

[0035] The drawings generally illustrate various embodiments of the present application by way of example and not by way of limitation.

[0036] Figure 1A-1B The identification of NTRK2 as a therapeutic target for endometrial tissue ectopic uterus was demonstrated. By gene expression profiling, NTRK2 isoform NM_006180 ( Figure 1A ) and NM-001007097( Figure 1B NTRK2 overexpression was identified in 14 samples of endometrial tissues obtained from normal women (control endometrium, CE, n=43), women with endometriosis (endometriosis patients, PE, n=104), and endometriotic lesions (ovarian endometrioma, OMA, n=28; deeply infiltrating endometriosis, DiE, n=91; peritoneal endometriosis, PeL, n=79). NTRK2 overexpression was also confirmed in three other endometriosis datasets, GSE25628, GSE23339, and GSE7305 (fold change >1.4, p<0.05).

[0037] Figures 2A-2K showed overexpression and activity of NTRK2 in stromal cells of endometriotic lesions. Figure 2A Western blot analysis showed that NTRK2 was more elevated in lysates from ectopic peritoneal lesions and ovarian endometriomas compared with eutopic normal endometrium or eutopic endometrium from patients with endometrial ectopic tissue. Figure 2B-2G: Immunohistochemistry of NTRK2 and negative control (NC) showed staining of stromal and epithelial cells in peritoneal endometriotic lesions. Similar results were observed in endometriotic lesions caused by endometrioma and rectal endometriosis. Figures 2H-2J : qRT-PCR showed that the induction of inflammatory genes PTGS2 / COX2, IL6, and IL8 mediated by PGE2 was reduced after NTRK2 was knocked out in primary stromal cells from endometrioma. Figure 2K : Western blot analysis of endometriotic stromal cells treated with siNTRK2 ± PGE2 showed that PGE2-induced CREB phosphorylation was inhibited after NTRK2 siRNA treatment.

[0038] Figure 3 Indicating that NTRK2 variants are associated with endometriosis. Analysis of 36,697 endometriosis cases and 116,071 controls in the FinnGen database identified 20 NTRK2 variants associated with endometriosis (i.e., -log 10 p value ≥ 3; p < 0.001). Note that 182 NTRK2 variants were found in this range: 0.001 < p < 0.01. Variants within the NTRK2 gene boundary are shaded darker than variants upstream or downstream of the NTRK2 gene boundary.

[0039] Figure 4 Provide the sequence of steps for using the DEC-Tec platform. (1) Generate compounds linked to DNA using key chemical reactions; (2) Prepare a library pool of >6 billion DNA-encoded drug-like compounds, each with a "DNA barcode"; (3) Perform affinity selection of the library against his-tagged protein; (4) Capture the his-tagged protein with nickel beads, where small molecules bind to the protein; (5) Separate the protein from unbound compounds; (6) Sequence the DNA barcode and perform informatics analysis to decode the molecular structures of putative selective, drug-like "hits"; and (7) Resynthesize the "hits" with / without DNA tags to test binding / inhibition.

[0040] Figure 5A-5BThe non-limiting use of the DEC-Tec platform to identify NTRK2 binders is shown. Parallel DEC-Tec selections were performed with NTRK2, without NTRK2 (control), or in the presence of a promiscuous kinase inhibitor, staurosporine (not shown). The enrichment of each library member from these selections was compared (measured by normalized z-scores). A similar series of compounds was significantly enriched in the NTRK2-only selection, but not in the control or NTRK2+staurosporine selections, consistent with competitive ligand binding. The selectors CDD-2262 and analog CDD-2330 are potent and metabolically stable molecules.

[0041] Figure 6A-6B Show live cell junction ( Fig. 6A ) idea and NTRK2 example ( Figure 6B ). Fig. 6A : Description of Promega's NanoBRET target engagement system, according to its website. The system involves cell-based competitive displacement of a fluorescent NanoBRET tracer that reversibly binds to a NanoLuc fusion protein. Test compounds displace the tracer based on their affinity for the target and reduce the loss of the NanoBRET signal. Figure 6B : Example of use of Promega's NTRK2 NanoBRET cell-based system. Individual NTRK2 compounds (Cpd) were assayed in kinase assays and cells. Multiple NTRK2 compounds entered cells and were potent nanomolar inhibitors in these assays (% normalized to control no Cpd). Staurosporine is a promiscuous kinase inhibitor and was a positive control in these tests.

[0042] Figure 7A-7B TREEspot showing KINOMEscan binding data for CDD-2330 across the entire human kinome phylogenetic tree TM express( Fig. 7A ) and Z'-LYTE indicating that CDD-2330 has low nanomolar affinity for the NTRK subfamily TM Kinase screening assay ( Figure 7B ). Fig. 7A : The larger the circle, the higher the ligand binding affinity; even when tested at 1 μM concentration, CDD-2330 is highly specific for NTRK1, NTRK2, and NTRK3 with minimal off-target binding. Figure 7B : Utilizing ThermoFisher Z'-LYTE TM In the screening assay, kinase specificity for the NTRK subfamily was observed.

[0043] Figures 8A-8BProvided are studies showing that CDD-3031 is effective in mouse liver microsomes (MLM) ( Fig. 8A ) and human liver microsomes ( Figure 8B ) in the metabolic stability diagram.

[0044] Figures 9A-9B Mouse brain showing CDD-2330 ( Fig.9A ) and testicles ( Fig. 9B ) distribution. Mice (n=3 per time point) were treated intraperitoneally with CDD-2330 and brain, testis and blood samples were collected. Samples were processed and analyzed by LC-MS.

[0045] Figures 10A-10C The results showed that hydroxyzine ( Fig. 10A ), Chlorpromazine ( Fig. 10B ) and CDD-3031( Fig. 10C ) distribution, indicating low brain penetration.

[0046] Figures 11A-11B Display CDD-2330( Fig.11A ) and CDD-3031( Fig. 11B ) Pharmacokinetics in mice. CDD-2330 was dissolved in 10% DMSO + 0.5% methylcellulose at 5 mg / mL. CDD-2330 was delivered orally to mice (n=4) at 50 mg / kg. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h. Samples were analyzed by LC-MS, and the concentration of CDD-2330 was quantified using a standard curve (range: 0-10 μM). CDD-3031 was administered by oral gavage at a dose of 50 mg / kg. Blood samples were collected at 0, 0.83, 0.167, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h.

[0047] Figures 12A-12C NTRK2 is shown to promote pro-inflammatory signaling and pain in endometriosis. Fig. 12A : Estrogen secreted by ovarian and endometriotic lesions signals to macrophages and nerve fibers, respectively, including the production of BDNF / NT-3 and proinflammatory cytokines. Fig. 12B :At the cellular level, our studies show that proinflammatory prostaglandin E2 (PGE2) signals via the EP2 / EP4 receptors on endometriotic stromal cells, inducing CREB (pCREB) phosphorylation and activation. Activated CREB acts on the PTGS2 promoter, producing a positive feedback mechanism, leading to increased inflammation. PGE2 signaling also stimulates PKA / PKC signaling to induce BDNF and NTF3 expression. Fig. 12CEndometriotic stromal cells were pre-treated with 1 μM entrectinib or various doses of CDD-2262 and then stimulated with 1 μM PGE2 for 6 h. The gene expression of PTGS2 was quantified by quantitative real-time PCR (RT-PCR).

[0048] Fig.13 Provided are the chemical structures of metabolites of CDD-2330 in mouse plasma.

[0049] Fig.14 A schematic diagram is provided depicting the experimental procedures for studies utilizing the endometrial ectopic mouse model described herein.

[0050] Figures 15A-15E Provides photographs showing that CDD-2737 reduces lesion number and size in a mouse model of endometrial ectopic tissue ( Figures 15A-15C ) and Figure ( Figures 15D-15E ).

[0051] Figures 16A-16B Graphs are provided demonstrating that CDD-2737 provides no total or serum effects on liver and kidney.

[0052] Figures 17A-17F The robust efficacy of inhibitory compounds of the present disclosure, exemplified by CDD-3132, as NTRK2 inhibitors in inhibiting the growth of endometriotic lesions in mice is depicted. Fig.17A A schematic overview of the experiments performed is provided. Figures 17B-17C Provides a control showing administration ( Fig. 17B ) or CDD-3132 (10 mg / kg / day) ( Fig. 17C ). Figures 17D-17F The data provided show the number of lesions per mouse ( Fig.17D ), lesion volume ( Fig.17E ) and lesion quality ( Fig.17F ) in the table below.

[0053] Figures 18A-18B Provided by H&E staining ( Fig.18A ) or confocal microscopy ( Fig.18B ) of lesions excised from mice administered vehicle or CDD-3132, demonstrating that NTRK2 inhibitors reduce proliferation and inflammation associated with endometriotic lesions.

[0054] Fig.19Provided are photographs of lesions excised from mice administered CDD-3031, CDD-3119, and PF-06273340 (10 mg / kg).

[0055] Figures 20A-20B Provided are graphs depicting total liver ( Fig. 20A ) and kidney( Fig. 20B ) weights, demonstrating that NTRK2 inhibitors had no significant effect on liver and kidney weights in mice treated for 14 days with certain compounds, including CDD-3031, CDD-3119, and CDD-3132. DETAILED DESCRIPTION

[0056] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are partially illustrated in the accompanying drawings. Although the 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 claims to the disclosed subject matter.

[0057] Throughout this document, values ​​expressed in range format should be interpreted in a flexible manner to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or sub-ranges contained within the range, as if each value and sub-range were explicitly stated. 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 sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. Unless otherwise indicated, the statement "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise indicated, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z".

[0058] In this document, unless the context clearly dictates otherwise, the terms "a", "an", or "the" are used to include one or more. Unless otherwise indicated, the term "or" is used to refer to a non-exclusive "or". The statements "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". In addition, it should be understood that the expressions or terms used herein are for descriptive purposes only and not for limiting purposes unless otherwise defined. The use of any section headings is to assist in reading this document and should not be construed as limiting; information related to the section headings may appear within or outside of that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, just as if incorporated by reference individually.

[0059] In the methods described herein, the actions can be performed in any order unless a time or order of operations is explicitly stated. In addition, specified actions can be performed simultaneously unless explicit claim language states that they are performed separately. For example, a claimed action of doing X and a claimed action of doing Y can be performed simultaneously in a single operation, and the resulting process will fall within the literal scope of the claimed method.

[0060] definition

[0061] As used herein, the term "about" can allow for a certain degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of the stated value or the limits of a stated range, and includes the exact stated value or range.

[0062] As used herein, the term "about" can allow for a certain degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of the stated value or the limits of a stated range, and includes the exact stated value or range.

[0063] As used herein, the term "acyl" refers to a group containing a carbonyl moiety, wherein the group is bound via a carbonyl carbon atom. The carbonyl carbon atom is bound 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, heteroaralkyl, or similar group. The acyl group may include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bound to the carbonyl group. The acyl group may include a double bond or a triple bond within the meaning of this article. An example of an acyl group is acryloyl. Acyl groups may also include heteroatoms within the meaning of this article. An example of an acyl group within the meaning of this article is nicotinoyl (pyridyl-3-carbonyl). Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl, etc. When a group containing a carbon atom bound to a carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. An example is trifluoroacetyl.

[0064] The term "alkenyl" as used herein refers to straight and branched chains and cyclic alkyl groups as defined herein, except that there is at least one double bond between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms or 2 to about 20 carbon atoms or 2 to 12 carbon atoms or 2 to 8 carbon atoms in various embodiments. 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, etc.

[0065] As used herein, the term "alkoxy" refers to an oxygen atom connected to an alkyl group (including cycloalkyl) as defined herein. Examples of straight chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc. Examples of branched chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, etc. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Alkoxy groups may include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms combined with oxygen atoms, and may further include double bonds or triple bonds, and may also include heteroatoms. For example, allyloxy or methoxyethoxy in the meaning herein are also alkoxy groups, as are methylenedioxy in the case where two adjacent atoms of a structure are substituted with them.

[0066] As used herein, the term "alkyl" refers to straight and branched alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons, 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. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" includes n-alkyl, isoalkyl, and anteisoalkyl, as well as other branched forms of alkyl groups. Representative substituted alkyl groups may be substituted one or more times by any of the groups listed herein, such as amino, hydroxyl, cyano, carboxyl, nitro, sulfenyl, alkoxy, and halogen groups.

[0067] As used herein, the term "alkylene" or "alkylenyl" refers to a divalent saturated aliphatic radical (e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, etc.). In certain embodiments, the term can be considered to be a moiety derived from an alkene by opening a double bond, or a moiety derived from an alkane by removing two hydrogen atoms from the same (e.g., -CH2-) or different (e.g., -CH2CH2-) carbon atoms.

[0068] As used herein, the term "alkynyl" refers to straight and branched alkyl groups, except that there is at least one triple bond between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbons, or in some embodiments 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), etc.

[0069] The term "amine" as used herein refers to primary, secondary and tertiary amines having, for example, the formula N(group)3, wherein each group can independently be H or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, alkylarylamines; R2NH, wherein each R is independently selected, such as dialkylamines, diarylamines, arylalkylamines, heterocyclylamines, etc.; and R3N, wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" also includes ammonium ions as used herein.

[0070] As used herein, the term "amino" refers to -NH2, -NHR, -NR2, -NR3 + Substituents of the form wherein each R is independently selected, and the protonated form of each, except -NR3 which cannot be protonated + Therefore, any compound substituted with an amino group can be regarded as an amine. In the meaning of this article, "amino" can be a primary amino group, a secondary amino group, a tertiary amino group or a quaternary amino group. "Alkylamino" includes monoalkylamino, dialkylamino and trialkylamino.

[0071] The term "aralkyl" as used herein refers to an alkyl group as defined herein, wherein a hydrogen bond or carbon bond of the alkyl group is replaced by a bond of an aryl group as defined herein. Representative aralkyl groups include benzyl and phenethyl, as well as fused (cycloalkylaryl) alkyl groups, such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein, wherein a hydrogen bond or carbon bond of the alkyl group is replaced by a bond of an aryl group as defined herein.

[0072] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group containing no heteroatoms in the ring. Thus, aryl includes, but is not limited to, phenyl, azulenyl, heptenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylene, pyrenyl, naphthyl, In some embodiments, the aryl group contains about 6 to about 14 carbons in the ring portion of the group. As defined herein, the aryl group can be unsubstituted or substituted. Representative substituted aryl groups can be monosubstituted or substituted more than once, such as, but not limited to, phenyl substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring or naphthyl substituted at any one or more of the 2- to 8-positions thereof.

[0073] 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, 2 atm is a pressure of 202 kPa, and so on.

[0074] The term "cycloalkyl" as used herein refers to cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group may have 3 to about 8-12 ring members, and in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Cycloalkyl further includes polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings, such as, but not limited to, decahydronaphthyl, etc. Cycloalkyl groups also include rings substituted with straight or branched alkyl groups as defined herein. Representative substituted cycloalkyl groups may be monosubstituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5- or 2,6-disubstituted cyclohexyl or mono-, di- or tri-substituted norbornyl or cycloheptyl, which may be substituted, for example, with amino, hydroxyl, cyano, carboxyl, nitro, sulfenyl, alkoxy and halogen groups. The term "cycloalkenyl" used alone or in combination means a cyclic alkenyl group.

[0075] "Disease" means a health condition in an animal in which the animal is unable to maintain homeostasis and in which the animal's health will continue to deteriorate if the disease is not ameliorated.

[0076] In contrast, a "disorder" in an animal is a healthy state in which the animal is able to maintain homeostasis, but the animal's health is less favorable than it would be without the disorder. Without treatment, a disorder will not necessarily lead to a further decline in the animal's health.

[0077] A disease or disorder is "alleviated" if the severity of the symptoms of the disease or disorder, the frequency with which the patient experiences such symptoms, or both, is reduced.

[0078] As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide a desired biological result. This result can be a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0079] As used herein, the term "epoxy-functional" or "epoxy-substituted" refers to a functional group wherein an oxygen atom, ie, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system. Examples of epoxy-substituted functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5-epoxypentyl, 2,3-epoxypropoxy, glycidoxypropyl, 2-epoxypropoxyethyl, 3-epoxypropoxypropyl, 4-epoxypropoxybutyl, 2-(epoxypropoxycarbonyl)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.

[0080]

[0046] The terms "halo," "halogen," or "halide" group as used herein, by themselves or as part of another substituent, refer, unless otherwise stated, to a fluorine, chlorine, bromine, or iodine atom.

[0081] As used herein, the term "haloalkyl" group includes monohaloalkyl, polyhaloalkyl, which may have all halogen atoms that are the same or different, and perhaloalkyl in which all hydrogen atoms are replaced by halogen atoms such as fluorine. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.

[0082] The term "heteroaryl" as used herein refers to an aromatic cyclic compound containing 5 or more ring members, one or more of which is a heteroatom, such as but not limited to N, O and S; for example, a heteroaryl ring can have 5 to about 8-12 ring members. A heteroaryl is a type of heterocyclic group with an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring containing two carbon atoms and three heteroatoms, a 6-ring containing two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so on. The sum of the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. Heteroaryl includes, but is not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, iso oxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzo oxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isocyanate The heteroaryl groups may be unsubstituted or substituted with groups as discussed herein. Representative substituted heteroaryl groups may be substituted one or more times with the groups listed herein.

[0083] Other examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thienyl (2-thienyl, 3-thienyl), furanyl (2-furanyl, 3-furanyl), indolyl, Oxazolyl, iso oxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), Azolyl (2- Azolyl, 4- Azolyl, 5- oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridinyl (2-pyridinyl, 3-pyridinyl, 4-pyridinyl), 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), quinolyl, 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 benzo[b]thienyl (2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), 2,3-dihydro-benzo[b]thienyl (2-(2,3-dihydro-benzo[b]thienyl), 3-(2,3-dihydro-benzo[b]thienyl), 4-(2,3-dihydro-benzo[b]thienyl), 5-(2,3-dihydro-benzo[b]thienyl), phenyl), 6-(2,3-dihydro-benzo[b]thienyl), 7-(2,3-dihydro-benzo[b]thienyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzo Azolyl (1-benzo Azolyl, 2-benzo oxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo[b,f]azepin (5H-dibenzo[b,f]azepin-1-yl, 5H-dibenzo[b,f]azepin-2-yl, 5H-dibenzo[b,f]azepin-3-yl, 5H-dibenzo[b,f]azepin-4-yl, 5H- 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl), 10,11-dihydro-5H-dibenzo[b,f]azepin-1-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-2-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-4-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl), etc.

[0084] The term "heteroaralkyl" as used herein refers to an alkyl group as defined herein wherein a hydrogen bond or a carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined herein.

[0085] The term "heterocyclylalkyl" as used herein refers to an alkyl group as defined herein, wherein a hydrogen bond or a carbon bond of the alkyl group as defined herein is replaced by a bond of 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.

[0086] 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, such as, but not limited to, N, O, and S. Therefore, the heterocyclyl group can be a cycloheteroalkyl or heteroaryl group, or if it is polycyclic, it can be any combination thereof. In some embodiments, the heterocyclyl group includes 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. The heterocyclyl group named C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms, etc. Similarly, the C4-heterocyclyl group can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so on. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. The heterocyclyl ring may also include one or more double bonds. The heteroaryl ring is an embodiment of the heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. For example, dioxolane and benzodioxolane ring systems (methylenedioxyphenyl ring systems) are heterocyclic groups within the meaning of this document. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinoline. Heterocyclic groups may be unsubstituted or substituted as discussed herein. Heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, iso oxazolyl, thiazolyl, pyridyl, phenylthio, benzophenylthio, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzo oxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isocyanate oxazolopyridinyl, thiazolyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl, tetrahydroquinolyl, quinoxalinyl and quinazolinyl. Representative substituted heterocyclic groups can be monosubstituted or substituted more than once, such as but not limited to piperidinyl or quinolyl, which are 2-, 3-, 4-, 5- or 6-substituted or disubstituted by those groups listed herein.

[0087] As used herein, the term "hydrocarbon" or "hydrocarbyl" refers to a molecule or functional group that includes carbon atoms and hydrogen atoms. The term may also refer to a molecule or functional group that typically includes both carbon atoms and hydrogen atoms but in which all hydrogen atoms are replaced by other functional groups.

[0088] As used herein, the term "hydrocarbyl" refers to a functional group derived from a linear, branched or cyclic hydrocarbon and may be an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl or any combination thereof. a -C b)alkyl, wherein a and b are integers and mean having any one of a to b carbon atoms. For example, (C1-C4)alkyl means that the alkyl group can be methyl (C1), ethyl (C2), propyl (C3) or butyl (C4), and (C0-C b ) hydrocarbon group means that in certain embodiments there is no hydrocarbon group.

[0089] Unless the context clearly indicates otherwise, the term "independently selected from" as used herein refers to the same, different, or mixed reference groups. Therefore, under this definition, the phrase "X 1 , X 2 and X 3 "independently selected from noble gases" would include, for example, X 1 , X 2 and X 3 All the same, X 1 , X 2 and X 3 All different, X 1 and X 2 Same but X 3 Different situations and other similar arrangements.

[0090] As used herein, the term "monovalent" refers to a substituent that is attached to the substituted molecule via a single bond. When a substituent is monovalent, such as, for example, F or Cl, it is attached to the atom it replaces via a single bond.

[0091] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples may include: oxygen-containing groups, such as alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylates; sulfur-containing groups, such as alkyl and aryl thioether groups; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, S02R, SO2N(R)2, S03R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (CH2) 0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N (R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R and substituted or unsubstituted (C1-C 100 ) hydrocarbyl, wherein R can be hydrogen (in examples including other carbon atoms) or a carbyl moiety, and wherein the carbyl moiety can be substituted or unsubstituted.

[0092] The term "room temperature" as used herein refers to a temperature of about 15°C to 28°C.

[0093] The terms "patient," "subject," or "individual" are used interchangeably herein and refer to any animal or cell thereof, whether in vitro or in situ, amenable to the methods described herein. In non-limiting embodiments, the patient, subject, or individual is a human.

[0094] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material can be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any components of the composition in which it is contained.

[0095] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the administered compound prepared from a pharmaceutically acceptable non-toxic acid or base, including an inorganic acid or base, an organic acid or base, a solvate, a hydrate or a clathrate thereof.

[0096] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and hydrogen sulfates) and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid classes of organic acids, examples of which 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, pamoic 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.

[0097] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts, metal salts including alkali metals, alkaline earth metals and transition metal salts, such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be prepared from the corresponding compounds by reacting, for example, an appropriate acid or base with the compound.

[0098] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle that participates in the delivery or transport of a compound described herein within or to a patient so that it can perform its intended function, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material. Typically, such a construct is delivered 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(s) described herein, and not causing harm 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, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, 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; ethanol; phosphate buffered solutions; and other nontoxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, etc., that are compatible with the activity of the compound(s) described herein and that are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of the compound(s) described herein. Other additional ingredients that may be included in pharmaceutical compositions for use with the methods or compounds described herein are known in the art and described in, for example, Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA) (which is incorporated herein by reference).

[0099] The term "solvent" as used herein refers to a liquid that can dissolve a solid, a liquid, or a gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0100] As used herein, the term "substantially" refers to a large portion 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" may refer to having no or a trace amount, such that the amount of material present does not affect the material properties of the composition including the material, such that the material of the composition is about 0wt% to about 5wt%, or about 0wt% to about 1wt%, or about 5wt% or less, or less than, equal to or greater than about 4.5wt%, 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 0.001wt% or less. The term "substantially free" can mean having trace amounts such that the material of the composition is 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, equal to, or greater than about 4.5 wt %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01 or about 0.001 wt % or less, or about 0 wt %.

[0101] The term "substituted" used herein with a molecule or organic group as defined herein refers to a state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that can be substituted or substituted onto a molecule or an 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, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups, carboxyl groups (including carboxylic acids, carboxylates, and carboxylates); 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, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazines, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be bonded to the substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O(oxo), S(thiocarbonyl), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, S02R, S02N(R)2, S03R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (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 and C(=NOR)R, wherein R can be hydrogen or a carbonyl moiety; for example, R can be hydrogen, (C1-C 100 ) is a hydrocarbon group, an alkyl group, an acyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heterocyclyl group, a heteroaryl group or a heteroarylalkyl group; or wherein the two R groups bound to a nitrogen atom or to adjacent nitrogen atoms may form a heterocyclyl group together with one or more nitrogen atoms.

[0102] "Therapeutic" treatment is treatment administered to a subject exhibiting signs of a pathology with the goal of reducing or eliminating those signs.

[0103] The term "thioalkyl" as used herein refers to a sulfur atom connected to an alkyl group as defined herein. The alkyl group in the thioalkyl group can be straight or branched. Examples of straight chain thioalkyl groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiohexyl, etc. Examples of branched chain alkoxy groups include, but are not limited to, isothiopropyl, secondary thiobutyl, tert-thiobutyl, isothiopentyl, isothiohexyl, etc. The sulfur atom can appear in any suitable position in the alkyl chain, such as the end of the alkyl chain or any position in the alkyl chain.

[0104]

[00136] The terms "treat," "treating," and "treatment" as used herein refer to reducing the frequency or severity of symptoms of a disease or condition experienced by a subject by administering an agent or compound to the subject.

[0105] 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.

[0106] 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.

[0107] The terms "LOXO-101" and "larotrectinib" are used interchangeably herein to refer to (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide.

[0108] The terms "LOXO-195" and "celitinib" are used interchangeably herein to refer to (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosan-1(24),7(12),8,10,18(25),19,22-hepten-17-one. ntacosa-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)-pyridin a-2(1,2)-pyrrolidinacyclooctaphan-8-one.

[0109] The terms "TPX-005" and "ripretinib" 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-hepten-14-one. 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.

[0110] As used herein, the term “PF06273340” refers to N-[5-[[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl]-3-pyridinyl]-5-chloro-2-pyridineacetamide.

[0111] describe

[0112] Neurotrophic receptor tyrosine kinases 1, 2, and 3 (NTRK1, NTRK2, and NTRK3) have been shown to be critical for various aspects of nervous system function, including nociceptive pain. Gene fusions involving 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) and amplify signaling cascades and act as oncogenic drivers.

[0113] In one aspect, the present disclosure relates to the identification of targets for treating patients with endometriosis and inflammation and pain associated with endometriosis. Accordingly, described herein is a bioinformatics analysis of overexpressed kinases in endometriosis tissue, which led to the identification of NTRK2 as a potential therapeutic target for endometriosis.

[0114] As shown here, NTRK2 is upregulated in endometriotic lesions, and silencing of NTRK2 in primary endometriotic stromal cells suppresses proinflammatory gene expression. Furthermore, administration of ANA-12, a selective NTRK2 inhibitor that rapidly crosses the blood-brain barrier leading to antidepressant and anxiolytic effects, leads to regression of endometriotic lesions in mice. These studies suggest that NTRK2 drives endometriosis-associated survival and inflammation.

[0115] The present disclosure further describes the identification, preparation and validation of NTRK2 inhibitors for use in treating, preventing and / or ameliorating endometriosis and / or its symptoms, cancer and pain in a subject.

[0116] Compound

[0117] In one aspect, the present disclosure provides a compound of formula (I), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0118]

[0119] in:

[0120] T is selected from

[0121] R 1 is selected from 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;

[0122] R 2 is selected from 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 ;

[0123] R 3a , R 3b , R 3c , R 3d and R 3e Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0124] R 4 is selected from 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;

[0125] R 5 Selected from H and -X 1 -A 1 ;

[0126] R 6a , R 6b , R 6c and R 6d are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b );

[0127] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0128] L 1 Yes-C(R 6a )(R 6b )-;

[0129] L 2 is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0130] X 1 Selected from bond, O and NR 7 ;

[0131] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl;

[0132] R a , R b and R c each independently selected from 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;

[0133] or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof.

[0134] In certain embodiments, if T is And -L 2 -R 5 If it is -H, then R 4 Not H;

[0135] In another aspect, the present disclosure provides a compound of formula (Ia), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0136]

[0137] in:

[0138] R 1is selected from 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;

[0139] R 2 is selected from 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 ;

[0140] R 3a , R 3b and R 3c Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0141] R 4is selected from 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;

[0142] R 5 Selected from H and -X 1 -A 1 ;

[0143] L 1 Yes-C(R 6a )(R 6b )-;

[0144] X 1 Selected from bond, O and NR 7 ;

[0145] R 6a and R 6b are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b );

[0146] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0147] L 2 is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0148] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl; and

[0149] R a , R b and R c Each is independently selected from 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.

[0150] In certain embodiments, if -L 2 -R 5 If it is -H, then R 4 Not H.

[0151] In another aspect, the present disclosure provides a compound of formula (Ib), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0152]

[0153] in:

[0154] R 1 is selected from 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;

[0155] R 2 is selected from 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 ;

[0156] R 3a , R 3b and R 3c Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0157] R 4 is selected from 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;

[0158] R 5 Selected from H and -X 1 -A 1 ;

[0159] R 6a and R 6b are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b );

[0160] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0161] L 1 Yes-C(R 6a )(R 6b )-;

[0162] L 2 is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0163] X 1 Selected from bond, O and NR 7 ;

[0164] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl;

[0165] Ra , R b and R c Each is independently selected from 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.

[0166] In another aspect, the present disclosure provides a compound of formula (Ic), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0167]

[0168] in:

[0169] R 1 is selected from 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;

[0170] R 3a , R 3b and R 3c Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0171] R 4 is selected from 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;

[0172] R 5 Selected from H and -X 1 -A 1 ;

[0173] R 6a , R 6b , R 6c and R 6d are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(Rb );

[0174] L 1 Yes-C(R 6a )(R 6b )-;

[0175] L 2 is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0176] X 1 Selected from bond, O and NR 7 ;

[0177] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0178] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl;

[0179] R a , R b and R c Each is independently selected from 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.

[0180] In another aspect, the present disclosure provides a compound of formula (I), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0181]

[0182] in:

[0183] R 1 is selected from 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(Ra )(R b )、S(=O)2N(R a )(R b ), CN and NO2;

[0184] R 2 is selected from 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 ;

[0185] R 3a , R 3b and R 3c Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0186] R 4 is selected from 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;

[0187] R 5 Selected from H and -X 1 -A 1 ;

[0188] R 6a , R6b , R 6c and R 6d are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b );

[0189] L 1 Yes-C(R 6a )(R 6b )-;

[0190] L 2 is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0191] X 1 Selected from bond, O and NR 7 ;

[0192] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0193] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl;

[0194] R a , R b and R c Each is independently selected from 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.

[0195] In another aspect, the present disclosure provides a compound of formula (Ie), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0196]

[0197] in:

[0198] R 3a , R 3b , R 3c and R3d Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0199] R 4 is selected from 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;

[0200] R 5 Selected from H and -X 1 -A 1 ;

[0201] R 6a , R 6b , R 6c and R 6d are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b );

[0202] L 1 Yes-C(R 6a )(R 6b )-;

[0203] L 2 is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0204] X 1 Selected from bond, O and NR 7 ;

[0205] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0206] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl;

[0207] R a , Rb and R c Each is independently selected from 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.

[0208] In another aspect, the present disclosure provides a compound of formula (If), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0209]

[0210] in:

[0211] R 3a , R 3b and R 3c Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0212] R 4 is selected from 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;

[0213] R 5 Selected from H and -X 1 -A 1 ;

[0214] R 6a , R 6b , R 6c and R 6d are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b );

[0215] L 1 Yes-C(R 6a )(R 6b )-;

[0216] L 2is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0217] X 1 Selected from bond, O and NR 7 ;

[0218] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0219] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl;

[0220] R a , R b and R c Each is independently selected from 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.

[0221] In another aspect, the present disclosure provides a compound of formula (Ig), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0222]

[0223] in:

[0224] R 3a , R 3b , R 3c , R 3d and R 3e Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0225] R 4is selected from 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;

[0226] R 5 Selected from H and -X 1 -A 1 ;

[0227] R 6a , R 6b , R 6c and R 6d are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b );

[0228] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0229] L 1 Yes-C(R 6a )(R 6b )-;

[0230] L 2 is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0231] X 1 Selected from bond, O and NR 7 ;

[0232] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl;

[0233] R a , R b and R c Each is independently selected from 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.

[0234] In certain embodiments, R 1 It's H.

[0235] 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, R 2 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 It is C(=O)NHOH.

[0236] In certain embodiments, selected from R 3a , R 3b and R 3c At least one of is H. In certain embodiments, the 3a , R 3b and R 3c At least two of are H. In certain embodiments, R 3a , R 3b and R 3c Each of is H. In certain embodiments, selected from R 3a , R 3b , R 3c , R 3d and R 3e At least three of are H. In certain embodiments, the group consisting of R 3a , R 3b , R 3c , R 3d and R 3e At least two of are H. In certain embodiments, the group consisting of R 3a , R 3b , R 3c , R 3d and R 3e At least three of are H. In certain embodiments, the group consisting of R 3a , R 3b , R 3c , R 3d and R 3e At least four of are H. In certain embodiments, R 3a , R 3b , R 3c , R3d and R 3e Each of them is H.

[0237] In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is In certain embodiments, T is

[0238] In certain embodiments, R 4 is H. In certain embodiments, R 4 In certain embodiments, R 4 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 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 is (CH2)3N(CH3)2. In certain embodiments, R 4 is C(=O)CH3. In certain embodiments, R 4 In certain embodiments, R 4 It is a benzyl group substituted by at least one C1-C6 alkyl group.

[0239] In certain embodiments, R 4 yes In certain embodiments, R 4 yes In certain embodiments, R 4 is -CH2CH2CH2O (phenyl substituted with at least one halogen). In certain embodiments, R 4 yes In certain embodiments, R 4 yes In certain embodiments, R 4 yes

[0240] In certain embodiments, A 1 is hydrogen. In certain embodiments, A 1 is phenyl substituted with at least one C1-C6 alkyl group. 1 is phenyl substituted with at least one C1-C6 alkoxy group. 1 is phenyl substituted with at least one C1-C3 haloalkyl. 1 is phenyl substituted with at least one C1-C3 haloalkoxy group. 1 is phenyl substituted with at least one phenoxy group. 1 is phenyl substituted with at least one halogen. 1 is a phenyl group substituted with at least one NO2. 1 is phenyl substituted with at least one C3-C8 cycloalkyl group, which is optionally substituted with at least one C1-C3 haloalkyl group. 1 is C2-C8 heteroaryl. In certain embodiments, A 1 is a C2-C8 heteroaryl substituted with at least one C1-C6 alkyl. 1 is a C2-C8 heteroaryl fused to a C2-C5 heteroaryl. 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes In certain embodiments, A 1 yes

[0241] In certain embodiments, R 6a is H. In certain embodiments, R 6b It's H.

[0242] In certain embodiments, L 1 It is -CH2-.

[0243] 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 In certain embodiments, L 2 yes In certain embodiments, L 2 yes In certain embodiments, L 2 yes

[0244] In certain embodiments, X 1 YesNR 7 In certain embodiments, X 1 In certain embodiments, X 1 In certain embodiments, X 1 Is O. In certain embodiments, X 1 is the key.

[0245] In certain embodiments, R 7 is H. In certain embodiments, R 7 It's me.

[0246] In certain embodiments, R 5 is H. In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes In certain embodiments, R 5 yes

[0247] In certain embodiments, the compound of formula (I) is selected from:

[0248] 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0249] 1-Cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0250] 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea;

[0251] 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0252] 1-cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0253] 1-cyclobutyl-3-(4-nitrophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0254] 1-phenyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0255] 1-Cyclopentyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0256] 1-Cyclopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0257] 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethyl)phenyl)urea;

[0258] 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(3-(trifluoromethyl)phenyl)urea;

[0259] N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide; 5-((cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester;

[0260] 3-(3-chlorophenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)propan-1-amine;

[0261] N,N-Bis(pyrazolo[1,5-a]pyridin-5-ylmethyl)cyclobutanamine;

[0262] 1-(3-(3-chlorophenoxy)propyl)-3-(4-phenoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0263] 1-(3-(3-chlorophenoxy)propyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0264] 3-(4-chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0265] 1-cyclobutyl-3-(4-fluorophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0266] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide;

[0267] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0268] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester;

[0269] 1-cyclobutyl-3-(4-methoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0270] (R)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide;

[0271] (S)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide;

[0272] 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0273] (S)-1-phenyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)ethan-1-amine;

[0274] 1-((3-fluoropyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0275] 1-((3-bromopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0276] 5-((1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0277] 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0278] 5-((1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0279] 5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0280] N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0281] 1-((3-cyanopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0282] 5-((1-isobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0283] 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0284] N-hydroxy-5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboximidamide;

[0285] 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0286] 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0287] 5-((2-(4-isopropylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0288] 5-((N-methyl-3-(4-(trifluoromethoxy)phenyl)propionylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0289] 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0290] 5-((N-isopropyl-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0291] 5-((N-(3-(dimethylamino)propyl)-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0292] 5-((2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0293] 5-((3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0294] 5-((3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0295] 5-((N-methyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0296] 5-((N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0297] 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0298] (R)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0299] (S)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0300] 5-((N-methyl-2-(4-(trifluoromethyl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0301] 5-((N-methyl-2-(3-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0302] 5-((2-(4-(tert-butyl)phenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0303] 5-((2-(4-(tert-butyl)phenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0304] 5-((2-((4-(tert-butyl)phenyl)(methyl)amino)-N-methylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0305] 5-((N-isopropyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0306] 5-((N-isopropyl-2-(4-(prop-1-en-2-yl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0307] 5-((2-(4-acetylphenoxy)-N-isopropylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0308] 5-((2-(4-acetylphenoxy)-N-methylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0309] 5-((N-methyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0310] 2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3-nitrophenyl)acrylamide;

[0311] (S)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3-nitrophenyl)acrylamide;

[0312] (R)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3-nitrophenyl)acrylamide;

[0313] N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide;

[0314] (R)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide;

[0315] (S)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide;

[0316] N-((1H-indol-5-yl)methyl)-N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamide;

[0317] 1-((1H-indol-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0318] 2-((6-(tert-butyl)pyridin-3-yl)amino)-N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide;

[0319] N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-((4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)acetamide;

[0320] 5-((methyl(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)amino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0321] 1-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0322] 1-Cyclopropyl-1-(pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0323] 1-Cyclopropyl-1-(pyrimidin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0324] 1-Cyclopropyl-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0325] 5-((N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0326] 5-((N-(4-(trifluoromethoxy)phenyl)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0327] 5-(((N-isopropyl-4-(trifluoromethyl)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0328] 5-(((N-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4] Oxazine)-6-sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0329] 5-(((N-methyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0330] 5-(((N-isopropyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0331] 5-((N-isopropyl-3-(4-methoxyphenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide);

[0332] (E)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamide)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0333] (Z)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamide)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0334] 5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0335] (E)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; and

[0336] (Z)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide.

[0337] In another aspect, the present disclosure provides a compound of formula (II), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0338]

[0339] in:

[0340] A 2 Selected from

[0341] R 8 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl and optionally substituted phenyl;

[0342] R 9a , R 9b , R 9c and R 9d are each independently selected from 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, CN and NO2;

[0343] R 10 is selected from optionally substituted C1-C6 alkyl,

[0344] R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g and R 11hEach is independently selected from 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 NR a S(=O)2R b ;

[0345] R 12a , R 12b and R 12c are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl;

[0346] L 3 Selected from

[0347] X 2 Selected from O and NR 14 ;

[0348] R 14 is selected from H and optionally substituted C1-C6 alkyl;

[0349] Z 1 Selected from CR 13a and N, Z 2 Selected from CR 13b and N, Z 3 Selected from CR 13c and N, and Z 4 Selected from CR 13d and N,

[0350] Among them, selected from Z 1 , Z 2 , Z 3 and Z 4 At least one of them is N;

[0351] R 13a , R 13b , R 13c and R 13dEach is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2; and

[0352] R a and R b Each is independently selected from 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.

[0353] In certain embodiments, R 8 In certain embodiments, R 8 It is phenyl.

[0354] In certain embodiments, R 9a is H. In certain embodiments, R 9a In certain embodiments, R 9a In certain embodiments, R 9b is H. In certain embodiments, R 9b In certain embodiments, R 9b In certain embodiments, R 9c is H. In certain embodiments, R 9c In certain embodiments, R 9c In certain embodiments, R 9d is H. In certain embodiments, R 9d In certain embodiments, R 9d It is trifluoromethyl.

[0355] In certain embodiments, A 2 yes In certain embodiments, A 2 yes

[0356] In certain embodiments, Z 1 is N and Z 2 , Z 3 and Z 4 In certain embodiments, at least one of Z is CH. 1 is N and Z 2 , Z 3 and Z 4 In certain embodiments, at least two of Z are CH. 1 is N and Z 2 , Z 3 and Z 4In certain embodiments, each of Z is CH. 2 is N and Z 1 , Z 3 and Z 4 In certain embodiments, at least one of Z is CH. 2 is N and Z 1 , Z 3 and Z 4 In certain embodiments, at least two of Z are CH. 2 is N and Z 1 , Z 3 and Z 4 Each of them is CH.

[0357] In certain embodiments, X 2 In certain embodiments, X 2 It is -NH-.

[0358] In certain embodiments, R 14 It's H.

[0359] In certain embodiments, R 11a is H. In certain embodiments, R 11a In certain embodiments, R 11b is H. In certain embodiments, R 11b In certain embodiments, R 11c is H. In certain embodiments, R 11c In certain embodiments, R 11d is H. In certain embodiments, R 11d In certain embodiments, R 11e is H. In certain embodiments, R 11e In certain embodiments, R 11f is H. In certain embodiments, R 11f In certain embodiments, R 11g is H. In certain embodiments, R 11g In certain embodiments, R 11h is H. In certain embodiments, R 11h It's a methoxy group.

[0360] In certain embodiments, R 12a is H. In certain embodiments, R 12a In certain embodiments, R 12a is C(=O)O(C(CH3)3. In certain embodiments, R 12b is H. In certain embodiments, R12b In certain embodiments, R 12b is C(═O)O(C(CH 3 ) 3 ). In certain embodiments, R 12c is H. In certain embodiments, R 12c In certain embodiments, R 12c It is C(=O)O(C(CH3)3).

[0361] In certain embodiments, R 10 In certain embodiments, R 10 yes In certain embodiments, R 10 yes

[0362] In certain embodiments, the compound of formula (II) is selected from:

[0363] N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4- oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)-N 4 -Methylterephthalamide (N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinamido)-3-methoxyphenyl)-N 4 -methylterephthalamide);

[0364] N 1 -(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)-N 4 -methylterephthalamide;

[0365] 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4- Tert-butyl5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl)picolinate;

[0366] 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- tert-Butyl oxadiazol-3-yl)picolinate;

[0367] (Z)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamoylimido)pyridinylamino)-3-methoxyphenyl)-N 4 -methylterephthalamide ((Z)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamimidoyl)picoli namido)-3-methoxyphenyl)-N 4 -methylterephthalamide); and

[0368] (4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- tert-butyl oxadiazol-3-yl)pyridinylamino)-3-methoxyphenyl)carbamate.

[0369] In another aspect, the present disclosure provides a compound of formula (III), or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof:

[0370]

[0371] in:

[0372] R 15a , R 15b and R 15c Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0373] R 16 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl and optionally substituted phenyl;

[0374] R 17a and R 17b are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl;

[0375] R18a and R 18b are each independently selected from H and optionally substituted C1-C6 alkyl;

[0376] A 3 is optionally substituted phenyl; and

[0377] A 4 is optionally substituted phenyl.

[0378] In certain embodiments, the compound of formula (III) is a compound of formula (IIIa):

[0379]

[0380] In certain embodiments, the compound of formula (III) is a compound of formula (IIIb):

[0381]

[0382] In certain embodiments, R 15a , R 15b and R 15c At least one of is H. In certain embodiments, R 15a , R 15b and R 15c At least two of are H. In certain embodiments, R 15a , R 15b and R 15c Each of them is H.

[0383] In certain embodiments, R 16 In certain embodiments, R 16 yes

[0384] In certain embodiments, R 17a is H. In certain embodiments, R 17b It's H.

[0385] 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 It's me.

[0386] In certain embodiments, A3 is In certain embodiments, A 3 yes

[0387] In certain embodiments, A 4 yes

[0388] In certain embodiments, the compound of formula (III) is selected from:

[0389] 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;

[0390] (S)-1-benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1H-benzo[d]imidazole-7-carboxamide; and

[0391] (S)-1-Benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide.

[0392] In certain embodiments, if present, each occurrence of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted benzyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heterocyclyl, and optionally substituted alkylene 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, N O2, 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 by at least one halogen, wherein each occurrence of R' and R" is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl and phenyl.

[0393] Table 1. Exemplary compounds

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409] The compounds described herein may have one or more stereocenters, and each stereocenter may exist independently in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. It should be understood that the compounds described herein include racemic, optically active, regioisomeric and stereoisomeric forms or combinations thereof having therapeutically useful properties as described herein. The preparation of optically active forms is achieved in any suitable manner, including, as non-limiting examples, by resolution of racemic forms using recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In certain embodiments, a mixture of one or more isomers is used 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 mixtures of enantiomers and / or diastereomers. The resolution of compounds and their isomers is achieved by any means, including, as non-limiting examples, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0410] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also referred to as polymorphs), solvates, amorphous phases and / or pharmaceutically acceptable salts of compounds having the structure of any compound (one or more) described herein, as well as metabolites and active metabolites of the same type of activity of these compounds. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates, and the like. In certain embodiments, the compounds described herein exist in solvated forms using pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in non-solvated forms.

[0411] In certain embodiments, the compound(s) described herein may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0412] In certain embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted into a parent drug in vivo. In certain embodiments, after in vivo administration, the prodrug is chemically converted into the biologically active, pharmaceutically active, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized into the biologically active, pharmaceutically active, or therapeutically active form of the compound by one or more steps or processes.

[0413] In certain embodiments, sites on the aromatic ring portion of, for example, the compounds described herein (one or more) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structure can reduce, minimize, or eliminate such metabolic pathways. In certain embodiments, by way of example only, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are deuterium, halogen, or alkyl.

[0414] 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 atomic mass number different from the atomic mass or atomic mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds described herein include, but are not limited to 2 H. 3 H. 11 C. 13 C. 14 C. 36 Cl, 18 F. 123 I. 125 I. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P and 35S. In certain embodiments, isotope-labeled compounds are used in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium provides greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N substitution is useful for examining substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds are prepared by any suitable method or by using an appropriate isotopically labeled reagent in place of an unlabeled reagent.

[0415] In certain embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0416] The compounds described herein, as well as other related compounds having various substituents, are prepared using the methods described herein and as described, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Vols. 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001) and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to introduce the various moieties present in the formulas provided herein.

[0417] The compounds described herein are synthesized using any suitable procedures, starting from compounds available from commercial sources, or prepared using the procedures described herein.

[0418] In some embodiments, protection reactive functional groups such as hydroxyl, amino, imino, thio group or carboxyl are to avoid them from participating in reaction unnecessarily. Protective group is used to block some or all of the reactive parts, and prevents this type of group from participating in chemical reaction until the protective group is removed. In other embodiments, each protective group can be removed by different means. The protective group that cleaves under completely different reaction conditions satisfies the requirement of difference removal.

[0419] In certain embodiments, the protecting group is removed by acid, base, reducing conditions (such as, for example, hydrogenolysis) and / or oxidizing conditions. Groups such as triphenyl, dimethoxytriphenyl, acetal and tert-butyldimethylsilyl are acid-labile, and are used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected by Cbz groups (which can be removed by hydrogenolysis) and alkali-unstable Fmoc groups. Carboxylic acid and hydroxyl reactive moieties are blocked by base-unstable groups (such as, but not limited to, methyl, ethyl and acetyl) in the presence of acid-unstable groups such as tert-butyl carbamate, or by acid and base-stable but hydrolyzable carbamate-blocked amines.

[0420] In certain embodiments, the carboxylic acid and hydroxyl reactive moieties are blocked by hydrolytically removable protective groups such as benzyl, and the amine groups capable of hydrogen bonding with acids are blocked by base labile groups such as Fmoc. The carboxylic acid reactive moieties are protected by conversion to simple ester compounds exemplified herein (including conversion to alkyl esters), or are blocked by oxidatively removable protective groups such as 2,4-dimethoxybenzyl, and the coexisting amino groups are blocked by fluorine-labile carbamate silyl esters.

[0421] Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups because the former are stable and subsequently removed by metal or π acid catalysts. For example, allyl blocked carboxylic acids are deprotected by palladium catalysis in the presence of acid-labile tert-butyl carbamate or base-labile acetate amine protecting groups. Another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, the functional group will be blocked and will not react. Once released from the resin, the functional group can react.

[0422] Typical blocking / protecting groups can 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), p-methoxybenzyl (PMB), triphenylmethyl (trityl), fluorenylmethoxycarbonyl (FMOC).

[0423] A detailed description of other protecting groups and techniques useful for their creation and removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

[0424] Composition

[0425] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0426] Compositions containing the compound (one or more) 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 in 1x PBS.

[0427] In certain embodiments, the composition is formulated for administration routes such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, buccal, urethral, ​​vaginal (e.g., vaginal and perivapal), nasal and rectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. In some embodiments, the composition is formulated as a pill, tablet, gelcap, or capsule for oral administration.

[0428] method

[0429] In one aspect, the present disclosure provides methods for treating, preventing and / or ameliorating endometrial tissue malformation in a subject in need thereof. In certain embodiments, the method comprises administering to the subject a neurotrophic receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0430] In certain embodiments, the NTRK inhibitor is a compound of the disclosure.

[0431] In another aspect, the present disclosure provides a method for treating, preventing and / or ameliorating endometriosis in a subject in need thereof, the method comprising administering a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure to the subject.

[0432] In certain embodiments, at least one selected from chronic pelvic pain, inflammation, and infertility is treated, prevented, and / or ameliorated in a subject.

[0433] In certain embodiments, the subject is female.

[0434] In another aspect, the present disclosure provides methods 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 receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0435] In certain embodiments, the NTRK inhibitor is a compound of the disclosure.

[0436] In another aspect, the present disclosure provides a method for treating, preventing and / or ameliorating cancer in a subject in need thereof, the method comprising administering a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure to the subject.

[0437] In another aspect, the present disclosure provides methods 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 receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising an NTRK inhibitor and a pharmaceutically acceptable carrier.

[0438] In certain embodiments, the NTRK inhibitor is a compound of the disclosure.

[0439] In another aspect, the present disclosure provides a method for treating, preventing and / or ameliorating pain in a subject in need thereof, the method comprising administering a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure to the subject.

[0440] In certain embodiments, neurotrophic receptor tyrosine kinase 1 (NTRK1) is overexpressed in the subject. In certain embodiments, neurotrophic receptor tyrosine kinase 2 (NTRK2) is overexpressed in the subject. In certain embodiments, neurotrophic receptor tyrosine kinase 3 (NTRK3) is overexpressed in the subject.

[0441] In certain embodiments, administration of a disclosed compound and / or disclosed pharmaceutical composition results in inhibition of NTRK1 in a subject. In certain embodiments, inhibition of NTRK1 results in treating, preventing, and / or ameliorating endometrial tissue malformation and / or one or more symptoms thereof, cancer, and / or pain.

[0442] In certain embodiments, administration of a compound of the disclosure and / or a pharmaceutical composition of the disclosure results in inhibition of NTRK2 in a subject. In certain embodiments, inhibition of NTRK2 results in treatment, prevention, and / or amelioration of endometrial tissue malformation and / or one or more symptoms thereof, cancer, and / or pain.

[0443] In certain embodiments, administration of a compound of the disclosure and / or a pharmaceutical composition of the disclosure results in inhibition of NTRK3 in a subject. In certain embodiments, inhibition of NTRK3 results in treatment, prevention, and / or amelioration of endometrial tissue malformation and / or one or more symptoms thereof, cancer, and / or pain.

[0444] In certain embodiments, a fusion gene comprising at least one selected from NTRK1, NTRK2, and NTRK3 is overexpressed in the subject.

[0445] In certain embodiments, the NTRK inhibitor is an NTRK2 inhibitor.

[0446] 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.

[0447] In certain embodiments, the selectivity of a compound for NTRK2 relative to NTRK1 comprises a half-maximal inhibitory concentration (IC) of the compound for NTRK2 of 50 ): Comparison of IC of the same compound against NTRK1 50 In some embodiments, the selectivity of the compound for NTRK2 relative to NTRK1 comprises the following half-maximal inhibitory concentration (IC) of the compound for NTRK2: 50): Comparison of IC of the same compound against NTRK3 50 At least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100 or 1000 times lower.

[0448] 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 ceritinib. In certain embodiments, the NTRK2 inhibitor is ripretinib. In certain embodiments, the NTRK2 inhibitor is PF-06273340.

[0449] In certain embodiments, administration of a compound of the present disclosure and / or a pharmaceutical composition of the present disclosure results in inhibition of a fusion gene product in a subject. In certain embodiments, inhibition of a fusion gene product results in treatment, prevention, and / or improvement of endometrial tissue malposition and / or one or more symptoms thereof, cancer, and / or pain.

[0450] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

[0451] Application / Dosage / Preparation

[0452] The administration regimen may affect what constitutes an effective amount. The therapeutic formulation may be administered to the subject before or after the onset of the disease or disorder. In addition, several separate doses and staggered doses may be administered daily or sequentially, or the dose may be a continuous infusion or a bolus injection. Furthermore, the dose of the therapeutic formulation may be proportionally increased or decreased as indicated by the urgency of the therapeutic or preventive situation.

[0453] The compositions described herein can be administered to a patient using known procedures, in an amount and for a period of time effective to treat a disease or disorder in the patient. The effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the patient's disease or disorder; the patient's age, sex, and weight; and the ability of the therapeutic compound to treat the patient's disease or disorder. The dosage regimen may be adjusted to provide the best therapeutic response. For example, as indicated by the urgency of the treatment situation, several separate doses may be administered daily or the dose may be proportionally reduced. A non-limiting example of an effective dosage range for the therapeutic compounds described herein is about 1 mg / kg to 5,000 mg / kg body weight / day. One of ordinary skill in the art will be able to study the relevant factors and determine the effective amount of the therapeutic compound without undue experimentation.

[0454] Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0455] In particular, the selected dosage level will depend upon a variety of factors, including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and like factors well known in the medical arts.

[0456] A physician (e.g., a physician or veterinarian) with ordinary skills in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start the dosage of the compound described herein used in the pharmaceutical composition at a level lower than required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0457] In a specific embodiment, formulating the compound in dosage unit form is particularly advantageous for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unit dosages for patients to be treated; each unit contains a predetermined amount of a therapeutic compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical vehicle. The dosage unit form of the compound(s) described herein is determined by and is directly dependent on: (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such therapeutic compounds.

[0458] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0459] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof and vegetable oils. Can, for example, be by using coatings such as lecithin, maintain the required particle size and maintain suitable fluidity by using a surfactant in the case of dispersion. Can be achieved by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.) to prevent microbial effects. In many cases, it is preferred to include isotonic agents in the composition, such as sugar, sodium chloride or polyols such as mannitol and sorbitol. Can extend the absorption of injectable compositions by including an agent such as aluminum monostearate or gelatin that delays absorption in the composition.

[0460] In certain embodiments, the compositions described herein are administered to a patient in an amount ranging from 1 to 5 or more times per day. In other embodiments, the compositions described herein are administered to a patient in a dosage range including, but not limited to, once a day, once every two days, once every three days to once a week and once every two weeks. It will be apparent to those skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual, depending on many factors, including, but not limited to, age, disease or disorder to be treated, sex, overall health, and other factors. Therefore, the administration of the compounds and compositions described herein should not be construed as being limited to any particular dosage regimen, and the exact dosage and composition to be administered to any patient is determined by the attending physician in consideration of all other factors of the patient.

[0461] The range of the compound(s) described herein for administration can be from about 1 μg to about 10,000 mg, from about 20 μg to about 9,500 mg, from about 40 μg to about 9,000 mg, from about 75 μg to about 8,500 mg, from about 150 μg to about 7,500 mg, from about 200 μg to about 7,000 mg, from about 350 μg to about 6,000 mg, from about 500 μg to about 5,000 mg, from about 750 μg to about 4,000 mg. g, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole and partial increments therebetween.

[0462] In some embodiments, the dose of the compounds described herein is from about 1 mg to about 2,500 mg. In some embodiments, the dose 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 and partial increments thereof.

[0463] In certain embodiments, the compositions described herein are packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient.

[0464] The preparation can be mixed with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier materials suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral or any other suitable administration known in the art. The pharmaceutical preparation can be sterilized and, if necessary, can be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure buffers, colorants, spices and / or aromatic substances, etc. If necessary, it can also be combined with other active agents such as other analgesics.

[0465] The administration routes of any composition described herein include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual or topical. The compounds used in the compositions described herein can be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, buccal, urethral, ​​vaginal (e.g., vaginal and perivasal), nasal and rectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation and topical administration.

[0466] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, caplets, 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 specific formulations and compositions described herein.

[0467] Oral administration

[0468] For oral administration, tablets, dragees, liquids, drops, suppositories or capsules, caplets and caplets are particularly suitable. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from inert, non-toxic, pharmaceutical excipients suitable for making tablets. Such excipients include, for example, inert diluents such as lactose; granulating agents and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or they may be coated by known techniques to enhance or delay the release of the active ingredient. Oral preparations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0469] For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., polyvinyl pyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silicon dioxide); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, suitable methods and coating materials such as those available from Colorcon, West Point, Pa. (e.g., OPADRY TM OY, OYC, organic enteric-coated OY-P, aqueous enteric-coated OY-A, OY-PM and OPADRY TM OPADRY (White, 32K18400) TMThe film coating system coats the tablet. Liquid preparations for oral administration may be in 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); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters or ethanol); and preservatives (e.g., methyl or propyl paraben or sorbic acid).

[0470] Parenteral administration

[0471] For parenteral administration, the compounds described herein can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for bolus administration and / or continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles can be used, optionally containing other formulating agents such as suspending agents, stabilizers and / or dispersing agents.

[0472] The sterile injectable form of the composition described herein can be an aqueous or oily suspension. These suspensions can be prepared according to techniques known in the art, using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. Sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are used to prepare injectables, and natural pharmaceutically acceptable oils such as olive oil or castor oil, especially its polyoxyethylated form, are also used to prepare injectables. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph.Helv or similar alcohols.

[0473] Other forms of administration

[0474] Additional dosage forms suitable for use with the compounds (one or more) and compositions described herein include dosage forms as described in U.S. Pat. Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compounds (one or more) and compositions described herein also include dosage forms as described in U.S. Patent Application Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compounds (one or more) and compositions described herein also include those described in PCT Application Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0475] Controlled release formulations and drug delivery systems

[0476] In certain embodiments, the formulations described herein may be, but are not limited to, short-term, rapid-offset, and controlled, e.g., sustained release, delayed release, slow release, and pulsatile release formulations.

[0477] The term sustained release when used in its conventional sense refers to a pharmaceutical formulation that provides a gradual release of a drug over an extended period of time, which, although not necessarily, results in a substantially constant blood level of the drug over an extended period of time. This period of time may be as long as a month or more, and should be a longer release time than the same amount of the dose administered in bolus form.

[0478] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that provides the compound with sustained release properties. Thus, the compound used with the method (s) described herein can be administered in microparticle form, such as by injection, or in wafer or disc form by implantation.

[0479] In some cases, the dosage form used can be provided as a sustained or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes or microspheres, or combinations thereof, to provide the desired release profile at different ratios. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be easily selected for use with the pharmaceutical compositions described herein. Thus, the compositions and dosage forms described herein encompass single unit dosage forms suitable for oral administration, such as tablets, capsules, caplets and caplets suitable for controlled release.

[0480] Most controlled-release drug products share a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of optimally designed controlled-release formulations in medical therapy is characterized by using the least amount of drug substance to cure or control a condition in the shortest amount of time. Advantages of controlled-release formulations include prolonged drug activity, reduced dosage frequency, and improved patient compliance. In addition, controlled-release formulations can be used to affect the time to onset of action or other characteristics, such as blood concentrations of the drug, which can affect the occurrence of side effects.

[0481] Most controlled-release formulations are designed to initially release a certain amount of drug, rapidly producing the desired therapeutic effect, and then gradually and continuously release additional amounts of drug to maintain 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 metabolized and excreted by the body.

[0482] The controlled release of active ingredients can be stimulated by various induction items, such as pH, temperature, enzymes, water or other physiological conditions or compounds. The term "controlled release component" is defined herein as one or more compounds, including but not limited to polymers, polymer matrices, gels, permeable membranes, liposomes or microspheres or combinations thereof that promote the controlled release of active ingredients. In some embodiments, the compound (one or more) described herein is administered to a patient alone or in combination with other agents using a sustained release formulation. In some embodiments, the compound (one or more) described herein is administered to a patient alone or in combination with other agents using a sustained release formulation.

[0483] The term delayed release when used herein in its conventional sense refers to a drug formulation that provides initial release of the drug after a delay after drug administration, and although not required, includes delays of about 10 minutes up to about 12 hours.

[0484] The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides for release of the drug in a manner that produces a pulsatile plasma profile following drug administration.

[0485] The term immediate release is used herein in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after administration of the drug.

[0486] As used herein, short-term refers to any period of time after drug administration, 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 after drug administration, and any or all full or partial increments thereof.

[0487] As used herein, rapid failure refers to any period of time after drug administration, 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 full or partial increments thereof.

[0488] Drug administration

[0489] The therapeutically effective amount or dosage of the compounds described herein depends on the age, sex and weight of the patient, the patient's current medical condition, and the progression of the disease or disorder being treated in the patient. A skilled artisan will be able to determine the appropriate dosage based on these and other factors.

[0490] Suitable doses of the compounds described herein may be in the range of about 0.01 mg to about 5000 mg per day, such as about 0.1 mg to about 1000 mg per day, for example about 1 mg to about 500 mg per day, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dose or multiple doses, for example 1 to 4 times or more per day. When multiple doses are used, the amounts of each dose may be the same or may be different. For example, a dose of 1 mg per day may be administered in two 0.5 mg doses, with an interval of about 12 hours between doses.

[0491] It should be understood that, in non-limiting examples, the amount of compound administered daily can be administered once every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, if administered every other day, a daily dose of 5 mg may be initiated on Monday, the first subsequent daily dose of 5 mg may be administered on Wednesday, the second subsequent daily dose of 5 mg may be administered on Friday, and so on.

[0492] In the case where the patient's condition does improve, at the doctor's discretion, the compound (or compounds) described herein may be optionally continued; alternatively, the dose of the administered drug may be temporarily reduced or the dose of the administered drug may be suspended for a period of time (i.e., a "drug holiday"). The duration of the drug holiday may optionally vary between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during a drug holiday include 10%-100%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0493] Once the patient's condition improves, a maintenance dose is administered as necessary. Subsequently, the dosage or frequency of administration, or both, is reduced to a level that maintains the improved disease. In certain embodiments, patients require long-term intermittent treatment as symptoms and / or infections recur.

[0494] The compounds described herein can be formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for patients receiving treatment, wherein each unit contains a predetermined amount of active material calculated to produce the desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form can be used for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 times or more per day). When multiple daily doses are used, the unit dosage forms of each dose may be the same or may be different.

[0495] Optionally, the toxicity and therapeutic efficacy of such treatment regimens are determined in cell culture or experimental animals, including but not limited to determining the LD 50 (a dose lethal to 50% of the population) and ED 50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, expressed as LD 50 With ED 50 The data obtained from the cell culture assays and animal studies are optionally used to formulate dosage ranges for use in humans. The dosage of such compounds is preferably within a circulating concentration range that includes the ED with minimal toxicity. 50 The amount optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0496] Those skilled in the art will recognize or be able to determine many equivalents of the specific procedures, embodiments, claims and examples described herein using only routine experiments. Such equivalents are considered to be within the scope of the present disclosure and are covered by the claims attached to the present disclosure. For example, it should be understood that modifications to reaction conditions including but not limited to reaction time, reaction scale / volume, and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions (e.g., nitrogen atmosphere) and reducing agents / oxidants using alternatives recognized in the art and using only routine experiments are within the scope of the present application.

[0497] It should be understood that in all parts where values ​​and ranges are provided herein, all values ​​and ranges encompassed by these values ​​and ranges are meant to be encompassed within the scope of the present disclosure. In addition, the application also contemplates the upper or lower limits of all values ​​and ranges falling within these ranges.

[0498] The following examples further illustrate various aspects of the present disclosure. However, they are by no means limitations of the teachings or disclosures of the present disclosure set forth herein.

[0499] Example

[0500] Various implementations of the present application can be better understood by reference to the following examples provided by way of illustration. The scope of the present application is not limited to the examples given herein.

[0501] Materials and Methods

[0502] Materials and instruments

[0503] All reactions involving air-sensitive reagents were performed in anhydrous solvents under nitrogen atmosphere. Reagents and solvents purchased from commercial suppliers were used as received. Reactions were monitored by thin layer chromatography (TLC) on silica gel plates (IB2-F) or by high performance liquid chromatography / mass spectrometry (HPLC-MS). Column chromatography was performed using a Teledyne ISCO CombiFlash system equipped with silica or C-18 columns. The HPLC-MS / MS spectrometer was used at room temperature to analyze the reaction mixture using a Bruker Avance III HD 600 MHz spectrometer (600 MHz). 1 H NMR) to record NMR spectra. Reference solvent signal [ 1H-NMR: DMSO-d6 (2.50 ppm) and CD3Cl3 (7.26 ppm)], chemical shifts (δ) are reported in parts per million (ppm). Signal patterns are reported as s (singlet), d (doublet), dd (doubledoublet), 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. The 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.

[0504] Example 1: Novel kinases as therapeutic targets for endometriosis

[0505] Balanced phosphorylation activity mediated by kinases and phosphatases encoded within the human genome is critical for controlling intracellular responses to internal and external cues. This balanced kinase and phosphatase activity is essential for maintaining cellular function and preventing dysregulated cell growth. Identification of inhibitors of overactive kinases and phosphatases in cancer is an area of ​​great interest to both the academic and industrial drug discovery communities. There are approximately 538 kinases and 200 phosphatases in the human genome, and there are 73 currently available FDA-approved kinase inhibitors. In addition to the 73 FDA-approved kinase inhibitors targeting 42 different major kinases, there are hundreds of clinical trials underway targeting an additional 15-20 protein kinases. Thus, of the 538 known kinases, only approximately 70 kinases are currently targeted for drug inhibition, indicating that a large number of therapeutic opportunities exist by targeting the kinase domain. Furthermore, these FDA-approved kinase inhibitors are often promiscuous, inhibiting multiple related kinases. For example, entrectinib, a pan-NTRK inhibitor, is a potent 7nM inhibitor of ROS1 and a 12nM inhibitor of anaplastic lymphoma kinase (ALK); pexidartinib inhibits FLT3-ITD, KIT, and CSF1R, IC 50 values ​​of 9, 12, and 17 nM, respectively; and Ripretinib with an IC of 3-7 nM 50 The range targets KIT, PDRFα, BRAF and DDR2.

[0506] To identify overexpressed kinases in endometriosis, a comprehensive database was analyzed comparing endometrial biopsies from 53 controls with lesions from endometriosis subtypes (i.e. peritoneal lesions (PeL), ovarian endometriomas (OMA), and deeply infiltrating endometriosis (DiE)) from 115 patients. To identify differentially expressed kinases, normalized microarray values ​​were analyzed to identify kinase-encoding genes that were upregulated (>1.4-fold, p<0.05), and genes that were highly expressed in all three subtypes were selected. From this analysis, 20 kinases were identified for validation and therapeutic targeting in endometriosis ( Figure 1A-1B ).

[0507] Example 2: Identification of NTRK2 as a target kinase for endometrial ectopic tissue

[0508] NTRK2 is one of the kinases identified in the studies described here and is the target of an FDA-approved small molecule inhibitor, entrectinib. Therefore, NTRK2 represents a kinase target with an FDA-approved inhibitor that can be evaluated as a tool compound for endometriosis.

[0509] NTRK1, NTRK2, and NTRK3 are tyrosine kinase receptors for their extracellular ligands, nerve growth factor (NGF), brain-derived nerve growth factor (BDNF), and neurotrophin 4 (NT-4) and neurotrophin 3 (NT-3), respectively. In addition, previous data have also shown that pharmacologically relevant exposures in the CNS lead to risks of on-target adverse events associated with both NTRK1 and NTRK2. Therefore, the development of a safer, peripherally restricted NTRK2 inhibitor must be considered for this non-life-threatening indication.

[0510] Western blot analysis revealed that NTRK2 protein levels were elevated in endometriotic tissue compared with normal tissue ( Figure 2A NTRK2 showed elevated expression in lysates of ectopic peritoneal lesions and ovarian endometriomas compared with orthotopic normal endometrium ( Figure 2B-2G ). We also determined that siRNA-mediated knockdown of NTRK2 reduced prostaglandin E2 (PGE2)-mediated induction of proinflammatory genes (PTGS2 / COX2, IL6, IL8) in primary endometriotic stromal cells of endometrioma ( Figures 2H-2J Western blot analysis showed that this NTRK2-mediated reduction in proinflammatory genes also reduced phosphorylated cAMP response element binding protein (CREB) ( Figure 2K ).

[0511] In addition, analysis of 36,697 endometriosis cases and 116,071 controls in the FinnGen database identified associations between 20 (p < 0.001) NTRK2 variants and various subtypes and stages of endometriosis. Figure 3 ).

[0512] Example 3: Identification of NTRK2 inhibitors

[0513] To identify NTRK2 selective inhibitors, a DNA-Encoded Chemistry Technology (DEC-Tec) strategy was used. DEC-Tec is a platform for identifying drug-like molecules that bind to target proteins with high affinity. The DEC-Tec platform allows exploration of chemical space at a higher level than traditional high-throughput screening methods. By using the "split and pool" combinatorial synthesis technology, DEC-Tec can effectively generate up to 10 9 Screening library of uniquely encoded chemical compounds ( Figure 4 ).

[0514] Parallel selections were performed on 4.25 billion DNA-encoded small molecules with NTRK2, without NTRK2 (i.e., control), or in the presence of a promiscuous kinase inhibitor, staurosporine. These selections included kinase-biased molecules. The enrichment of each library member across these selections was compared (measured by normalized z-scores). A series of compounds were significantly enriched in the NTRK2-only selection, but not in the control or NTRK2 plus staurosporine selections, consistent with competitive ligand binding.

[0515] Because this series of NTRK2 hits had multiple drug-like characteristics, several tri-synthon hits and analogs were selected for off-DNA synthesis for in vitro testing, including CDD-2262 and its smaller analog CDD-2330 (Figure 5).

[0516] Example 4: Compound Synthesis

[0517] General Procedure I: Reductive Amination

[0518]

[0519] Aryl aldehyde (1.0 eq.), primary amine (2.0 eq.) and CHCl3 (0.2-0.4 M) were charged into an oven-dried microwave vial equipped with a magnetic stirring bar. The solution was stirred at room temperature for at least 2 hours, and then NaBH(OAc)3 (1.5 eq.) was added in portions. After overnight, NaBH(OAc)3 (1.5 eq.) was added. After 4 hours, NaOH (1.0 M) was added to quench the reaction mixture until pH = 9. The aqueous layer was extracted 3 times with DCM / MeOH (9: 1). The combined organic layers were concentrated and the residue was separated by chromatography to give the desired secondary amine product. Compounds 13-15 and 27 were prepared according to General Procedure I.

[0520] General Procedure II: Urea Synthesis

[0521]

[0522] The secondary amine (1.0 eq) was dissolved in DCM (0.2 M) and then the isocyanate (2.0 eq) was added. The reaction was allowed to proceed overnight and then the solution was concentrated and the crude product was purified by chromatography to give the desired urea product. In certain embodiments, the secondary amine can 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.

[0523] General Procedure III: Amide Coupling

[0524]

[0525] The carboxylic acid (1.0 eq.) was dissolved in DMF (0.2 M), followed by the addition of HATU (1.2 eq.). After stirring at room temperature for 5 min, the secondary amine (1.3 eq.) was added, followed by the addition of Et3N (1.8 eq.). 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 a crude product, which was purified by chromatography to give the desired amide product. In certain embodiments, the secondary amine can be obtained as described in General Procedure I. Compounds 12 and 24-25 were prepared according to General Procedure III.

[0526] General Procedure IV: Ester Hydrolysis

[0527]

[0528] The methyl ester was dissolved in a solvent mixture comprising THF / MeOH / H2O (4:1:1, 0.2M), and then aqueous LiOH (2.0M, 5 equiv.) was added dropwise at room temperature. The reaction was allowed to proceed for 4 hours, and then aq.LiOH was added. The reaction was allowed to proceed overnight, after which it was quenched with 1M HCl, and the pH was adjusted to pH = 2-3. The mixture was concentrated to give a crude product, which 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.

[0529] General Procedure V: Amide Coupling

[0530]

[0531] The carboxylic acid (1.0 eq.) was dissolved in DMF (0.2 M), followed by the addition of HATU (1.2 eq.). After stirring at room temperature for 5 minutes, ammonium chloride or methylamine salt (1.3 eq.) was added, followed by Et3N (1.8 eq.). 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.

[0532]

[0533] 5-((1-Isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-4-carboxylic acid (1)

[0534] 1H NMR (600MHz, CDCl3) δ (ppm) 8.46 (d, J = 6.6Hz, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.34 (d, J = 9.0Hz, 2H), 7.08 (d ,J=8.4Hz,2H),6.96(d,J=6.0Hz,2H),6.69(s,1H),4.56(s,2H),4.45(t,J=6.0Hz,3H),1.22(d,J=6.0,6H); 13 C NMR (600MHz, CDCl3) δ (ppm) 168.3, 155.6, 146.0, 141.1, 137.5, 129.5, 121.7, 121.6, 119.6, 115.7, 113.1, 103.0, 53.4, 47.8, 45.0, 20.9; C 20 H 19 F3N4O4 HRMS(ESI)m / z[M+H] + Calculated value 437.1358, measured value 437.1421.

[0535]

[0536] 1-Cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(2)

[0537] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.44 (d, J = 7.2Hz, 1H), 7.96 (s, 1H), 7.49 (s, 1H), 7.27 (d, J = 9.0Hz, 2H), 7.08 (d, J = 8.4Hz, 2H), 6.68 (dd ,J=7.2Hz,1H),6.49(d,J=1.8Hz,1H),6.32(s,1H),4.50(s,2H),4.25(m,1H),1.96(m,2H),1.72(m,2H),1.65(m,4H),1.51(m,4H).

[0538]

[0539] 1-Cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea(3)

[0540] 1H NMR(600MHz, CDCl3)δ(ppm)8.43(d,J=7.2Hz,1H),8.29(d,J=7.2Hz,1H),7.93(d,J=1.8Hz,1H),7.40(s,1H),7.25(m,1H),7.18(m,1H),7 .01(m,1H),6.80(s,1H),6.68(dd,J=7.2Hz,1H),6.45(d,J=1.8Hz,1H),4.64(s,2H),4.45(m,1H),2.32(m,2H),2.18(m,2H),1.75(m,2H).

[0541]

[0542] 1-Isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(4)

[0543] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.46 (d, J = 7.2Hz, 1H), 7.97 (d, J = 1.8Hz, 1H), 7.50 (s, 1H), 7.28 (d, J = 9.0Hz, 2H), 7.09 (d, J = 9.0Hz,2H),6.70(dd,J=7.2Hz,1H),6.50(d,J=1.8Hz,1H),6.33(s,1H),4.63(m,1H),4.48(s,2H),1.25(d,J=6.6Hz,6H); 13 C NMR (600MHz, CDCl3) δ (ppm) 155.4, 144.6, 142.6, 139.9, 137.6, 134.3, 129.1, 121.6, 121.1, 114.7, 110.4, 97.1, 47.1, 44.9, 20.8; C 19 H 19 F3N4O2 HRMS(ESI)m / z[M+H] + Calculated value 393.1460, measured value 393.1533.

[0544]

[0545] 1-Cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(5)

[0546] 1H NMR (600MHz, CDCl3) δ (ppm) 8.43 (d, J = 7.2Hz, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.49 (s, 1H), 7.27 (d, J = 9.0Hz, 2H), 7.08 (d, J = 9.0Hz, 2H), 6.67 (dd, J =7.2Hz,1H),6.48(d,J=1.8Hz,1H),6.35(s,1H),4.50(s,2H),4.17(m, 1H),1.89(m,2H),1.82(m,2H),1.68(m,1H),1.39(m,4H),1.098(m,1H). C 22 H 23 F3N4O2 HRMS(ESI)m / z[M+H] + Calculated value 433.1773, measured value 433.1842.

[0547]

[0548] 1-Cyclobutyl-3-(4-nitrophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea(6)

[0549] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.37 (d, J = 7.2Hz, 1H), 8.09 (d, J = 6.0Hz, 2H), 7.88 (d, J = 2.4, 1H), 7.50 (d, J = 9.0Hz, 2H), 7.35 (s, 1H ),7.17(s,1H),6.63(dd,J=7.2Hz,1H),6.43(d,J=1.8Hz,1H),4.61(s,2H),4.43(m,1H),2.25(m,2H),2.11(m,2H),1.68(m,2H).

[0550]

[0551] 1-Phenyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(7)

[0552] 1H NMR (600MHz, CDCl3) δ (ppm) 8.40 (d, J = 7.2Hz, 1H), 7.91 (d, J = 1.8Hz, 1H), 7.43 (m, 2H), 7.38 (m, 1H), 7.33 (s, 1H), 7.31 (m, 2 H), 7.21 (d, J = 7.2Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 6.84 (dd, J = 7.2Hz, 1H), 6.41 (d, J = 1.8Hz, 1H), 6.24 (s, 1H), 4.93 (s, 2H).

[0553]

[0554] 1-Cyclopentyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(8)

[0555] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.45 (d, J = 7.2Hz, 1H), 7.95 (d, J = 1.8Hz, 1H), 7.46 (s, 1H), 7.29 (d, 9.0Hz, 2H), 7.09 (d, J = 8.4Hz, 2H), 6.67 (dd, J =7.2Hz,1H),6.48(d,J=1.8Hz,1H),6.34(s,1H),4.62(m,1H),4.49(s, 2H),2.00(m,2H),1.72(m,2H),1.64(m,2H),1.61(m,2H),1.53(m,2H). C 21 H 21 F3N4O2 HRMS(ESI)m / z[M+H] + Calculated value 419.1617, measured value 419.1669.

[0556]

[0557] 1-Cyclopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(9)

[0558] 1H NMR (600MHz, CDCl3) δ (ppm) 8.39 (d, J = 7.2Hz, 1H), 7.92 (d, J = 2.4Hz, 1H), 7.50 (dd, J = 7.2Hz, 2H), 7.41 (d, J = 9.6Hz, 2H), 7.16(d,J=8.4Hz,2H),6.75(dd,J=7.2Hz,1H),6.45(d,J=1.8Hz,1H),4.62(s,2H),2.59(m,1H),0.99m,2H),0.93(m,2H). C 19 H 17 F3N4O2 HRMS (ESI) m / z [M+H] + Calculated value 391.1304, measured value 391.1375.

[0559]

[0560] 1-Cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethyl)phenyl)urea(10)

[0561] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.43 (d, J = 7.2Hz, 1H), 8.13 (d, J = 8.4Hz, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.51 (m, 2H) ,7.39(s,1H),7.13(m,1H),6.77(s,1H),6.68(dd,J=7.2Hz,1H),6.46(d,J=1.8Hz,1H),4.66(s,2H),4.45(m 1H),2.30(m,2H),2.16(m,2H),1.74(m,2H).

[0562]

[0563] 1-Cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(3-(trifluoromethyl)phenyl)urea(11)

[0564] 1H NMR (600MHz, CDCl3) δ (ppm) 8.41 (d, J = 7.2Hz, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.67 (s, 1H), 7.52 (d, J = 8.4Hz, 1H), 7.39 (s, 1H), 7.36 (m, 1H),7.27(m,1H),6.66(dd,J=7.2Hz,1H),6.48(d,J=19.2Hz,2H),4.63(s,2H),4.42(m,1H),2.30(m,2H),2.19(m,2H),1.74(m,2H).

[0565]

[0566] N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide (12)

[0567] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.49 (dd, J = 13.8Hz, 1H), 7.95 (dd, J = 9.0Hz, 1H), 7.34, 7.28 (ds, 1H), 7.16 (m, 2 H),7.09(d,J=8.4Hz,1H),6.93(m,1H),6.87(d,J=8.4Hz,1H),6.78(d,J=10.8Hz,1H),6.77(d,J=9.0Hz,1H) ,6.68(dd,J=8.4Hz,1H),6.61(dd,J=20.4Hz,1H),6.45(dd,J=9.0Hz,1H),4.78(s,1H),4.71(s,1H),4.66(d ,J=9.0Hz,2H),3.95,3.87(dt,2H),3.61,3.55(dt,2H),2.84(m,1H),2.06(m,1H),1.20(dd,J=22.8Hz,6H).

[0568]

[0569] 5-((Cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (13)

[0570] 1H NMR (600MHz, CDCl3) δ (ppm) 8.45 (d, J = 7.2Hz, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.07 (dd, J = 7.2 Hz,1H),3.90(s,3H),3.85(s,2H),3.32(m,1H),2.23(m,2H),1.83(m,2H),1.76,1.74(m,2H).

[0571]

[0572] 3-(3-Chlorophenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)propan-1-amine (14)

[0573] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.36 (s, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.42 (s, 1H), 7.15 (t, J = 8.4Hz, 1H), 6.88 (dd, J = 18.0Hz, 1H), 6.87 ( s,1H),6.73(dd,J=17.4Hz,1H),6.40(s,1H),4.02(t,J=6.0Hz,2H),3.80(s,2H),2.81(t,J=6.6Hz,2H),1.96(m,2H),1.81(bs,1H).

[0574]

[0575] N,N-Bis(pyrazolo[1,5-a]pyridin-5-ylmethyl)cyclobutanamine(15)

[0576] This compound is an over-reductive amination product. 1 H NMR (600MHz, CDCl3) δ (ppm) 8.38 (d, J = 7.2Hz, 2H), 7.89 (s, 2H), 7.38 (s, 2H), 6.77 (d, J = 4.8H z,2H),6.41(s,2H),3.50(s,4H),3.22(m,1H),1.97(m,2H),1.88(m,2H),1.68,1.63(m,2H).

[0577]

[0578] 1-(3-(3-chlorophenoxy)propyl)-3-(4-phenoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea(16)

[0579] 1H NMR (600MHz, CDCl3) δ (ppm) 8.55 (d, J = 7.2Hz, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.47 (s, 1H), 7.30 (t, J = 7.8Hz, 2H), 7.20 (m, 3H) ,6.90(m,6H),6.80(m,2H),6.51(d,J=1.8Hz,1H),4.63(s,2H),4.08(t,J=5.4Hz,2H),3.58(t,J=6.6Hz,2H),2.11(m,2H).

[0580]

[0581] 1-(3-(3-chlorophenoxy)propyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-trifluoromethoxy)phenyl)urea(17)

[0582] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.53 (d, J = 7.2Hz, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.4 6(s,1H),7.25(dd,J=7.2Hz,2H),7.21(t,J=8.4Hz,1H),7.06(m,3H),6.99(dd ,J=8.4Hz,1H),6.93(t,J=2.4Hz,1H),6.80(m,2H),6.50(d,J=1.8Hz,1H),4.6 3(s,2H), 4.08(t,J=5.4Hz,2H), 3.58(t,J=6.6Hz,2H), 2.09(t,J=6.0Hz,2H).

[0583]

[0584] 3-(4-Chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea(18)

[0585] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.51 (d, J = 7.2Hz, 1H), 7.95 (d, J = 2.4Hz, 1H), 7.42 (s, 1H), 7.29 (d, J = 9.0Hz, 2H), 7.21 (d, J = 9. 0Hz, 2H), 6.72 (dd, J = 7.2Hz, 1H), 6.48 (d, J = 1.8Hz, 1H), 6.37 (s, 1H), 4.63 (s, 2H), 4.41 (m, 1H), 2.16 (m, 2H), 1.72 (m, 2H).

[0586]

[0587] 1-Cyclobutyl-3-(4-fluorophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea(19)

[0588] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.52 (d, J = 7.2Hz, 7.95 (d, J = 2.4Hz, 1H), 7.43s, 1H), 7.29 (dd, J = 9.0Hz, 2H), 6.96 (t, J = 9.0Hz, 2H) ,6.73(dd,J=7.2Hz,1H),6.48(d,J=2.4Hz,1H),6.32(s,1H),4.63(s,2H),4.42(m,1H),2.30(m,2H),2.16(m,2H),1.72(m,2H).

[0589]

[0590] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (20) 1 H NMR (600MHz, CDCl3) δ (ppm) 8.60 (d, J = 7.2Hz, 1H), 8.38 (s, 1H), 8.17 (s, 1H), 7.53 (d, J = 9.0Hz, 2H), 7.21 ( d,J=9.0Hz,2H),7.03(dd,J=7.2Hz,1H),4.85(s,2H),2.95(s,3H),2.34(m,2H),2.16(m,2H),1.72(m,2H).

[0591]

[0592] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (21)

[0593] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.65 (d, J = 7.2Hz, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.52 (dd, J = 7.2Hz, 2H), 7.21 ( d,J=8.4Hz,2H),7.08(dd,J=8.4Hz,1H),4.87(s,2H),4.68(m,1H),2.32(m,2H),2.23(m,2H),1.77(m,2H). C21 H 19 F3N4O4 HRMS(ESI)m / z[M+H] + Calculated value 449.1358, measured value 449.1426.

[0594]

[0595] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (22)

[0596] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.46 (d, J = 7.2Hz, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.39 (d, J = 9.0Hz, 2H), 7.13 (d, J = 7.2Hz, 2 H), 6.93 (dd, J = 7.2Hz, 1H), 6.44 (s, 1H), 4.72 (s, 2H), 4.33 (m, 1H), 3.89 (s, 3H), 2.33 (m, 2H), 2.22 (m, 2H), 1.79 (m, 2H).

[0597]

[0598] 1-Cyclobutyl-3-(4-methoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea(23)

[0599] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.49 (d, J = 7.2Hz, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.43 (s, 1H), 7.25 (d, J = 8.4Hz, 2H), 6.82 (d, J = 8.4Hz, 2H), 6.7 2(dd,J=7.2Hz,1H),6.48(d,J=1.8Hz,1H),6.23(s,1H),4.63(s,2H),4.42(m,1H),3.77(s,3H),2.29(m,2H),2.17(m,2H),1.75(m,2H).

[0600]

[0601] (R)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide (24)

[0602] 1H NMR (600MHz, CDCl3) δ (ppm) 8.47, 8.41 (d, J = 7.2Hz, 1H), 7.95, 7.91 (s, 1H), 7. 25(m,5H),7.06(m,2H),6.90(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),6.56,6. 40(d,J=7.2Hz,1H),6.44,6.38(s,1H),6.22,5.35(m,1H),4.61,4.38(d,J=15 .6,1),4.15(m,1H),4.05(m,2H),3.98(m,1H),3.58(m,1H),1.48,1.42(m,6H).

[0603]

[0604] (S)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide (25)

[0605] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.33, 8.26 (d, J = 7.2Hz, 1H), 7.90, 7.84 (s, 1H), 7.25 (m ,5H),7.04(m,2H),6.87(d,J=8.4Hz,1H),6.78(d,J=8.4Hz,1H),6.49,6.36(d,J=7. 2Hz,1H),6.40,6.30(s,1H),6.19,5.32(m,1H),4.64,4.35(d,J=15.6Hz,1H),4.13 ,3.96(d,J=18.0Hz,1H),4.00(m,2H),3.86(m,1H),3.56(m,1H),1.44,1.38(m,6H). C 26 H 27 N3O2 HRMS (ESI) m / z [M+H] + Calculated value 414.2103, measured value 414.2174.

[0606]

[0607] 1-Cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(26)

[0608] 1H NMR (600MHz, CDCl3) δ (ppm) 8.41 (d, J = 7.2Hz, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.39 (s, 1H), 7.36 (d, J = 9.0Hz, 2H), 7.11 (d, J = 9 .0Hz,2H),6.64(d,J=7.2Hz,1H),6.46(d,J=1.8Hz,2H),4.61(s,2H),4.43(m,1H),2.29(m,2H),2.15(m,2H),1.72(m,2H). C 20 H 19 F3N4O2 HRMS (ESI) m / z [M+H] + Calculated value 405.1460, measured value 405.1523.

[0609] (S)-1-phenyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)ethan-1-amine (27)

[0610] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.39 (d, J = 7.2Hz, 1H), 7.91 (d, J = 2.4Hz, 1H), 7.42 (s, 1H), 7.36 (d, J = 4.2Hz, 4H), 7.28 ( m,1H),6.72(d,J=6.0Hz,1H),6.43(d,J=1.8Hz,1H),3.84(m,1H),3.65(m,2H),1.68(bs,1H),1.41(d,J=6.6Hz,3H).

[0611]

[0612] 1-((3-Fluoropyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea(28)

[0613] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.29 (d, J = 6.8Hz, 1H), 7.82 (d, J = 3.4Hz, 1H), 7.46 (s, 1H), 7.31 (d, J = 8.8Hz, 2H), 7.11 (d ,J=8.4Hz,2H),6.71(d,J=6.5Hz,1H),6.34(s,1H),4.53(dd,J=13.0,6.5Hz,1H),4.48(s,2H),1.27(d,J=6.7Hz,6H).

[0614]

[0615] 1-((3-Bromopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea(29)

[0616] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.43 (d, J = 7.2Hz, 1H), 7.94 (s, 1H), 7.44 (s, 1H), 7.31 (d, J = 9.0Hz, 2H ), 7.12 (d, J = 8.5Hz, 2H), 6.81 (d, J = 6.2Hz, 1H), 6.34 (s, 1H), 4.53 (s, 3H), 1.27 (d, J = 6.7Hz, 6H).

[0617]

[0618] 5-((1-Cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (30)

[0619] 1 H NMR (600MHz, CDCl3) δ8.44(s,1H),8.35(d,J=8.4Hz,1H),7.99(d,J=7.8Hz,1H),7.46(t,J=8.4Hz,2H),7.14(t ,J=7.8Hz,2H),6.95(s,1H),4.67(d,J=7.8Hz,2H),2.61(m,1H),0.99(t,J=6.6Hz,2H),0.91(d,J=3.6Hz,2H).

[0620]

[0621] 5-((1-Isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (31)

[0622] 1 H NMR (600MHz, CDCl3) δ8.37(d,J=7.2Hz,1H),8.15(s,1H),8.12(s,1H),7.29(d,J=9.0Hz,2H), 7.02(d,J=8.4Hz,2H),6.59(s,1H),4.51(d,J=7.8Hz,2H),4.39(m,1H),1.19(d,J=6.6Hz,6H).

[0623]

[0624] 5-((1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (32)

[0625] 1 H NMR (600MHz, CDCl3) δ8.33(d,J=7.2Hz,1H),8.07(d,J=12.6Hz,1H),7.42(d,J=9.0Hz,2H),7.08(d,J=8.4Hz,2H) ,6.90-6.89(m,1H),5.80(bs,2H),4.62(s,2H),2.62-2.60(m,1H),0.94(d,J=5.4Hz,2H),0.86(d,J=3.0Hz,2H).

[0626]

[0627] 5-((1-Isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (33)

[0628] 1 H NMR (600MHz, CDCl3) δ8.52(d,J=7.2Hz,1H),8.47(s,1H),8.06(s,1H),7.29(d,J=8.4Hz,2H),7 .19(d,J=8.4Hz,2H),6.96-6.95(m,1H),4.28(s,2H),4.12-4.10(m,1H),1.04(d,J=6.6Hz,6H).

[0629]

[0630] N-Hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (34)

[0631] 1 H NMR (600MHz, CDCl3) δ8.41(t,J=7.2Hz,1H),8.27(s,1H),8.02(d,J=6.6Hz,1H),7.29(d,J=9.0Hz,2H),7.23(d,J=8 .4Hz,2H),7.09(m,1H),6.79(s,1H),4.17(d,J=7.8Hz,2H),4.05-4.03(m,1H),3.09(s,3H),0.99(t,J=7.2Hz,6H).

[0632]

[0633] 1-((3-cyanopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea(35)

[0634] 1 H NMR (600MHz, CDCl3) δ8.52(d,J=7.2Hz,1H),8.24(s,1H),7.68(s,1H),7.41(d,J=9.0Hz,2H),7.17(d, J=8.4Hz,2H),7.08-7.06(m,1H),6.51(s,1H),4.62(s,2H),4.34-4.32(m,1H),1.32(d,J=6.6Hz,6H).

[0635]

[0636] 5-((1-isobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (36)

[0637] 1 H NMR (600MHz, CDCl3) δ8.54(d,J=7.2Hz,1H),8.38(s,1H),7.98(s,1H),7.33(d,J=9.0Hz,2H),7.08(d,J=8. 4Hz, 2H), 6.96 (m, 1H), 6.40 (s, 1H), 4.66 (s, 2H), 3.11 (d, J = 7.8Hz, 2H), 2.02 (m, 1H), 0.96 (d, J = 6.6Hz, 6H).

[0638]

[0639] 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (37)

[0640] 1H NMR (600MHz, CDCl3) δ8.52(d,J=7.2Hz,1H),8.47(s,1H),8.15(s,1H),7.36(d,J=9.0Hz,2H),7.13(d,J=8.4Hz,2H),7.04(m,1H),6.57(s, 1H), 4.65 (d, J = 17.4Hz, 1H), 4.54 (d, J = 17.4Hz, 1H), 4.21 (m, 1H), 1.70 (m, 1H), 1.57 (m, 1H), 1.26 (d, J = 6.6Hz, 3H), 0.98 (t, J = 7.2Hz, 3H).

[0641]

[0642] N-Hydroxy-5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboximidamide (38)

[0643] 1 H NMR (600MHz, CDCl3) δ8.42(t,J=7.8Hz,1H),8.23,8.16(s,1H),8.11,7.92(s,1H),7.33(t,J=9.0Hz, 2H), 7.01 (d, J = 9.0Hz, 2H), 6.82 (d, J = 7.2Hz, 1H), 4.53 (s, 2H), 4.46-4.44 (m, 1H), 1.26-1.24 (m, 6H).

[0644]

[0645] N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4- oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)-N 4 -Methylterephthalamide (39)

[0646] 1H NMR (600MHz, DMSO-d6) δ (ppm) 10.40 (d, J = 3.6 Hz, 2H), 9.36 (s, 1H), 8.72 (d, J = 1.8 Hz,1H),8.71(d,J=2.4Hz,1H),8.60(b,J=4.8Hz,1H),8.39(t,J=8.4Hz,2H),8.04 (d,J=8.4Hz,2H),7.97(d,J=8.4Hz,2H),7.71(m,2H),7.57(d,J=8.4Hz,2H),7.46 (dd, J = 8.4Hz, 1H), 7.10 (s, 1H), 3.96 (s, 3H), 2.82 (d, J = 4.8Hz, 3H), 1.22 (s, 9H).

[0647]

[0648] N 1 -(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)-N 4 -Methylterephthalamide (40)

[0649] 1 H NMR (600MHz, CDCl3) δ (ppm) 10.40 (d, J = 3.6Hz, 2H), 9.36 (s, 1H), 8.66 (d, J = 3.6Hz, 1H), 8.40 (d, J = 8.4Hz, 1H), 8.24 (m, 1H), 7.95 (d, J = 4.2H z,2H),7.89(d,J=8.4Hz,1H),7.83(d,J=8.4Hz,1H),7.38(dd,J=8.4Hz,1H),4.98(m,1H),4.05(s,3H),2.98(s,3H),1.74(d,J=7.2Hz,6H).

[0650]

[0651] 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4- Tert-butyl oxadiazole-3-yl)picolinate (41)

[0652] 1H NMR (600MHz, CDCl3) δ (ppm) 9.51 (d, J = 1.2Hz, 1H), 8.57 (dd, J = 8.4Hz, 1H), 8.14 (d, J = 8 .4Hz,1H),7.51(m,3H),7.44(d,J=7.8Hz,2H),6.96(s,1H),1.66(s,9H),1.26(s,9H).

[0653]

[0654] 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- Tert-butyl oxadiazole-3-yl)picolinate (42)

[0655] 1 H NMR (600MHz, CDCl3) δ (ppm) 9.52 (d, J = 1.2Hz, 1H), 8.76 (d, J = 1.2Hz, 1H), 8.57 (dd, J = 8.4Hz, 1H), 8.26 (dd, J =8.4Hz, 1H), 8.19 (dd, J = 8.4Hz, 1H), 7.82 (d, J = 8.4Hz, 1H), 4.99 (m, 1H), 1.76 (d, J = 7.2Hz, 6H), 1.67 (s, 9H).

[0656]

[0657] (Z)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamoylimido)pyridinylamino)-3-methoxyphenyl)-N 4 -Methylterephthalamide (43)

[0658] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.86 (s, 1H), 8.38 (d, J = 8.4Hz, 1H), 8.31 (d, J = 8.4Hz, 1H), 8.14 (d, J = 8.4Hz, 1H), 7.87 (d, J = 7. 8Hz, 2H), 7.78 (d, J = 7.8Hz, 2H), 7.70 (s, 1H), 7.38 (m, 10H), 7.04 (d, J = 9.0Hz, 1H), 3.93 (s, 3H), 2.89 (s, 3H), 1.09 (s, 9H).

[0659]

[0660] N1-(4-(5-(N-hydroxycarbamoylimide)pyridinylamino)-3-methoxyphenyl)-N4-methylterephthalamide (Int-1)

[0661] 1 H NMR (600MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 10.32 (s, 1H), 9.21 (s, 1H), 8.61 (d, J = 4.8Hz, 2H), 8.33 (m, 2H), 8.04 (d, J = 7.8Hz, 2H), 7.97 (d,J=7.8Hz,2H),7.71(s,1H),7.47(d,J=7.8Hz,1H),6.43(bs,1H),6.12(s,1H),5.69(bs,1H),5.16(bs,1H),3.95(s,3H),2.82(s,3H).

[0662]

[0663] (4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- Tert-butyl)oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)carbamate (44)

[0664] 1 H NMR (600MHz, CDCl3) δ (ppm) 10.39 (d, J = 9.6Hz, 1H), 9.05 (s, 1H), 8.44 (d, J = 7.8Hz, 1H), 8.33 (m, 2H), 7.42 (s, 1H), 6.66 (s, 1H), 6.53(s,1H),6.28(bs,1H),5.81(bs,1H),4.94(m,1H),3.97(s,3H),1.72(d,J=7.2Hz,3H),1.53(d,J=7.2Hz,3H),1.52(s,9H).

[0665]

[0666] 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 (45)

[0667] 1H NMR (600MHz, CDCl3) δ (ppm) 9.31 (bs, 1H), 7.91 (d, J = 7.8Hz, 1H), 7.45 (bs, 2H), 7.37 (m, 1H), 7.18 (m, 1H), 7.01 (m, 3H), 6.91(m,2H),6.75(m,2H),6.48(s,1H),5.89(bs,1H),4.82(m,1H),3.26(m,1H),3.04(m,1H),2.66(s,3H),1.25(m,3H).

[0668]

[0669] (S)-1-Benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1H-benzo[d]imidazole-7-carboxamide (46)

[0670] 1 H NMR (600MHz, CDCl3) δ (ppm) 7.94 (d, J = 8.4Hz, 1H), 7.49 (d, J = 8.4Hz, 2H), 7.37 (d, J = 7.8Hz, 1H), 7.32 (d, J = 7.8Hz, 1H), 7.2 7(m,3H),7.05(m,3H),6.96(s,1H),6.76(d,J=8.4Hz,1H),6.67(d,J=7.2Hz,2H),5.51(bs,2H),4.35(m,1H),1.25(m,3H).

[0671]

[0672] (S)-1-Benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide (47)

[0673] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.59 (bs, 1H), 8.02 (d, J = 7.8Hz, 1H), 7.63 (m, 3H), 7.43 (m, 2H), 7.24(d,J=7.8Hz,2H),7.13(bs,3H),6.69(s,2H),6.24(bs,1H),4.46(m,1H),1.26(m,3H).

[0674]

[0675] (S)-2-(Benzylamino)-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-3-nitrobenzamide (Int-2)

[0676] 1 H NMR (600MHz, CDCl3) δ (ppm) 8.14 (d, J = 8.4Hz, 1H), 7.71 (d, J = 7.8Hz, 2H), 7.47 (d, J = 7.8Hz, 7.23 (m, 5H), 7.12 (d, J = 7.2Hz, 2H), 6.80 (t, J = 7.8Hz, 1H), 4.66 (m, 1H), 4.27 (q, J = 22.8Hz, 2H), 1.46 (d, J = 7.8Hz, 3H).

[0677]

[0678] 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (48)

[0679] 1 H NMR(600MHz, CDCl3)δ8.40(d,J=7.2Hz,1H),8.25(s,1H),8.02(s,1H),7.38(d,J=9 .0Hz,2H),7.12(d,J=8.4Hz,2H),7.03(d,J=7.2Hz,1H),5.29(s,2H),3.22(s,3H).

[0680]

[0681] 5-((1-Isopropyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (49)

[0682] 1 H NMR (600MHz, CDCl3) δ8.42(d,J=7.2Hz,1H),8.25(s,1H),8.07(s,1H),7.24(d,J=7.8Hz,2H),7.23(s ,1H),7.07(d,J=8.4Hz,2H),6.93(d,J=7.2Hz,1H),5.22(m,1H),4.99(s,2H),1.24(d,J=6.6Hz,6H).

[0683]

[0684] 5-((N-methyl-3-(4-(trifluoromethoxy)phenyl)propionylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (51)

[0685] 1 H NMR (600MHz, CDCl3) δ8.42-8.39(m,1H),8.17(s,1H),8.14(s,1H),7.29-7.24(m,2H),7.14(d,J=8.1Hz,2H) ,6.82(dd,J=7.1,2.0Hz,1H),4.66(s,2H),3.04(t,J=7.6Hz,2H),2.94(s,3H),2.72(dd,J=8.3,7.1Hz,2H).

[0686]

[0687] 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (52)

[0688] 1 H NMR (600MHz, CDCl3) δ8.41 (d, J = 7.8Hz, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.44 (d ,J=9.0Hz,2H),7.12(d,J=9.0Hz,2H),6.92(m,1H),4.65(s,2H),3.05(s,3H).

[0689]

[0690] 5-((N-isopropyl-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (53)

[0691] 1 H NMR (600MHz, CDCl3) δ8.25 (bs, 1H), 8.12 (d, J = 5.4Hz, 1H), 8.02 (bs, 1H), 7.10-7.00 (m, 2H), 6.73-6.66 (m ,2H),6.66-6.61(m,1H),4.76(bs,2H),4.56(bs,2H),4.33(m,1H),2.81-2.78(m,1H),1.16-1.12(m,12H).

[0692]

[0693] 5-((N-(3-(Dimethylamino)propyl)-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (54)

[0694] 1 H NMR(600MHz,MeOD)δ8.51(d,J=7.1Hz,1H),8.34(s,1H),8.01(s,1H),7.07(d,J=8.6Hz,1 H),6.97(d,J=8.7Hz,2H),6.88(dd,J=7.2,2.0Hz,1H),6.84(d,J=8.8Hz,1H),6.66(d,J= 8.7Hz,2H),4.74(d,J=2.6Hz,4H),3.47(t,J=6.7Hz,2H),3.25(s,2H),3.02(d,J=7.4Hz, 3H), 2.76-2.74 (m, 1H), 1.94-1.87 (m, 3H), 1.11 (d, J = 6.9Hz, 2H), 1.07 (d, J = 6.9Hz, 6H).

[0695]

[0696] 5-((2-(4-isopropylphenoxy)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (55)

[0697] 1 H NMR(600MHz, CDCl3)δ8.42(dd,J=7.1,0.9Hz,1H),8.20(s,1H),8.15(s,1H),7.16(d,J=8.7Hz,3H),6.93-6.9 0(m,1H),6.85(d,J=8.8Hz,2H),4.62(d,J=6.3Hz,2H),4.57(s,2H),2.91-2.84(m,1H),1.22(d,J=6.9Hz,6H).

[0698]

[0699] 5-((3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (56)

[0700] 1H NMR(600MHz,MeOD)δ8.56(d,J=7.3Hz,1H),8.41(s,1H),8.18(dd,J=2.1,1.1Hz,1H ),7.50-7.46(m,2H),7.19-7.15(m,2H),7.05(dd,J=7.2,2.0Hz,1H),4.51(s,2H).

[0701]

[0702] 5-((3-(4-(Trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (57)

[0703] 1 H NMR (600MHz, MeOD) δ8.55(d,J=6.9Hz,1H),8.41(s,1H),8.15(s,1H),7.58-7.48(m,2H),7.29(d,J=8.3Hz,2H),7.13-7.06(m,1H),4.95(s,2H).

[0704]

[0705] 5-((N-methyl-2-(4-(trifluoromethoxy)phenoxy)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (58)

[0706] 1 H NMR (600MHz, DMSO-d6) δ8.71(d,J=7.2Hz,1H),8.53(s,1H),8.05(s,1H),7.77(bs,1H),7.30(d,J=8.4Hz,2H ),7.09(bs,1H),7.04(d,J=9.0Hz,2H),6.88(d,J=7.2Hz,1H),5.02(s,2H),4.62(s,2H),3.03,2.89(s,3H).

[0707]

[0708] 5-((N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (59) 1H NMR (600MHz, DMSO-d6) δ8.63(d,J=7.2Hz,1H),8.49(s,1H),8.03(s,1H),7.72(bs,1H),7.30(d,J=9.0Hz ,2H),7.03(d,J=9.0Hz,2H),6.89(m,1H),5.08(s,2H),4.55(s,2H),4.22(m,1H),1.18(d,J=6.6Hz,6H).

[0709]

[0710] (R)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (60)

[0711] 1 H NMR (600MHz, DMSO-d6) δ8.66(t,J=7.2Hz,1H),8.47(s,1H),8.10(s,1H),7.67(bs,1H),7.51(d,J=9.0Hz,2H),7.20(d,J=8.4Hz,2H),6.97( m,1H),4.66(d,J=18.0Hz,1H),4.46(d,J=17.4Hz,1H),4.26(m,1H),1.58(m,1H),1.46(m,1H),1.11(d,J=6.6Hz,3H),0.81(t,J=7.2Hz,3H).

[0712]

[0713] (S)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (61)

[0714] 1 H NMR (600MHz, CDCl3) δ8.37(d,J=7.2Hz,1H),8.21(s,1H),8.09(s,1H),7.28(t,J=7.2Hz,2H),7.03(d,J=9.0Hz,2H),6.92(d,J=7.2Hz,1 H), 4.59 (d, J = 17.4Hz, 1H), 4.38 (d, J = 17.4Hz, 1H), 4.13 (m, 1H), 1.60 (m, 1H), 1.49 (m, 1H), 1.18 (d, J = 6.6Hz, 3H), 0.88 (t, J = 7.2Hz, 3H).

[0715]

[0716] 5-((N-methyl-2-(4-(trifluoromethyl)phenoxy)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (62)

[0717] 1 H NMR (600MHz, CDCl3) δ8.42(d,J=7.2Hz,1H),8.23(s,1H),8.17(s,1H),7.59(d,J=8.4Hz,2H ), 7.07 (d, J = 8.4Hz, 2H), 6.80 (m, 1H), 6.05 (bs, 2H), 4.89 (s, 2H), 4.70 (s, 2H), 3.10 (s, 3H).

[0718]

[0719] 5-((N-methyl-2-(3-(trifluoromethoxy)phenoxy)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (63)

[0720] 1 H NMR (600MHz, CDCl3) δ8.32 (d, J = 7.2Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.24 (t, J = 8. 4Hz, 1H), 6.84 (d, J = 8.4Hz, 2H), 6.81 (m, 2H), 4.73 (m, 2H), 4.62 (s, 2H), 3.00 (s, 3H).

[0721]

[0722] 5-((2-(4-(tert-butyl)phenoxy)-N-methylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (64)

[0723] 1 H NMR (600MHz, CDCl3) δ8.27(d,J=7.2Hz,1H),8.16(s,1H),8.05(s,1H),7.24(d,J=9.0Hz,2H ), 6.83 (d, J = 9.0Hz, 2H), 6.71 (m, 1H), 4.71 (s, 2H), 4.60 (s, 2H), 2.99 (s, 3H), 1.22 (s, 9H).

[0724]

[0725] 5-((2-(4-(tert-Butyl)phenoxy)-N-isopropylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (65)

[0726] 1 H NMR (600MHz, CDCl3) δ8.22(d,J=7.2Hz,1H),8.07(s,1H),8.02(s,1H),7.26(d,J=8.4Hz,2H),6.8 5(d,J=9.0Hz,2H),6.71(m,1H),4.77(s,2H),4.56(s,2H),4.32(m,1H),1.23(s,9H),1.18(m,6H).

[0727]

[0728] 5-((2-((4-(tert-butyl)phenyl)(methyl)amino)-N-methylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (66)

[0729] 1 H NMR (600MHz, CDCl3) δ8.32(d,J=7.2Hz,1H),8.08(m,2H),7.23(d,J=8.4Hz,2H),6.77(d,J=6.0Hz, 2H),6.62(m,1H),5.60(bs,2H),4.58(s,2H),4.16(s,2H),3.07(s,3H),2.96(s,3H),1.22(s,9H).

[0730]

[0731] 5-((N-isopropyl-2-((4-(trifluoromethoxy)phenyl)amino)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (67)

[0732] 1 H NMR (600MHz, DMSO-d6) δ8.63(d,J=7.2Hz,1H),8.47(s,1H),8.01(s,1H),7.70(bs,1H),7.07(d,J=8.4Hz,2H),6.91 (d,J=7.8Hz,2H),6.69(d,J=9.1Hz,1H),5.90(s,1H),4.56(s,2H),4.33(m,1H),4.12(s,2H),1.16(d,J=6.6Hz,6H).

[0733]

[0734] 5-((N-isopropyl-2-(4-(prop-1-en-2-yl)phenoxy)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (68) 1 H NMR(600MHz,DMSO-d6)δ8.73(d,J=7.2Hz,1H),8.48(s,1H),8.04(s,1H),7.72(bs,1H),6.99(m,2H),6.74(d,J=9.0Hz,1H), 5.01(s,2H),4.98(d,J=12.0Hz,1H),4.66(d,J=12.6Hz,1H),4.55(s,2H),4.25(m,1H),2.06(s,3H),1.19(d,J=6.6Hz,6H).

[0735]

[0736] 5-((2-(4-acetylphenoxy)-N-isopropylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (69)

[0737] 1 H NMR(600MHz,DMSO-d6)δ8.59(s,1H),8.44(s,1H),7.98(s,1H),7.88(d,J=7.8Hz,2H),7.70(bs,1H),6.98 (d,J=8.4Hz,2H),6.83(m,1H),5.11(s,2H),4.49(s,2H),4.17(m,1H),2.45(s,3H),1.13(d,J=6.0Hz,6H).

[0738]

[0739] 5-((2-(4-Acetylphenoxy)-N-methylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (70)

[0740] 1 H NMR (600MHz, DMSO-d6) δ8.70(d,J=7.2Hz,1H),8.52(s,1H),8.04(s,1H),7.93(d,J=9.0Hz,2H),7.77(bs,1 H), 7.08 (bs, 1H), 7.04 (d, J = 9.0Hz, 2H), 6.88 (m, 1H), 5.10 (s, 2H), 4.62 (s, 2H), 3.04 (s, 3H), 2.52 (s, 3H).

[0741]

[0742] 5-((N-methyl-2-((4-(trifluoromethoxy)phenyl)amino)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (71)

[0743] 1 H NMR (600MHz, DMSO-d6) δ8.68(d,J=7.2Hz,1H),8.51(s,1H),8.03(s,1H),7.75(bs,1H),7.07(d,J=8.4Hz ,2H),6.83(d,J=7.2Hz,1H),6.69(d,J=8.4Hz,2H),5.92(m,1H),4.64(s,2H),4.04(s,2H),3.05(s,3H).

[0744]

[0745] N-((1H-Indol-5-yl)methyl)-N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamide (74)

[0746] 1 H NMR (600MHz, CDCl3) δ8.45 (s, 1H), 7.50 (s, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.22 (s, 1H), 7.18-7.12 (m, 2H), 7.07-7.02(m,4H),6.78(d,J=8.6Hz,2H),6.51(s,1H),4.61(s,2H),4.57(s,2H),1.20(d,J=6.8Hz,6H).

[0747]

[0748] 1-((1H-Indol-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea(75)

[0749] 1 H NMR(600MHz, CDCl3)δ8.46(s,1H),7.64(s,1H),7.43(d,J=8.4Hz,1H),7.30-7.24(m,1H),7.17(dd,J=8.5,1.7Hz,1H), 7.10-7.03(m,2H),6.98(d,J=8.6Hz,2H),6.51(d,J=3.1Hz,2H),4.92-4.79(m,1H),4.53(s,2H),1.28(d,J=6.8Hz,6H).

[0750]

[0751] 2-((6-(tert-Butyl)pyridin-3-yl)amino)-N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide (76)

[0752] 1 H NMR (600MHz, CDCl3) δ8.39(d,J=7.2Hz,1H),8.06(d,J=2.9Hz,1H),7.92(d,J=2.3Hz,1H),7.34(s,1H),7.20(d,J=8.6Hz,1H),6.96(d,J =7.1Hz,1H),6.67(dd,J=7.2,1.9Hz,1H),6.43(d,J=2.2Hz,1H),4.60(s,2H),4.07(d,J=4.1Hz,2H),1.35(s,9H),1.26(d,J=6.7Hz,6H).

[0753]

[0754] N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-((4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)acetamide (77)

[0755] 1 H NMR (600MHz, CDCl3) δ8.39 (d, J = 7.3Hz, 1H), 7.91 (d, J = 2.3Hz, 1H), 7.35 (d, J = 3. 7Hz,2H),7.29(d,J=8.2Hz,2H),7.19(d,J=8.1Hz,1H),6.67(dd,J=7.3,1.9Hz,1H ),6.61(d,J=8.1Hz,2H),6.49-6.44(m,1H),6.43(d,J=2.4Hz,1H),4.59(s,2H), 4.06 (s, 2H), 1.25 (d, J = 6.3Hz, 6H), 1.19 (d, J = 6.8Hz, 2H), 0.93 (d, J = 6.7Hz, 2H).

[0756]

[0757] 5-((Methyl(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)amino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (78)

[0758] 1H NMR (600MHz, DMSO-d6) δ8.64(d,J=7.2Hz,1H),8.50(s,1H),8.10(s,1H),7.73(bs,1H),7.30(m,4H),6.83(m,1H),4.36(s,2H),2.68(s,3H).

[0759]

[0760] 1-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)urea(79)

[0761] 1 H NMR (600MHz, CDCl3) δ8.55(d,J=7.2Hz,1H),8.36(s,1H),7.67(s,1H),7.51(d,J=8.4Hz,2H),7.47(s,1H),7.2 0(d,J=8.4Hz,2H),7.11-7.10(m,1H),4.75(s,2H),2.67(m,1H),1.05(d,J=4.8Hz,2H),0.97(d,J=3.0Hz,2H).

[0762]

[0763] 1-Cyclopropyl-1-(pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(80)

[0764] 1 H NMR (600MHz, CDCl3) δ8.57(d,J=6.0Hz,2H),7.51(d,J=9.0Hz,2H),7.47(s,1H),7.25(d,J=6.0Hz, 2H), 7.19 (d, J = 8.4Hz, 2H), 4.65 (s, 2H), 2.67 (m, 1H), 1.02 (d, J = 4.8Hz, 2H), 0.93 (d, J = 3.0Hz, 2H).

[0765]

[0766] 1-Cyclopropyl-1-(pyrimidin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(81)

[0767] 1H NMR (600MHz, CDCl3) δ9.08(s,1H),8.60(d,J=4.8Hz,1H),7.47(s,1H),7.41(d,J=8.4Hz,2H),7.23(s ,1H),7.09(d,J=9.0Hz,2H),4.62(s,2H),2.82(m,1H),0.95(d,J=4.8Hz,2H),0.89(d,J=3.6Hz,2H).

[0768]

[0769] 1-Cyclopropyl-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea(82)

[0770] 1 H NMR (600MHz, CDCl3) δ8.06(s,1H),7.58(s,1H),7.53(d,J=1.2Hz,1H),7.46(d,J=6.6Hz,2H),7.43(s, 1H),7.13(d,J=6.6Hz,2H),6.82(m,1H),4.61(s,2H),2.60(m,1H),0.96(m,2H),0.90(t,J=2.4Hz,2H)

[0771]

[0772] 5-((N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (83)

[0773] 1 H NMR (600MHz, CDCl3) δ8.37,8.30(m,1H),8.14(s,1H),8.08(d,J=7.2Hz,1H),7.09(m,3H),6.86-6.70(m,5H) ,6.63(m,1H),5.99(m,2H),4.73(s,2H),4.67(t,J=7.2Hz,2H),3.88-3.79(m,2H),3.54-3.47(m,2H),2.78(m 1H),2.03-1.97(m,2H),1.17-1.13(m,6H).

[0774]

[0775] 5-((N-(4-(Trifluoromethoxy)phenyl)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (84)

[0776] 1 H NMR (600MHz, CDCl3) δ8.38(d,J=7.2Hz,1H),8.08(s,1H),7.94(s,1H),7.13(d,J=8.4Hz,2 H), 7.04 (d, J = 8.4Hz, 2H), 6.96 (t, J = 6.0Hz, 1H), 5.68 (bs, 2H), 4.90 (s, 2H), 1.88 (s, 3H).

[0777]

[0778] 5-(((N-isopropyl-4-(trifluoromethyl)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (85)

[0779] 1 H NMR (600MHz, CDCl3) δ8.41(m,1H),8.15(d,J=8.4Hz,1H),8.09(d,J=12.0Hz,1H),7.90(d,J=7.8Hz,2H ),7.71(m,2H),7.29(d,J=8.4Hz,1H),7.14(m,1H),4.40(d,J=12.6Hz,2H),4.16(m,1H),0.92(m,6H).

[0780]

[0781] 5-(((N-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4] Oxazine)-6-sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (86)

[0782] 1 H NMR (600MHz, CDCl3) δ8.37(m,2H),8.23(s,1H),7.77(s,1H),7.51(m,1H),6.97(m ,1H),6.90(m,1H),3.81(m,1H),3.78(m,1H),3.07(m,1H),1.01(d,J=6.6Hz,6H).

[0783]

[0784] 5-(((N-methyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (87)

[0785] 1H NMR (600MHz, CDCl3) δ8.43(d,J=7.2Hz,1H),8.10(s,2H),7.84(d,J=9.0Hz,2H ),7.35(d,J=7.8Hz,2H),7.08(m,1H),5.66(bs,2H),4.18(s,2H),2.61(s,3H).

[0786]

[0787] 5-(((N-isopropyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide (88)

[0788] 1 H NMR (600MHz, CDCl3) δ8.41(d,J=7.2Hz,1H),8.12(d,J=9.6Hz,2H),7.83(d,J=9.0Hz,2H),7.28 (d,J=8.4Hz,2H),7.18(m,1H),5.73(bs,2H),4.40(s,2H),4.14(m,1H),0.93(d,J=7.2Hz,6H).

[0789] Example 5: Validation of NTRK (NTRK1, NTRK2 and / or NTRK3) activity of selected compounds

[0790] As described elsewhere herein, selected compounds, including but not limited to CDD-2262 and its smaller analog CDD-2330, were synthesized off-DNA and evaluated for their activity against NTRK2. The selected compounds (i.e., CDD-2299, CDD-2219, CDD-2330, CDD-2262, CDD-2737, and CDD-3032, among others) showed low nanomolar potency (IC 50 3.7, 13, 3.5, 32, 2.3 and 6.1 nM, respectively; see Table 2) and were also able to penetrate the cell membrane in the NanoBRET assay to induce effects ( Figure 6A-6B ).

[0791] The inhibitory properties of the selected compounds of the present disclosure on NTRK1, NTRK2 and NTRK3 were analyzed (Table 2). In addition, the apparent inhibition constant (K) of the selected compounds on NTRK2 was also determined. i app )(Table 3). IC 50 Compounds ≥ 10,000 nM were considered inactive herein.

[0792] Table 2. Exemplary NTRK2 inhibition data for certain compounds

[0793]

[0794]

[0795] Table 3. Apparent inhibition constants (K) of NTRK2 for selected compounds i app )data

[0796] Compound <![CDATA[NTRK2 K i app (nM)]]> CDD-2262 17±10 CDD-2222 34±10 CDD-2219 21±7

[0797] Example 6: Validation of NTRK2 specificity of CDD-2330

[0798] To broadly evaluate the kinome-wide selectivity of CDD-2330, the KINOMEscan profiling platform ( Fig. 7A ). At 1 μM concentration, CDD-2330 showed high specificity for NTRKs, with MAP3K19 being the only possible off-target. Further dose response evaluation of CDD-2330 in the ThermoFisher Z'-LYTE assay ( Figure 7B ) demonstrated that CDD-2330 has single-digit nanomolar activity (IC 50 : 1.2-3.8 nM) binds to NTRK and shows >100-fold selectivity over MAP3K19 (IC 50 :401nM).

[0799] Similarly, the selectivity of CDD-3031 for NTRK kinases was evaluated in a kinase occupancy assay using 192 kinases (Promega K192 cell-based NanoBRET assay) (Table 4). In this assay, CDD-3031 was delivered at 1 μM and showed higher selectivity for NTRK2 and NTRK1, confirming the findings in Table 2.

[0800] Table 4. CDD-3031 kinase occupancy (%)

[0801] Kinase average value(%) Repeat 1(%) Repeat 2 (%) NTRK2 92.92 94.61 91.24 NTRK1 73.22 71.41 75.03 MUSK 19.82 17.46 22.19 TIE1 14.02 8.54 19.49 MAP3K19 13.32 53.26 -26.61 TEK 10.20 13.06 7.34 JAK2(V617F) 9.92 31.45 -11.62 CDKL1 8.23 2.80 13.66 MAP3K12 7.58 21.20 -6.05 AURKB 7.37 3.71 11.04 FLT3 7.12 -10.34 24.58 DYRK1A 6.50 8.58 4.42 STK11 5.85 6.96 4.74 ITK 5.61 14.16 -2.94 NEK5 5.02 -0.81 10.85 WEE1 4.94 9.23 0.65 CLK1 4.92 3.65 6.20 STK36 4.82 -3.75 13.40 MKNK2 4.61 7.96 1.26 CSNK1A1L 4.58 9.24 -0.08 ULK2 4.48 -5.12 14.09 SGK1 4.31 1.93 6.69 PKMYT1 4.17 5.47 2.88 AURKC 4.09 -7.48 15.66

[0802] Example 7: Pharmacokinetic Data of Compounds of the Disclosure

[0803] Previous data suggest that pharmacologically relevant exposures in the central nervous system result in on-target adverse event risks associated with both NTRK1 and NTRK2. Both FDA-approved small molecule pan-NTRK inhibitors, namely entrectinib and larotrectinib, have demonstrated crossover of the blood-brain barrier, which is considered a major concern for the treatment of endometriosis, a non-life-threatening disease. Therefore, in certain non-limiting embodiments, peripherally restricted NTRK-specific inhibitors with novel chemotypes are safer alternatives and have great potential in treating bot inflammation and pain associated with endometriosis.

[0804] In vitro using mouse and human liver microsomes, CDD-2262 was shown to be a metabolically stable compound (t 1 / 2 >7hr), while the analog CDD-2330 was found to be even more stable (t 1 / 2 >25hr) (Table 5). Further provided herein are certain pharmacokinetic properties (e.g., clearance) of the exemplary compound CDD-3031 (Tables 6-7 and Figures 8A-8B ).

[0805] Taken together, these data demonstrate that the compounds described herein are potent, metabolically stable, and NTRK-specific compounds.

[0806] Table 5. Half-life in mouse liver microsomes (MLM) and human liver microsomes (HLM)

[0807]

[0808] Table 6. Exemplary Clearance Data for CDD-3031

[0809] Mouse liver microsomes (MLM) Human Liver Microsomes (HLM) <![CDATA[CL int (μL / min / mg)]]> <![CDATA[CL int (μL / min / mg)]]> 1.8 0.0

[0810] Table 7. Exemplary pharmacokinetic data of CDD-3031 (n=3, mean ± SD)

[0811]

[0812]

[0813] Compared with antidepressants such as atomextine (brain: plasma ratio at 4 h: 20), the brain uptake of CDD-2330 is low (brain: plasma ratio at 4 h: 0.31) ( Fig.9A ), and the testicular uptake was also low (testis: plasma 0.31 at 4h) ( Fig. 9B ). Similarly, the brain uptake of CDD-3031 was relatively low compared to chlorpromazine (positive control), but high compared to hydroxyzine (negative control) ( Figures 10A-10C ).

[0814] Table 8. Exemplary brain uptake data for certain compounds

[0815] Compound Brain concentration at 24h (ng / mg) PF-06273340 0.08 CDD-3119 0.14 CDD-2737 0.04 CDD-3031 0.35 CDD-2738 2.3

[0816] Furthermore, analysis of potential liver and other tissue toxicity following high doses of certain exemplary compounds, including CDD-2330 and CDD-3031 (ie, 50 mg / kg), indicated minimal effects (Tables 9-10).

[0817] Table 9. Evaluation of potential liver and other tissue toxicity in mice treated with high doses of CDD-2330 a

[0818] Mouse number unit ALT AST 1 U / L 13.97 19.45 2 U / L 26.17 18.92 3 U / L 13.44 26.17 4 U / L 18.74 13.26 Comparison U / L 11.67 15.03

[0819] a Plasma ALT and AST levels were assessed 48 h after oral administration of 50 mg / kg CDD-2330 in mice (n=4)

[0820] Table 10. Evaluation of potential liver and other tissue toxicity in mice treated with high doses of CDD-3031 a

[0821]

[0822]

[0823] a Plasma ALT and AST levels were assessed 24 h after administration of 50 mg / kg CDD-3031 to mice by oral gavage

[0824] Furthermore, initial pharmacokinetic analysis of orally administered CDD-2330 indicated that it disappeared rapidly from the blood, which may be due, at least in part, to metabolism ( Fig.11A ). Thus, the present disclosure suggests that CDD-2330 and its analogs may be safer peripherally restricted pan-NTRK inhibitors for the treatment of endometriosis and various cancers.

[0825] In certain embodiments, compounds of the invention comprising a carboxyl group at the 3-position of the pyrazolo[1,5-a]pyridine skeleton possess potent NTRK1, NTRK2 and / or NTRK3 activity. In certain embodiments, substitution of the carboxyl functional group at the 3-position of the pyrazolo[1,5-a]pyridine skeleton with any of a variety of substituents, including but not limited to halogen, amidine, N-hydroxyamidine, N-hydroxyamide (e.g., Weinreb amide), improves the pharmacokinetic properties of the compound. Without wishing to be bound by theory, it is believed that substitution of the carboxyl group with any of a variety of substituents improves the pharmacokinetics of the compound by reducing glucuronidation.

[0826] Example 8: CDD-2330 administration results in downregulation of markers associated with inflammation in endometrial ectopic cells

[0827] Estrogen produced by ovarian and endometriotic lesions is a key molecule that induces macrophage secretion of BDNF / NT3 and neurofibrillary proinflammatory signaling ( Fig. 12A ). This signaling mechanism exacerbates the proinflammatory state of endometriotic lesions and promotes nerve fiber outgrowth and pain. At the cellular level, it has been determined that PGE2 and BDNF / NT-3 signaling stimulate PTGS2 expression through the phosphorylation and activation of CREB ( Fig. 12B ). In addition, inhibition of NTRK2 using siRNA attenuated pro-inflammatory gene expression.

[0828] Preliminary studies using CDD-2262, an analog of CDD-2330, showed that inhibition of NTRK2 at concentrations >100 nM statistically suppressed prostaglandin-endoperoxidase synthase 2 (PTGS2) mRNA expression over a 6-hour period. Fig. 12C ). Thus, the present disclosure provides evidence that administration of CDD-2330 results in the inhibition of markers associated with inflammation and is therefore suitable for the treatment of endometriosis.

[0829] Example 9: Exemplary data of certain NTRK2 inhibitors in a mouse model of endometrial ectopic tissue

[0830] In one aspect, the present disclosure provides exemplary data related to administration of NTRK2 inhibitors in a mouse model of endometrial ectopic tissue ( Fig.14 ). In some embodiments, the NTRK2 inhibitor and / or control is administered to the recipient mice on day 14 after intraperitoneal injection into the endometrium of the donor mice. In some embodiments, the recipient mice are sacrificed on day 28 and quantitatively evaluated.

[0831] The present disclosure provides exemplary data demonstrating that administration of CDD-2737 to a mouse model of endometrial ectopic tissue resulted in a decrease in the number of lesions and a reduction in the size of lesions compared to controls ( Figures 15A-15E In addition, administration of CDD-2737 showed no overall effects on the liver and / or kidneys ( Figures 16A-16B ) or potential liver or other tissue toxicity (Table 11).

[0832] Table 11. Potential liver and other tissue toxicity assessed in mice treated with CDD-2737 at 10 mg / kg / day for 14 days

[0833] Mouse# ALT(U / L) AST(U / L) Comparison C350 34.74 32.35 C351 21.48 37.75 C352 32.18 30.06 C353 20.16 31.03 C354 22.28 76.11 average value 26.2 41.5 n-Butyrate 100mM C371 11.14 31.03 C372 16.53 70.54 C373 36.33 39.25 C374 27.58 51.01 average value 22.9 48.0 CDD-2737 C355 13.79 28.11 C356 13.61 47.21 C357 10.25 27.58 C358 23.16 22.28 average value 15.2 31.3

[0834] The present disclosure further demonstrates the robust efficacy of NTRK inhibitors (e.g., CDD-3132) in inhibiting the growth of endometriotic lesions in mice ( Fig.17A In certain embodiments, a reduction in the size of endometriotic lesions was observed with administration of CDD-3132 (10 mg / kg) compared to vehicle control ( Figures 17B-17C In certain embodiments, a reduction in lesions, 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 ).

[0835] The present disclosure further demonstrates that, for example, administration of CDD-3132 (10 mg / kg) reduces proliferation, vascularization, macrophage infiltration, and / or inflammation within endometriotic lesions ( Figures 18A-18B ).

[0836] The present disclosure further demonstrates the efficacy of certain NTRK inhibitors (non-limiting examples include CDD-3031, CDD-3119, CDD-3132, and PF-06273340 (10 mg / kg)) in inhibiting the growth of endometriotic lesions in mice ( Fig.19 ).

[0837] The present disclosure further demonstrates that certain NTRK2 inhibitors (non-limiting examples include CDD-3031, CDD-3119, CDD-3132, and PF-0672 (10 mg / kg)) have little effect on liver and / or kidney weights and / or ALT and AST serum elevations in mice with endometriosis ( Figures 20A-20B and Table 12).

[0838] Table 12. Evaluation of potential liver and other tissue toxicity (ALT and AST levels) in mice administered exemplary NTRK inhibitors (ip dose of 10 mg / kg / day for 14 days) or control (vehicle)

[0839]

[0840]

[0841] Examples of implementation methods

[0842] The following exemplary embodiments are provided, the numbering of which should not be construed as designating a level of importance:

[0843] Embodiment 1 provides a compound selected from:

[0844] (a) Compound of formula (I):

[0845]

[0846] in:

[0847] T is selected from:

[0848]

[0849] R 1 is selected from 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;

[0850] R 2 is selected from 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 )(Rb ), 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 ;

[0851] R 3a , R 3b , R 3c , R 3d and R 3e Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0852] R 4 is selected from 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;

[0853] R 5 Selected from H and -X 1 -A 1 ;

[0854] R 6a , R 6b , R 6c and R 6d are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b );

[0855] L 1 Yes-C(R 6a )(R 6b )-;

[0856] L 2is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene;

[0857] X 1 Selected from bond, O and NR 7 ;

[0858] R 7 is selected from H and optionally substituted C1-C6 alkyl;

[0859] A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl;

[0860] R a , R b and R c each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl; and

[0861] Among them, if T is And -L 2 -R 5 If it is -H, then R 4 Not H;

[0862] or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof;

[0863] (b) Compounds of formula (II):

[0864]

[0865] in:

[0866] A 2 Selected from:

[0867]

[0868] R 8 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl;

[0869] R 9a , R 9b , R 9c and R 9d are each independently selected from 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, CN and NO2;

[0870] R 10 is selected from optionally substituted C1-C6 alkyl,

[0871] R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g and R 11h Each is independently selected from 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 NR a S(=O)2R b ;

[0872] R 12a , R 12b and R 12c are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl;

[0873] R 13a , R 13b , R 13c and R 13dEach is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0874] R 14 is selected from H and optionally substituted C1-C6 alkyl;

[0875] L 3 Selected from:

[0876]

[0877] X 2 Selected from O and NR 14 ;

[0878] Z 1 Selected from CR 13a and N, Z 2 Selected from CR 13b and N, Z 3 Selected from CR 13c and N, and Z 4 Selected from CR 13d and N,

[0879] Among them, selected from Z 1 , Z 2 , Z 3 and Z 4 At least one of is N; and

[0880] R a and R b each independently selected from 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;

[0881] or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof; and

[0882] (c) Compounds of formula (III):

[0883]

[0884] in:

[0885] R 15a , R 15b and R 15c Each is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, halogen, CN and NO2;

[0886] R16 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl and optionally substituted phenyl;

[0887] R 17a and R 17b are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, and optionally substituted phenyl;

[0888] R 18a and R 18b are each independently selected from H and optionally substituted C1-C6 alkyl;

[0889] A 3 is optionally substituted phenyl; and

[0890] A 4 is optionally substituted phenyl;

[0891] or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof.

[0892] Embodiment 2 provides a compound of embodiment 1, wherein each occurrence of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heterocyclyl, and optionally substituted alkylene, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy alkyl, 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 by at least one halogen, wherein each occurrence of R' and R" is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl and phenyl.

[0893] Embodiment 3 provides a compound of embodiment 1 or 2, which is a compound of formula (I) selected from the following:

[0894]

[0895] Embodiment 4 provides a compound according to any one of embodiments 1-3, wherein R 1 It's H.

[0896] Embodiment 5 provides a compound according to any one of embodiments 1-4, wherein R 2 Selected from H, F, Br, CN, C(═O)OH, C(═O)NH2, C(═O)NHMe, C(═O)NHOH and C(═NH)NH(OH).

[0897] Embodiment 6 provides a compound of any one of embodiments 1-5, wherein at least one of the following applies:

[0898] (a) Selected from R 3a , R 3b , R 3c , R 3d and R 3e At least one of them is H;

[0899] (b) selected from R 3a , R 3b , R 3c , R 3d and R 3e At least two of them are H;

[0900] (c) selected from R 3a , R 3b , R 3c , R 3d and R 3e At least three of them are H;

[0901] (d) selected from R 3a , R 3b , R 3c , R 3d and R 3e At least four of them are H; and

[0902] (e)R 3a , R 3b , R 3c , R 3d and R 3e Each of them is H.

[0903] Embodiment 7 provides a compound of any one of embodiments 1-6, wherein T is selected from:

[0904]

[0905] Embodiment 8 provides a compound according to any one of embodiments 1-7, wherein R 4Selected from H, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (CH2)3N(CH3)2, C(=O)CH3, phenyl, benzyl substituted by at least one C1-C6 alkyl; and -CH2CH2CH2O (phenyl substituted by at least one halogen).

[0906] Embodiment 9 provides a compound according to any one of embodiments 1-7, wherein R 4 Selected from

[0907] Embodiment 10 provides a compound according to any one of embodiments 1-9, wherein A 1 is selected from H; a phenyl group substituted by at least one substituent selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, a C3-C8 cycloalkyl group optionally substituted by a C1-C3 haloalkyl group, a phenoxy group, a halogen and NO2; a phenyl group fused with a C2-C6 heterocycloalkyl group; and a C2-C8 heteroaryl group optionally substituted by a C1-C6 alkyl group or fused with a C2-C5 heteroaryl group.

[0908] Embodiment 11 provides the compound of any one of embodiments 1-10, wherein A 1 Selected from:

[0909]

[0910]

[0911] Embodiment 12 provides a compound of any one of embodiments 1-11, wherein L 1 It is -CH2-.

[0912] Embodiment 13 provides a compound of any one of embodiments 1-12, wherein L 2 is selected from a bond, -C(=O)-, -C(=S)-, S(=O)2-, -CH2-,

[0913] Embodiment 14 provides a compound according to any one of embodiments 1-13, wherein X 1 Selected from bond, O and NR 7 .

[0914] Embodiment 15 provides compounds of embodiment 14, wherein R 7 Selected from H and Me.

[0915] Embodiment 16 provides a compound according to any one of embodiments 1-15, wherein R 5 Selected from:

[0916] H.

[0917] Embodiment 17 provides a compound of any one of embodiments 1-16 selected from:

[0918] 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0919] 1-Cycloheptyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0920] 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethoxy)phenyl)urea;

[0921] 1-isopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0922] 1-cyclohexyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0923] 1-cyclobutyl-3-(4-nitrophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0924] 1-phenyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0925] 1-Cyclopentyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0926] 1-Cyclopropyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0927] 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(2-(trifluoromethyl)phenyl)urea;

[0928] 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(3-(trifluoromethyl)phenyl)urea;

[0929] N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide;

[0930] 5-((Cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester;

[0931] 3-(3-chlorophenoxy)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)propan-1-amine;

[0932] N,N-Bis(pyrazolo[1,5-a]pyridin-5-ylmethyl)cyclobutanamine;

[0933] 1-(3-(3-chlorophenoxy)propyl)-3-(4-phenoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0934] 1-(3-(3-chlorophenoxy)propyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0935] 3-(4-chlorophenyl)-1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0936] 1-cyclobutyl-3-(4-fluorophenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0937] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide;

[0938] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0939] 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester;

[0940] 1-cyclobutyl-3-(4-methoxyphenyl)-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)urea;

[0941] (R)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide;

[0942] (S)-2-(4-ethoxyphenyl)-N-(1-phenylethyl)-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide;

[0943] 1-cyclobutyl-1-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0944] (S)-1-phenyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)ethan-1-amine;

[0945] 1-((3-fluoropyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0946] 1-((3-bromopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0947] 5-((1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0948] 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0949] 5-((1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0950] 5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0951] N-hydroxy-5-((1-isopropyl-3-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0952] 1-((3-cyanopyrazolo[1,5-a]pyridin-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0953] 5-((1-isobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0954] 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

[0955] N-Hydroxy-5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboximidamide;

[0956] 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0957] 5-((1-isopropyl-3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0958] 5-((2-(4-isopropylphenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0959] 5-((N-methyl-3-(4-(trifluoromethoxy)phenyl)propionylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0960] 5-((1-methyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0961] 5-((N-isopropyl-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0962] 5-((N-(3-(dimethylamino)propyl)-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0963] 5-((2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0964] 5-((3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0965] 5-((3-(4-(trifluoromethoxy)phenyl)thioureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0966] 5-((N-methyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0967] 5-((N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0968] 5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0969] (R)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0970] (S)-5-((1-(sec-butyl)-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0971] 5-((N-methyl-2-(4-(trifluoromethyl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0972] 5-((N-methyl-2-(3-(trifluoromethoxy)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0973] 5-((2-(4-(tert-butyl)phenoxy)-N-methylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0974] 5-((2-(4-(tert-butyl)phenoxy)-N-isopropylacetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0975] 5-((2-((4-(tert-butyl)phenyl)(methyl)amino)-N-methylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0976] 5-((N-isopropyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0977] 5-((N-isopropyl-2-(4-(prop-1-en-2-yl)phenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0978] 5-((2-(4-acetylphenoxy)-N-isopropylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0979] 5-((2-(4-acetylphenoxy)-N-methylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0980] 5-((N-methyl-2-((4-(trifluoromethoxy)phenyl)amino)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0981] 2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3-nitrophenyl)acrylamide;

[0982] (S)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3-nitrophenyl)acrylamide;

[0983] (R)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3-nitrophenyl)acrylamide;

[0984] N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide;

[0985] (R)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide;

[0986] (S)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide;

[0987] N-((1H-indol-5-yl)methyl)-N-isopropyl-2-(4-(trifluoromethoxy)phenoxy)acetamide;

[0988] 1-((1H-indol-5-yl)methyl)-1-isopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0989] 2-((6-(tert-butyl)pyridin-3-yl)amino)-N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)acetamide;

[0990] N-isopropyl-N-(pyrazolo[1,5-a]pyridin-5-ylmethyl)-2-((4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)acetamide;

[0991] 5-((methyl(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)amino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0992] 1-([1,2,4]triazolo[1,5-a]pyridin-7-ylmethyl)-1-cyclopropyl-3-(4-(trifluoromethoxy)phenyl)urea;

[0993] 1-Cyclopropyl-1-(pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0994] 1-Cyclopropyl-1-(pyrimidin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0995] 1-Cyclopropyl-1-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;

[0996] 5-((N-(3-(3-chlorophenoxy)propyl)-2-(4-isopropylphenoxy)acetamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0997] 5-((N-(4-(trifluoromethoxy)phenyl)acetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0998] 5-(((N-isopropyl-4-(trifluoromethyl)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[0999] 5-(((N-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4] Oxazine)-6-sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[1000] 5-(((N-methyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[1001] 5-(((N-isopropyl-4-(trifluoromethoxy)phenyl)sulfonamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[1002] 5-((N-isopropyl-3-(4-methoxyphenyl)acrylamide)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[1003] (E)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamide)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[1004] (Z)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamide)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[1005] 5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[1006] (E)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamide)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

[1007] (Z)-5-((N-isopropyl-3-(4-(trifluoromethyl)phenyl)acrylamido)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide.

[1008] Embodiment 18 provides a compound of embodiment 1 or 2 which is a compound of formula (II).

[1009] Embodiment 19 provides compounds of embodiment 18, wherein R 8 Selected from isopropyl and phenyl.

[1010] Embodiment 20 provides compounds of embodiment 18 or 19, wherein R 9a , R 9b , R 9c and R 9d Each is independently selected from hydrogen, tert-butyl and trifluoromethyl.

[1011] Embodiment 21 provides a compound of any one of embodiments 18-20, wherein A 2 Selected from

[1012] Embodiment 22 provides a compound of any one of embodiments 17-20, wherein one of the following is applicable:

[1013] (a) Z 1 is N and Z 2 , Z 3 and Z 4 At least one of them is CH;

[1014] (b) Z 1 is N and Z 2 , Z 3 and Z 4 At least two of them are CH;

[1015] (c)Z 1 is N and Z 2 , Z 3 and Z 4 Each of them is CH;

[1016] (d) Z 2 is N and Z 1 , Z 3 and Z 4 At least one of them is CH;

[1017] (e)Z 2 is N and Z 1 , Z 3 and Z 4 At least two of are CH; or

[1018] (f)Z 2 is N and Z 1 , Z 3 and Z 4 Each of them is CH.

[1019] Embodiment 23 provides a compound of any one of embodiments 18-22, wherein X 2 is selected from -O- and -NH-.

[1020] Embodiment 24 provides a compound of any one of embodiments 18-23, wherein R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g and R 11h are each independently selected from H and methoxy.

[1021] Embodiment 25 provides a compound of any one of embodiments 18-24, wherein R 12a , R 12b and R 12c Each is independently selected from H, methyl and C(═O)O(C(CH 3 ) 3 ).

[1022] Embodiment 26 provides a compound of any one of embodiments 18-25, wherein R 10 Selected from tert-butyl,

[1023]

[1024] Embodiment 27 provides a compound of any one of embodiments 1-2 and 18-26 selected from:

[1025] N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4- oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)-N 4 -methylterephthalamide;

[1026] N 1 -(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)-N 4 -methylterephthalamide;

[1027] 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4- tert-Butyl oxadiazol-3-yl)picolinate;

[1028] 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- tert-Butyl oxadiazol-3-yl)picolinate;

[1029] (Z)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamoylimido)pyridinylamino)-3-methoxyphenyl)-N 4 -methylterephthalamide; and

[1030] (4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- tert-butyl oxadiazol-3-yl)pyridinylamino)-3-methoxyphenyl)carbamate.

[1031] Embodiment 28 provides a compound of embodiment 1 or 2, wherein the compound is a compound of formula (III).

[1032] Embodiment 29 provides a compound of embodiment 28, wherein the compound of formula (III) is selected from:

[1033]

[1034] Embodiment 30 provides compounds of embodiment 28 or 29, wherein at least one of the following applies:

[1035] (a)R 15a , R 15b and R 15c At least one of them is H;

[1036] (b)R 15a , R 15b and R 15c At least two of are H; and

[1037] (c)R 15a , R 15b and each of R15c is H.

[1038] Embodiment 31 provides a compound of any one of embodiments 28-30, wherein R 16 Selected from benzyl and

[1039] Embodiment 32 provides a compound of any one of embodiments 28-31, wherein R 17a and R 17b Each independently is H.

[1040] Embodiment 33 provides a compound of any one of embodiments 28-32, wherein R 18a and R 18b are each independently selected from H and Me.

[1041] Embodiment 34 provides a compound of any one of embodiments 28-33, wherein A 3 Selected from

[1042] Embodiment 35 provides a compound of any one of embodiments 28-34, wherein A 4 yes

[1043] Embodiment 36 provides a compound of any one of embodiments 1-2 and 28-35 selected from:

[1044] 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;

[1045] (S)-1-benzyl-2-(2-chloro-4-hydroxyphenyl)-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-1H-benzo[d]imidazole-7-carboxamide; and

[1046] (S)-1-Benzyl-N-(1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)-2-(2,3,6-trichlorophenyl)-1H-benzo[d]imidazole-7-carboxamide.

[1047] Embodiment 37 provides a pharmaceutical composition comprising a compound of any one of embodiments 1-36 and a pharmaceutically acceptable carrier.

[1048] Embodiment 38 provides a method for treating, preventing and / or ameliorating endometrial tissue ectopic in a subject in need thereof, the method comprising administering to the subject at least one neurotrophic receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

[1049] Embodiment 39 provides the method of embodiment 38, wherein at least one selected from chronic pelvic pain, inflammation, and infertility is treated, prevented, and / or ameliorated in the subject.

[1050] Embodiment 40 provides the method of embodiment 38 or 39, wherein the subject is female.

[1051] Embodiment 41 provides a method for treating, preventing and / or ameliorating cancer in a subject in need thereof, the method comprising administering to the subject at least one neurotrophic receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

[1052] Embodiment 42 provides a method for treating, preventing and / or ameliorating pain in a subject in need thereof, the method comprising administering to the subject at least one neurotrophic receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

[1053] Embodiment 43 provides the method of any one of embodiments 38-42, wherein at least one selected from neurotrophic receptor tyrosine kinase 1 (NTRK1), neurotrophic receptor tyrosine kinase 2 (NTRK2), and neurotrophic receptor tyrosine kinase 3 (NTRK3) is overexpressed in the subject.

[1054] Embodiment 44 provides the method of any one of embodiments 38-44, wherein at least one selected from NTRK1, NTRK2, and NTRK3 is inhibited in the subject.

[1055] Embodiment 45 provides the method of any one of embodiments 38-44, wherein a fusion gene comprising at least one selected from NTRK1, NTRK2, and NTRK3 is overexpressed in the subject.

[1056] Embodiment 46 provides the method of embodiment 45, wherein the fusion gene product is inhibited in the subject.

[1057] Embodiment 47 provides the method of any one of embodiments 38-46, wherein the NTRK inhibitor comprises a compound of any one of embodiments 1-35 or a pharmaceutical composition thereof comprises a pharmaceutical composition of embodiment 36.

[1058] Embodiment 48 provides the method of any one of embodiments 38-47, wherein the NTRK inhibitor is an NTRK2 inhibitor.

[1059] Embodiment 49 provides the method of embodiment 48, wherein the NTRK2 inhibitor selectively inhibits NTRK2 relative to NTRK1 and / or NTRK3.

[1060] Embodiment 50 provides the method of any one of embodiments 38-49, wherein the at least one NTRK2 inhibitor is selected from staurosporine, larotrectinib, entrectinib, ceritinib, ripretinib, and PF-06273340.

[1061] Embodiment 51 provides the method of any one of embodiments 38-50, wherein the subject is a mammal.

[1062] Embodiment 52 provides the method of embodiment 51, wherein the mammal is a human.

[1063] The terms and expressions used herein are used as descriptive terms rather than limiting terms, and when using these terms and expressions, it is not intended to exclude any equivalents of the features shown and described or parts thereof, but it should be recognized that various modifications are possible within the scope of the embodiments of the present application. Therefore, it should be understood that although the present application describes specific embodiments and optional features, those of ordinary skill in the art may modify and change the compositions, methods and concepts disclosed herein, and such modifications and changes are considered to be within the scope of the embodiments of the present application.

Claims

1. A compound selected from: (a) Compound of formula (I): in: T is selected from: R 1 is selected from 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 selected from 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 ; R 3a , R 3b , R 3c , R 3d and R 3e Each is independently selected from 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 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 Selected from H and -X 1 -A 1 ; R 6a , R 6b , R 6c and R 6d are each independently selected from H, optionally substituted C1-C6 alkyl and C(=O)N(R a )(R b ); L 1 Yes-C(R 6a )(R 6b )-; L 2 is selected from a bond, -C(=O)-, -C(=O)(optionally substituted C1-C3 alkylene), -C(=O)(optionally substituted C2-C3 alkenylene), -C(=S)-, -C(=S)(optionally substituted C1-C3 alkylene), -C(=S)(optionally substituted C2-C3 alkenylene), -S(=O)2-, -S(=O)2(optionally substituted C1-C3 alkylene), -S(=O)2(optionally substituted C2-C3 alkenylene), optionally substituted C1-C3 alkylene, and optionally substituted C2-C3 alkenylene; X 1 Selected from bond, O and NR 7 ; R 7 is selected from H and optionally substituted C1-C6 alkyl; A 1 is selected from optionally substituted phenyl, optionally substituted naphthyl and optionally substituted C2-C8 heterocyclyl; R a , R b and R c each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl; and Among them, if T is And -L 2 -R 5 If it is -H, then R 4 Not H; or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof; (b) Compounds of formula (II): in: A 2 Selected from: R 8 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl; R 9a , R 9b , R 9c and R 9d are each independently selected from 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, CN and NO2; R 10 is selected from optionally substituted C1-C6 alkyl, R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g and R 11h Each is independently selected from 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 NR a S(=O)2R b ; R 12a , R 12b and R 12c are each independently selected from 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 13d Each is independently selected from 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 H and optionally substituted C1-C6 alkyl; L 3 Selected from: X 2 Selected from O and NR 14 ; Z 1 Selected from CR 13a and N, Z 2 Selected from CR 13b and N, Z 3 Selected from CR 13c and N, and Z 4 Selected from CR 13d and N, Among them, selected from Z 1 , Z 2 , Z 3 and Z 4 At least one of is N; and R a and R b each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl and optionally substituted C2-C8 heterocyclyl; or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof; and (c) Compounds of formula (III): in: R 15a , R 15b and R 15c Each is independently selected from 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 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 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 H and optionally substituted C1-C6 alkyl; A 3 is optionally substituted phenyl; and A 4 is optionally substituted phenyl; or a salt, solvate, isotopomer, prodrug, stereoisomer or tautomer thereof, or any mixture thereof.

2. The compound of claim 1, wherein each occurrence of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heterocyclyl, and optionally substituted alkylene, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy alkyl, 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 by at least one halogen, wherein each occurrence of R' and R" is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl and phenyl.

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

4. A compound according to any one of claims 1 to 3, wherein R 1 It's H.

5. The compound according to any one of claims 1 to 4, wherein R 2 Selected from H, F, Br, CN, C(═O)OH, C(═O)NH2, C(═O)NHMe, C(═O)NHOH and C(═NH)NH(OH).

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

7. The compound according to any one of claims 1 to 6, wherein T is selected from:

8. A compound according to any one of claims 1 to 7, wherein R 4 Selected from H, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (CH2)3N(CH3)2, C(=O)CH3, phenyl, benzyl substituted by at least one C1-C6 alkyl; and -CH2CH2CH2O (phenyl substituted by at least one halogen).

9. The compound according to any one of claims 1 to 7, wherein R 4 Selected from 10. The compound according to any one of claims 1 to 9, wherein A 1 is selected from H; a phenyl group substituted by at least one substituent selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, a C3-C8 cycloalkyl group optionally substituted by a C1-C3 haloalkyl group, a phenoxy group, a halogen and NO2; a phenyl group fused with a C2-C6 heterocycloalkyl group; and a C2-C8 heteroaryl group optionally substituted by a C1-C6 alkyl group or fused with a C2-C5 heteroaryl group.

11. A compound according to any one of claims 1 to 10, wherein A 1 Selected from:

12. A compound according to any one of claims 1 to 11, wherein L 1 It is -CH2-.

13. A compound according to any one of claims 1 to 12, wherein L 2 is selected from a bond, -C(=O)-, -C(=S)-, S(=O)2-, -CH2-, 14. A compound according to any one of claims 1 to 13, wherein X 1 Selected from bond, O and NR 7 .

15. The compound according to claim 14, wherein R 7 Selected from H and Me.

16. A compound according to any one of claims 1 to 15, wherein R 5 Selected from: H、 17. A compound according to any one of claims 1 to 16, selected from: 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; 5-((Cyclobutylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester; 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; 5-((1-cyclobutyl-3-(4-(trifluoromethoxy)phenyl)ureido)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester; 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)propionylamino)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-methylacetylamino)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-isopropylacetylamino)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; 5-((2-(4-acetylphenoxy)-N-methylacetylamino)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)acrylamide; (S)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3-nitrophenyl)acrylamide; (R)-2-(3-(2-chloro-6-(trifluoromethyl)phenyl)ureido)-N,N-dimethyl-3-(3-nitrophenyl)acrylamide; N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide; (R)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide; (S)-N-methyl-3-(4-nitrophenyl)-2-(3-(4-phenoxyphenyl)ureido)acrylamide; 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)acetylamino)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)acrylamide)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; (E)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamide)methyl)pyrazolo[1,5-a]pyridine-3-carboxamide; (Z)-5-((N-isopropyl-3-(4-methoxyphenyl)acrylamide)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.

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

19. The compound according to claim 18, wherein R 8 Selected from isopropyl and phenyl.

20. The compound according to claim 18 or 19, wherein R 9a , R 9b , R 9c and R 9d Each is independently selected from hydrogen, tert-butyl and trifluoromethyl.

21. A compound according to any one of claims 18 to 20, wherein A 2 Selected from 22. A compound according to any one of claims 17-20, wherein one of the following is applicable: (a) Z 1 is N and Z 2 , Z 3 and Z 4 At least one of them is CH; (b) Z 1 is N and Z 2 , Z 3 and Z 4 At least two of them are CH; (c)Z 1 is N and Z 2 , Z 3 and Z 4 Each of them is CH; (d) Z 2 is N and Z 1 , Z 3 and Z 4 At least one of them is CH; (e)Z 2 is N and Z 1 , Z 3 and Z 4 At least two of are CH; or (f)Z 2 is N and Z 1 , Z 3 and Z 4 Each of them is CH.

23. A compound according to any one of claims 18 to 22, wherein X 2 is selected from -O- and -NH-.

24. A compound according to any one of claims 18 to 23, wherein R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g and R 11h are each independently selected from H and methoxy.

25. A compound according to any one of claims 18 to 24, wherein R 12a , R 12b and R 12c Each is independently selected from H, methyl and C(═O)O(C(CH 3 ) 3 ).

26. A compound according to any one of claims 18 to 25, wherein R 10 Selected from tert-butyl, 27. A compound according to any one of claims 1-2 and 18-26, selected from: N 1 -(4-(5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4- oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)-N 4 -methylterephthalamide; N 1 -(4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- oxadiazole-3-yl)pyridinylamino)-3-methoxyphenyl)-N 4 -methylterephthalamide; 5-(5-(5-(tert-butyl)-1-phenyl-1H-pyrazol-3-yl)-1,2,4- tert-Butyl oxadiazol-3-yl)picolinate; 5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- tert-butyl oxadiazol-3-yl)picolinate; (Z)-N 1 -(4-(5-(N'-((5-(tert-butyl)-1-phenyl-1H-pyrazole-3-carbonyl)oxy)carbamoylimido)pyridinylamino)-3-methoxyphenyl)-N 4 - methylterephthalamide; and (4-(5-(5-(1-isopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4- tert-butyl oxadiazol-3-yl)pyridinylamino)-3-methoxyphenyl)carbamate.

28. The compound according to claim 1 or 2, wherein the compound is a compound of formula (III).

29. The compound according to claim 28, wherein the compound of formula (III) is selected from:

30. The compound according to claim 28 or 29, wherein at least one of the following applies: (a)R 15a , R 15b and R 15c At least one of them is H; (b)R 15a , R 15b and R 15c At least two of are H; and (c)R 15a , R 15b and each of R15c is H.

31. A compound according to any one of claims 28-30, wherein R 16 Selected from benzyl and 32. A compound according to any one of claims 28 to 31, wherein R 17a and R 17b Each independently is H.

33. A compound according to any one of claims 28-32, wherein R 18a and R 18b are each independently selected from H and Me.

34. according to the compound described in any one of claims 28-33, wherein A 3 Selected from 35. according to the compound described in any one of claims 28-34, wherein A 4 yes 36. A compound according to any one of claims 1-2 and 28-35, selected from: 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.

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

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

39. The method according to claim 38, wherein at least one selected from chronic pelvic pain, inflammation and infertility is treated, prevented and / or improved in the subject.

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, the method comprising administering to the subject at least one neurotrophic receptor tyrosine kinase (NTRK) inhibitor or a pharmaceutical composition comprising the NTRK inhibitor and a pharmaceutically acceptable carrier.

42. A method for treating, preventing and / or ameliorating pain in a subject in need thereof, the method comprising administering to the subject at least one neurotrophic 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 38-42, wherein at least one selected from neurotrophic receptor tyrosine kinase 1 (NTRK1), neurotrophic receptor tyrosine kinase 2 (NTRK2), and neurotrophic receptor tyrosine kinase 3 (NTRK3) is overexpressed in the subject.

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

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

46. ​​The method of claim 45, wherein the fusion gene product is suppressed 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 a pharmaceutical composition thereof, including the pharmaceutical composition of claim 36.

48. The method of any one of claims 38-47, 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. The method of any one of claims 38-49, wherein the at least one NTRK2 inhibitor is selected from staurosporine, larotrectinib, entrectinib, ceritinib, ripretinib, and PF-06273340.

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

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

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